Systemic
ADT Class and Cardiovascular Risk (Hahn, ASCO GU 2026)
ForProstate cancer pts starting GnRH agonist or antagonist ADT
TL;DRMACE ~four per 100 person-yrs overall; ~37% numerically lower with GnRH antagonist vs agonist; 11 per 100 person-yrs with preexisting CVD.
Reported via UroToday →
In men with preexisting cardiovascular disease starting ADT, this supports flagging them for cardiology or primary care input given ~11 MACE per 100 person-yrs; it does not establish antagonist superiority over agonist, which rests on an unadjusted, degarelix-dominated comparison. The longer read
10 details 1 trial watching
Retrospective real-world analysis of commercial and Medicare claims databases, indexed at the date ADT was prescribed. Data cutoff May 2024. Presented at ASCO GU 2026 and discussed in a UroToday interview, not a full paper.
~17,000 pts with prostate cancer receiving ADT. ~90% GnRH agonist, ~10% GnRH antagonist (degarelix ~two-thirds, relugolix ~a third). Agonist pts were older, more likely on Medicare, and had longer median f/u.
Primary: two- and three-point MACE. Secondary: MACE before vs after 2021, the year HERO and PRONOUNCE reported.
Overall MACE ~four per 100 person-yrs. Antagonist pts had ~37% numerically lower MACE than agonist pts. Preexisting CVD carried ~11 per 100 person-yrs, about threefold. Post-2021 showed a modest reduction vs pre-2021.
Direction matches HERO, which the presenter cited for lower MACE with relugolix vs agonist. PRONOUNCE was cited for the value of cardiologist involvement, which frames the preexisting-CVD finding as a referral question, not only a drug-choice question.
Baseline age, payer and f/u imbalances bias the crude class comparison. MACE misses earlier cardiometabolic harm (diabetes, metabolic syndrome, renal dysfunction), as the interviewer pointed out. The pre/post-2021 shift is a secular trend with no causal link to the trials.
The more robust signal is the preexisting-CVD rate, which identifies who needs cardiovascular co-management whatever the ADT class. A PCF consensus statement on risk-tiered cardiology referral is described as forthcoming.
Retrospective claims comparison, 'numerically lower' with no CI or adjustment reported; agonist group older, more Medicare, longer f/u. Antagonist group mostly degarelix.
- Does the antagonist MACE difference persist after adjustment for age and payer?
- Relugolix vs degarelix cardiovascular risk
- Does risk-tiered cardiology referral lower MACE on ADT? recruiting High Cardiovascular Risk Intervention With Cardio-Oncology Consultation for Prostate Cancer Following Androgen Receptor Pathway Inhibitor (ARPI) Therapy (Heart-Safe) Phase 2n=80 · primary completion 2030-08 · cardio-oncology referral vs PCP notice, high CV risk
📚 Sources · 📄 1 paper
Abstract
AZUR-1 NCT05723562
FordMMR/MSI-H locally advanced rectal cancer, treatment-naive
TL;DRcCR12 68% (investigator) and cCR12+pCR 76% with dostarlimab alone in dMMR/MSI-H LARC, no recurrences to date at 26.3mo median f/u.
The RT-omission read hinges on the assessor: investigator cCR12 is 68%, central review 47% (54/116) with 38 pts still pending. Either figure exceeds the 21-41% post-TNT cCR range the source cites, which supports MMR testing before any pelvic RT is planned in LARC.
In dMMR/MSI-H LARC, this supports checkpoint-first, organ-preservation discussion before committing to chemoRT or TNT; it does not extend to pMMR/MSS rectal cancer. The longer read
Central review cCR12 is 47% (54/116) against investigator 68%, with 38 pts pending; both exceed the 21-41% post-TNT cCR range cited. In dMMR/MSI-H LARC, pelvic RT is shifting toward a salvage role, so MMR status should be known before simulation.
Nine cycles of dostarlimab 500 mg q3w delivered 68% cCR12 (INV) with 88% completing therapy and G≥3 immune-mediated AEs in 4 pts. This positions PD-1 monotherapy as the first move in dMMR/MSI-H LARC, ahead of oxaliplatin-based TNT.
Only 15 pts underwent resection after dostarlimab alone and 12 (80%) were pCR, so most surgical specimens showed no residual tumour. The surgical question becomes timing of salvage and surveillance intervals, not upfront TME, in dMMR/MSI-H LARC.
10 details 2 trials watching
Global single-arm phase II, registrational. Interim analysis, N=154 enrolled, median f/u 26.3 mo (range 2-36).
dMMR/MSI-H locally advanced rectal cancer. 144 pts had ≥12 mo f/u for investigator-assessed cCR12.
Dostarlimab 500 mg IV q3w for 9 cycles as monotherapy; chemotherapy, radiation and surgery reserved for non-responders.
Key endpoints: sustained cCR for 12 months (cCR12) after end of treatment by investigator and independent central review, and composite cCR12 (INV) + pCR.
cCR12 68% (INV) vs 47% (54/116) (ICR); composite cCR12+pCR 76%. Of 15 resected pts, 12 (80%) had pCR; no recurrences to date after cCR or pCR.
| Assessor | Evaluable | cCR12 |
|---|---|---|
| Investigator | 144 | 68% |
| Independent central review | 116 | 54/116 (47%) |
88% completed all 9 cycles. G≥3 immune-mediated AEs in 4 pts.
Post-TNT cCR is cited at 21-41% in LARC broadly; AZUR-1 exceeds that in a biomarker-selected group. It scales up the earlier small dostarlimab study that first showed durable cCR in dMMR LARC.
Investigator and central review diverge on cCR12, and ICR evaluability lagged because cCR was confirmed later. cCR12 is a surrogate for durable organ preservation; local regrowth risk beyond 3 years is unmeasured.
Durable cCR with no recurrences so far makes RT omission a realistic default question in dMMR LARC. Open: how long surveillance must run, and what salvage looks like for late regrowth.
Single-arm interim analysis without a randomised comparator; investigator vs central review cCR12 diverge, and durability beyond 26.3mo median f/u is unproven.
- Will ICR cCR12 converge with investigator rate as pending pts mature?
- Late local regrowth risk beyond 3 years without RT or surgery not yet Non-Operative Management and Following Immunotherapy for Colorectal Cancer and Other GI Cancersn=50 · primary completion 2029-06 · dMMR/MSI-H W&W registry after neoadjuvant IO
- Role of RT for dMMR pts without cCR after dostarlimab recruiting Study of Induction PD-1 Blockade in Subjects With Locally Advanced Mismatch Repair Deficient Solid Tumors Phase 2n=212 · primary completion 2026-11 · dostarlimab then capecitabine-IMRT in dMMR LARC
📚 Sources · 📄 2 papers
Abstract
Abstract
DASL-HiCaP NCT04136353
ForVery high-risk localised PCa, or PSA persistent/recurrent within 1 yr of RP
HR 0.42
95% CI 0.27-0.66, p=0.0001; 4-yr 95% vs 88%
TL;DR4-yr MFS-CI 95% vs 88%, HR 0.42 (0.27-0.66), adding darolutamide to 96-wk ADT plus prostate/bed and pelvic nodal RT in very high-risk disease.
Every pt received pelvic nodal RT with 96 wk of LHRH analog, so darolutamide's MFS-CI HR 0.42 is measured on top of elective nodal coverage, not instead of it. 29% were node-positive on CT and the benefit held across primary vs salvage RT and N+ vs N0 (subgroup HRs not in source). The decision it moves is ARSI intensification alongside whole-pelvis RT, not RT field or dose.
In very high-risk localised prostate cancer planned for 96 wk of ADT with prostate and pelvic nodal RT, this supports darolutamide intensification for MFS-CI; it does not yet establish an OS gain and gives thin data for post-RP salvage pts (15% of the cohort). The longer read
The RT backbone was fixed: prostate or prostate bed plus pelvic nodes in both arms, so the HR 0.42 adds to elective nodal RT rather than replacing it. Benefit was reported consistent for salvage RT and for CT node-positive pts (29%), but only 15% had prior RP and subgroup HRs are not in source.
Darolutamide 600 mg BID for 96 wk on top of 96 wk ADT cut MFS-CI events 27 vs 63 with G≥3 AEs 43% vs 36%, and fractures and cardiac G≥2 events no higher than placebo. OS (HR 0.88) and PCSS remain immature, so the ARSI choice in this setting hinges on surrogacy holding.
10 details 1 trial watching
International, placebo-controlled, randomised 1:1 phase III, N=1,106 accrued 30APR20 to 09AUG23. Single prespecified interim after 87 MFS-CI events, disclosed only if 2-sided p<0.012. Median follow-up 3.8 yr (IQR 3.3-4.5).
Very high-risk localised prostate cancer, or biochemically persistent/recurrent disease within 1 yr after RP. Median age 71, Gleason 9-10 in 73%, pelvic nodal involvement on CT in 29%, prior RP in 15%.
Darolutamide 600 mg BID vs placebo for 96 wk, both arms on an LHRH analog for 96 wk.
Definitive or salvage RT to prostate or prostate bed plus pelvic nodes in both arms. Dose and fractionation not reported in source.
Primary: MFS on conventional imaging (CT and/or Tc bone scan), chosen per ICECaP surrogacy for OS. Secondary: PSA-PFS, PCSS, OS.
Primary met at interim (table above). OncLive reports MFS benefit consistent across primary vs salvage RT and N+ vs N0, and castration resistance and subsequent hormonal therapy endpoints favouring darolutamide; no numbers given for those.
| Endpoint | Darolutamide N=553 | Placebo N=553 | HR (95% CI) |
|---|---|---|---|
| MFS-CI | 27 (95%) | 63 (88%) | 0.42 (0.27-0.66), p=0.0001 |
| PSA-PFS | 46 (91%) | 95 (83%) | 0.47 (0.33-0.67) |
| PCSS | 4 (99%) | 7 (99%) | 0.58 (0.17-1.97) |
| OS | 21 (97%) | 24 (95%) | 0.88 (0.49-1.59) |
| AE | Darolutamide | Placebo |
|---|---|---|
| Fatigue/asthenia G≥2 | 14% | 10% |
| Hypertension G≥2 | 7% | 9% |
| Fractures G≥2 | 2% | 3% |
| Cardiac G≥2 | 3% | 3% |
| Any AE G≥3 | 43% | 36% |
Any G≥3 AE 43% vs 36%. G≥2 fatigue/asthenia 14% vs 10%; hypertension, fractures and cardiac events not higher with darolutamide.
Tests the same ARSI-added-to-ADT-plus-RT question as ENZARAD (enzalutamide) and ATLAS (apalutamide), and sits against the STAMPEDE abiraterone data that currently anchor intensification in high-risk nonmetastatic disease. DASL-HiCaP differs by mandating pelvic nodal RT and including early post-RP salvage pts.
Staging and progression on conventional imaging in a PSMA-era practice; salvage pts are only 15%. Backbone was 96 wk ADT plus pelvic RT in everyone, so benefit with shorter ADT or prostate-only fields is untested.
The MFS-CI gain is large but OS events are few (21 vs 24) and PCSS is 99% in both arms at 4 yr. Whether this becomes a darolutamide option alongside abiraterone in this setting depends on surrogacy holding at final analysis.
CONSORT flow
Prespecified interim analysis, not the final primary analysis; MFS-CI surrogate with PCSS and OS immature (OS HR 0.88, CI crosses 1). Randomised, placebo-controlled design is otherwise clean.
- Does MFS-CI benefit translate to OS at final analysis?
- Benefit in PSMA PET-staged very high-risk disease recruiting Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers Phase 2/3n=493 · primary completion 2030-07 · ph3 RT ± darolutamide, tracer-staged high-risk
- Darolutamide vs abiraterone intensification with pelvic RT
📚 Sources · 📄 3 papers
Abstract
Abstract
Abstract
DeLLphi-305 NCT06211036
ForES-SCLC, no progression after 1L platinum-etoposide + durvalumab, ECOG 0-1
HR 0.42
95% CI 0.32-0.54, P<0.001; mOS 21.1 vs 12.7 mo
TL;DRmOS 21.1 vs 12.7 mo, HR 0.42 (0.32-0.54), adding tarlatamab to durvalumab 1L maintenance in ES-SCLC after chemo-IO induction.
Asymptomatic untreated brain mets were eligible and brain/liver mets were a stratification factor, so a cranial-disease subgroup read should exist; it is not in the source. The source also does not state whether consolidative thoracic RT or PCI was permitted, which gates how this maintenance backbone integrates with RT consolidation in ES-SCLC.
In ES-SCLC with no progression after 4 cycles of platinum-etoposide + durvalumab and ECOG 0-1, including asymptomatic brain mets, this supports adding tarlatamab to durvalumab maintenance; it does not inform pts who progressed on induction or ECOG ≥2. The longer read
Adds a BiTE to durvalumab maintenance with an OS HR of 0.42 and mOS 21.1 vs 12.7 mo, moving tarlatamab from later-line into 1L maintenance for induction nonprogressors. The post-dose monitoring requirement (1-2h, 6-8h in some regions) is an operational cost to plan for; AE rates are not in the source.
| Metric | Tarlatamab + Durvalumab (n = 282) | Durvalumab (n = 281) |
|---|---|---|
| Median OS, mo (95% CI) | 21.1 (20.8-NE) | 12.7 (11.2-14.8) |
| Median FU, mo | 15.9 | 16.1 |
| HR (95% CI); P | 0.42 (0.32-0.54); P < 0.001 | ref |
+2 more figures
10 details 1 trial watching
Phase 3, open-label, multicenter, randomized 1:1, N=563. OS interim analysis at 243 events (61% IF), two-sided boundary 0.008. Data cutoff 7 Jul 2026.
ES-SCLC after 4 cycles platinum-etoposide + durvalumab induction with no disease progression, ECOG PS 0-1, age ≥18. Asymptomatic untreated or treated brain mets allowed.
Tarlatamab 10 mg Q2W + durvalumab 1500 mg Q4W vs durvalumab 1500 mg Q4W alone, 28-day cycles, until progression or toxicity. On-site monitoring 1-2h (6-8h in some regions) after early tarlatamab doses.
Primary: OS. Key secondary: PFS. Secondary: ORR, DOR, safety. Tested hierarchically OS → PFS → ORR.
mOS 21.1 vs 12.7 mo, HR 0.42 (0.32-0.54), P<0.001; PFS 7.4 vs 1.9 mo, HR 0.34 (0.28-0.42); ORR 26% vs 4%.
| Endpoint | Tarlatamab + durvalumab | Durvalumab | Effect |
|---|---|---|---|
| Median PFS | 7.4 mo | 1.9 mo | HR 0.34 (0.28-0.42), P<0.001 |
| ORR | 26% | 4% | n/a |
Control arm is the current chemo-IO maintenance standard established by CASPIAN-era durvalumab, so the comparator is contemporary. Tarlatamab previously moved into later lines (DeLLphi-304); this trial tests it earlier, in the maintenance window.
Efficacy stop at 61% IF risks an inflated HR; median FU ~16 mo leaves the OS tail unknown. No safety data in source, and thoracic RT/PCI permissibility not stated.
A BiTE added at the point of maximal disease control nearly halves the death hazard over durvalumab alone. Unsettled: toxicity cost, durability beyond the interim, and integration with consolidative RT.
CONSORT flow
Randomized phase 3, OS primary met at prespecified interim boundary, labeled primary analysis; source calls it a game-changer. Safety data absent from source.
- Role of consolidative thoracic RT alongside tarlatamab maintenance
- OS durability with follow-up beyond the interim analysis
- Benefit and safety in pts with brain metastases n=35 · primary completion 2029-02 · ph2 tarlatamab intracranial efficacy, active SCLC brain mets
📚 Sources · 🐦 1 tweet
💥Game-changer in small cell #lungcancer! #ESMO26 LBA3 DeLLphi-305: Tarlatamab + durvalumab vs durvalumab 1L maintenance in ES-SCLC (n=563) after chemo-IO. Median OS ⬆️ 21.1 vs 12.7 mo (HR 0.42), PFS ⬆️7.4 vs 1.9 mo (HR 0.34), ORR 26% vs 4%. ☢️44% of pts still on T+D due to… pic.twitter.com/zwBot7Pt3N
— Shankar Siva (@_ShankarSiva) October 24, 2026
PEACE-1
ForMetastatic prostate cancer on ADT+docetaxel, high or low volume
TL;DRmOS 6.2 vs 4.4y (HR 0.68) adding abiraterone to ADT+docetaxel at 8y FU, n=710; no treatment-by-volume interaction (P=0.5552).
Low volume is where prostate RT sits, and abiraterone still more than doubled 7-yr rPFS there (43.4% vs 20.9%, HR 0.54) with no volume interaction (p=0.5552). Models adjusted for prostate RT, but an abiraterone-by-RT interaction is not reported in source, so this does not settle whether triplet and prostate RT add independently.
In metastatic prostate cancer starting ADT+docetaxel, this supports abiraterone intensification in both high- and low-volume disease; it does not address pts not receiving docetaxel. The longer read
Low volume is the prostate RT population, and abiraterone still lifted 7-yr rPFS 43.4% vs 20.9% there. Models adjusted for prostate RT, but abiraterone effect by RT stratum is not reported in source, so additivity with local RT remains untested here.
The volume-agnostic read is the decision point: no interaction (p=0.5552), and low-volume rPFS HR 0.54 matches high-volume 0.50. Low-volume OS HR 0.74 (0.51-1.05) reflects few events, not absent effect, so volume alone is a weak reason to withhold abiraterone from a docetaxel doublet.
| Volume | Median OS, y (Abi vs SOC) | 7-yr OS % (Abi vs SOC) | Adj HR (95.1% CI) | p |
|---|---|---|---|---|
| High | 4.6 vs 3.5 | 40.9 vs 22.4 | 0.67 (0.54-0.85) | 0.0007 |
| Low | 7.8 vs 6.2 | 54.2 vs 46.0 | 0.74 (0.51-1.05) | 0.091 |
+1 more figure
| Volume | Median rPFS, y (Abi vs SOC) | 7-yr rPFS % (Abi vs SOC) | Adj HR (99.9% CI) | p |
|---|---|---|---|---|
| High | 3.2 vs 1.5 | 33.4 vs 10.9 | 0.50 (0.35-0.73) | <0.0001 |
| Low | 5.9 vs 2.7 | 43.4 vs 20.9 | 0.54 (0.32-0.91) | <0.0001 |
10 details
Randomized trial, 8y FU long-term analysis presented at ESMO (Madrid). This report is restricted to the ADT+docetaxel population (n=710), split by metastatic extent.
High volume: n=224 Abi vs n=231 SOC. Low volume: n=131 Abi vs n=124 SOC.
SOC (ADT+docetaxel, ± prostate RT) with vs without abiraterone. Dose and schedule not reported in source.
Prostate RT was a factor within SOC ("+/- RXT"); Cox models adjusted for prostate RT. RT dose, fractionation and the abiraterone effect within each RT stratum are not reported in source.
Pooled OS benefit holds at 8y; volume-specific OS and rPFS are in the figure tables. No treatment-by-volume interaction (p=0.5552).
| Endpoint | Triplet (+Abi) | Doublet | Effect |
|---|---|---|---|
| Median OS | 6.2 y | 4.4 y | HR 0.68 |
| 8-yr OS | 40.3% | 27.1% | n/r |
Extends the earlier PEACE-1 triplet result with longer follow-up and sits alongside ARASENS as the second ARPI + docetaxel triplet dataset. No cross-trial figures in source.
Low-volume OS rests on 67 vs 60 events with CI 0.51-1.05. Post-progression therapy, abiraterone exposure and safety at 8y are not reported in source.
The absence of interaction argues against restricting the triplet to high-volume disease, even though low-volume OS has not cleared significance on its own. The rPFS signal in low volume is as large as in high volume, so the OS gap more likely reflects event count and the longer natural history of low-volume disease.
Randomized long-term update in the docetaxel population, direction unchanged. Volume subgroups underpowered for OS (low-volume CI crosses 1), but no interaction supports a uniform effect.
- Is abiraterone benefit independent of concurrent prostate RT?
- Will low-volume OS benefit reach significance with more events?
- Abiraterone vs darolutamide as the triplet partner
📚 Sources · 🐦 1 tweet
🚨 PEACE-1: 8y FU long-term analysis
— MJosé Juan (@mjuanfi81) October 24, 2026
In patients receiving ADT+docetaxel (n=710), adding abiraterone delivers:
🔹mOS: 6.2 vs 4.4 years (HR 0.68)
🔹 8-yOS: 40.3% vs 27.1%
🔹 High-vol OS: HR 0.67
🔹 Low-vol OS: HR 0.74
🔹 No treatment-by-volume interaction (P=0.5552).@OncoAlert pic.twitter.com/ME1u6GQKGQ
DASL-HiCaP NCT04135353
ForVery high-risk or N1 prostate, radical or early salvage RT + 2y ADT
HR 0.42
95% CI 0.27-0.66, p=0.0001; 4-yr MFS-CI 95% vs 88%
TL;DR4-yr MFS-CI 95% vs 88%, HR 0.42, adding darolutamide to prostate/bed + pelvic LN RT and 96 wk ADT in very high-risk prostate cancer.
Every metastasis-free survival (MFS) difference comes from metastases (9 vs 46). Deaths without prior metastases were 18 vs 17. Both arms got prostate/bed plus pelvic nodal RT with 96 wk ADT, so this is darolutamide on top of an already intensified RT backbone, in both radical and salvage settings. RT dose was not reported.
For a very high-risk patient (GG5, GG4 with adverse T stage or PSA, or cN1/pN1) planned for pelvic nodal RT with 2y ADT, this supports discussing darolutamide intensification. It does not extend to shorter ADT courses or to RT without nodal coverage. The longer read
Darolutamide cut metastases (9 vs 46) even though both arms got pelvic nodal RT and 96 wk ADT, so nodal coverage did not remove the distant-failure risk the drug addresses. The result covers both radical and early salvage RT. Dose/fractionation is not in the source, so it can't be checked against your own regimen.
The secondary endpoints all point the same way: time to CRPC HR 0.22 (0.09-0.52) and subsequent hormonal therapy HR 0.36 (0.21-0.60). This makes darolutamide the ARPI with placebo-controlled data alongside 2y ADT and RT. OS HR 0.88 (0.49-1.59) is still immature.
| MFS-CI | RT + ADT + Darolutamide N=553 | RT + ADT + Placebo N=553 |
|---|---|---|
| Events, n (%) | 27 (5%) | 63 (11%) |
| 4-yr MFS-CI | 95% | 88% |
| Metastases | 9 (33%) | 46 (73%) |
| Death (w/o prior metastases) | 18 (67%) | 17 (27%) |
| HR (95% CI), p | 0.42 (0.27-0.66), p=0.0001 | ref |
+2 more figures
| Secondary endpoint (interim) | HR (95% CI) |
|---|---|
| PSA-PFS | 0.47 (0.33-0.67) |
| CRPC | 0.22 (0.09-0.52) |
| Subsequent hormonal therapy | 0.36 (0.21-0.60) |
| PCSS | 0.58 (0.17-1.97) |
| OS | 0.88 (0.49-1.59) |
9 details
International, randomized, placebo-controlled phase 3, 1:1, N=1,106. Enrolment April 2020 to August 2023. Interim analysis triggered at the 87th MFS-CI event (67%); final analysis planned at 130 events.
DASL very high-risk pts getting radical RT (ISUP GG5, GG4 with cT2b-T4 / rT3a-T4 / PSA >20 ng/mL, or cN1) or salvage RT for PSA persistence or rise ≥0.1 ng/mL within 12 mo with pN1/cN1, GG5, or GG4 pT3a-pT4. Stratified by prior RP, planned docetaxel, pelvic N1.
Darolutamide 600 mg BID x 96 wk vs placebo. Both arms got 96 wk ADT. Docetaxel use was allowed as a stratification factor.
Both arms: prostate/bed + pelvic LNs. Dose, fractionation and imaging used for staging are not reported in the source.
Primary: MFS by conventional imaging (MFS-CI). Secondary: OS, PCSS, PSA-PFS, time to subsequent hormonal therapy, time to castration resistance, AEs, HRQoL.
Primary met at interim, HR 0.42 (0.27-0.66), p=0.0001, against a rejection boundary of 0.012. Authors report the benefit was consistent across all subgroups (no subgroup HRs in source).
Authors describe the treatment burden as similar to placebo. No AE rates or grade breakdown in source.
This sits alongside ENZARAD and the STAMPEDE M0 abiraterone work, which ask the same ARPI-plus-RT intensification question. DASL-HiCaP is the placebo-controlled test, it mandates pelvic nodal RT in both arms, and it includes an early-salvage cohort.
Event-driven interim with only 27 vs 63 events, so the estimate may shrink by the final analysis. MFS is read on conventional imaging, which may not match PSMA-staged practice. Primary vs salvage results are not shown separately.
The drug's effect is on metastases, not competing mortality, which supports a real anticancer benefit. Whether it becomes an OS benefit at PCSS HR 0.58 and OS HR 0.88 is still unknown.
CONSORT flow
Clean placebo-controlled phase 3, but this is the interim analysis (87/130 events). MFS is a surrogate and OS is immature. The prespecified final analysis is the gate.
- Does the MFS benefit translate to OS at final analysis?
- Is benefit similar in salvage vs radical RT cohorts?
- Does the effect hold in PSMA-PET staged pts?
📚 Sources · 🐦 1 tweet
DASL-HiCaP at #ESMO26, presented by @Niazi_Dr7: darolutamide + RT + 2 yrs ADT vs placebo in very high-risk prostate cancer (n=1,106)
— Alan Tan (@alantanmd) October 24, 2026
▪️ MFS HR 0.42, 4-yr MFS 95% vs 88%
▪️ PSA-PFS HR 0.47
▪️ Time to CRPC HR 0.22
▪️ OS immature (HR 0.88)#ProstateCancer pic.twitter.com/pfDHyuM2qW
EBCTCG 20-year recurrence after 5 years of endocrine therapy
ForER+ T1-T2, 0-9 nodes, disease-free after 5y adjuvant endocrine therapy
TL;DRAfter stopping endocrine therapy at 5y, distant recurrence in years 5-20 ran from 13% (T1N0) to 41% (T2N4–9), at a steady annual rate.
In ER+ T1-T2 early breast cancer disease-free at 5 years, this frames the extension discussion around TN status, with T1N0 still carrying 13% distant risk over years 5 to 20; it does not address genomic-assay-selected or trastuzumab-treated HER2+ pts. The longer read
11 details
EBCTCG individual patient data meta-analysis of 88 trials. Kaplan-Meier and Cox regression, stratified by trial and treatment, from year 5 to year 20.
62,923 women with ER-positive T1-T2 disease, 0-9 positive nodes, diagnosed before age 75, scheduled to stop endocrine therapy at 5 years and event-free at year 5. 63% tamoxifen, 17% AI, 20% a tamoxifen-AI sequence; all had lymph-node dissection.
Distant recurrence, any breast-cancer event (distant, locoregional, contralateral), and death from breast cancer by log-rank subtraction.
Recurrences continued at a steady rate from year 5 to 20 in every TN category. Given TN status, grade and Ki-67 carried only moderate independent value after year 5; PR and HER2 status were not predictive.
| Nodal status | T1 | T2 |
|---|---|---|
| N0 | 13% | 19% |
| N1–3 | 20% | 26% |
| N4–9 | 34% | 41% |
| Grade | Distant recurrence | Any recurrence or contralateral BC |
|---|---|---|
| Low | 10% | 17% |
| Moderate | 13% | 22% |
| High | 17% | 26% |
| Nodal status | Distant recurrence | Death from breast cancer |
|---|---|---|
| N0 | 22% | 15% |
| N1–3 | 31% | 28% |
| N4–9 | 52% | 49% |
The source restates EBCTCG data that 5y tamoxifen cut recurrence by about 30% in years 5-10 versus no therapy. Extension trials such as ATLAS and MA.17 test the intervention; this analysis supplies the untreated baseline risk that their proportional benefit acts on.
Grade and Ki-67 were often locally assessed, and Ki-67 was available in only 7692 pts. Few pts received trastuzumab (2%), and treatment eras predate modern staging and systemic therapy.
No TN subgroup had a late risk low enough to dismiss extension outright, even low-grade T1N0 at 10% distant recurrence. Whether extension actually lowers mortality, and in whom it outweighs toxicity, is left to randomised data.
Large multi-trial IPD prognostic analysis, not a randomised test of extension. Quantifies baseline late risk; extended-therapy benefit must come from separate randomised trials.
- Does a genomic low-risk score identify pts safe to stop at 5 years?
- Does extended endocrine therapy reduce breast-cancer mortality, not just recurrence?
- How much do modern-era treatments lower these late risks?
📚 Sources · 📄 1 paper
SAKK 23/82
ForGood-risk ILRR after mastectomy, post excision + RT, TAM-naive
TL;DR5-yr DFS 61% vs 40% with tamoxifen after excision + RT for good-risk post-mastectomy ILRR; OS unchanged (median 11.5 vs 11.2 yr, P=0.79).
For the RT reader, failure after excision plus 5000 cGy at 200 cGy/fx was mostly further local recurrence, and TAM mainly reduced that, not distant spread. Endocrine therapy works here as a local-control partner to chest wall RT. ILRR is also not always a metastatic marker: about 30% stayed relapse-free on local therapy alone.
In a postmenopausal woman with ER+ isolated chest wall or nodal recurrence after mastectomy, resected and irradiated, this supports adding endocrine therapy for DFS. It does not cover premenopausal pts, who gained no DFS, or pts who already had adjuvant TAM. The longer read
Even after excision plus 5000 cGy at 200 cGy/fx, further local recurrence was the dominant failure, and TAM mainly reduced it. The trial supports full-dose curative-intent RT for good-risk ILRR combined with endocrine therapy as a local-control partner, not a replacement.
The DFS gain from TAM was confined to postmenopausal women (5-yr 61% vs 33%, P=0.006) and did not translate into OS. Because pts with prior adjuvant TAM were excluded, the trial does not say which agent to use for today's endocrine-pretreated ER+ ILRR.
11 details
Phase III randomized, central telephone randomization at SAKK, stratified by menopausal status, adjuvant chemo and axillary nodes at diagnosis. 178 randomized, 11 ineligible (6%). Median f/u 11.6 yr for surviving pts.
Good-risk ILRR after mastectomy: first recurrence in the ipsilateral chest wall, shoulder, neck or upper arm, or in regional nodes. Eligibility required an ER+ recurrence, or ER unknown with DFI >12 mo and <4 nodules ≤3 cm. Pts with prior adjuvant TAM were excluded.
Every pt had radical excision, then 5000 cGy at 200 cGy/fx, 5 days a week, to the involved region. RT was fixed across arms, so the trial tests systemic therapy added to full local therapy.
Tamoxifen 20 mg/d orally until progression vs observation.
DFS favored TAM (log-rank P=0.053, Gehan-Wilcoxon P=0.008), with no OS difference (P=0.79). The benefit was confined to postmenopausal pts (5-yr DFS 61% vs 33%, P=0.006). In the multivariate model, TAM and DFI >12 mo predicted longer DFS.
| Endpoint | TAM | Observation | P |
|---|---|---|---|
| Median DFS | 6.5 yr | 2.7 yr | 0.053 log-rank; 0.008 Gehan-Wilcoxon |
| 5-yr DFS | 61% | 40% | n/a |
| Median OS | 11.5 yr | 11.2 yr | 0.79 |
| 5-yr OS | 73% | 79% | n/a |
| Subgroup | TAM | Observation | P |
|---|---|---|---|
| Premenopausal DFS | 60% | 60% | n/a |
| Postmenopausal DFS | 61% | 33% | 0.006 |
| Premenopausal OS | 67% | 90% | 0.175 |
| Postmenopausal OS | 75% | 75% | n/a |
No deaths from pulmonary embolism or endometrial cancer attributable to TAM in either menopausal group.
The authors describe this as the only randomized trial of systemic therapy for ILRR to reach its accrual goal. IBCSG Trial 27 was opened to test chemotherapy vs local treatment alone in LRR, a question this trial does not address.
The early-weighted test carries the DFS result while log-rank misses 0.05. The menopausal split rests on small subgroups. Receptor status was not determined in about a third of pts.
The DFS benefit has persisted since the first analysis, but OS is unchanged, possibly because there were few events and competing mortality in postmenopausal pts. The premenopausal OS deficit with TAM is unexplained and nonsignificant, so it reads as noise more than harm.
Mature phase III, but small, 1980s accrual, borderline log-rank DFS and no OS gain. Backs current endocrine therapy after resected ILRR without defining it for TAM-pretreated pts.
- Aromatase inhibitor benefit after ILRR in tamoxifen-pretreated pts
- Role of chemotherapy for poor-risk ILRR
- Optimal RT dose and volume after ILRR excision
📚 Sources · 📄 1 paper
REVELUTION (relugolix vs leuprolide + RT, PROs)
ForLocalized intermediate/high-risk prostate cancer, RT + ADT, ADT-naive
TL;DRAt 12 mo, relugolix vs leuprolide with RT: IPSS 5.66 vs 9.22 (p=0.039), EPIC-CP total 12.25 vs 17.25 (p=0.02); post hoc.
The PRO gap tracks with faster testosterone recovery on relugolix (mean 199.7 vs 142.0 ng/dL at 12 mo, P=.010), which plausibly explains better urinary and EPIC-CP total scores. For RT + short-course ADT, that recovery kinetic is the relevant variable when choosing GnRH agent; whether it costs anything in biochemical control is untested here.
In an ADT-naive man with localized intermediate- or high-risk prostate cancer starting RT + ADT, this offers hypothesis-level support for relugolix on 12-mo urinary and overall PRO burden; it says nothing about biochemical or oncologic control.
In RT + ADT for localized intermediate/high-risk disease, relugolix was linked to lower IPSS (5.66 vs 9.22) and EPIC-CP total (12.25 vs 17.25) at 12 mo, with higher mean testosterone. That informs agent choice when RT-related urinary and bowel symptoms are the concern, pending oncologic data.
Mean testosterone at 12 mo was higher on relugolix (199.7 vs 142.0 ng/dL), consistent with faster recovery after an oral antagonist. The PRO benefit may reflect that recovery; disease control with relugolix in this curative RT setting is not addressed by this analysis.
Also covered Jun 16
+2 more figures
| Arm | Mean testosterone at 12 MONTHS (ng/dL) | P |
|---|---|---|
| Relugolix | 199.7 | .010 |
| Leuprolide | 142.0 | .010 |
9 details 1 trial watching
Post hoc QoL analysis of a 1:1 randomized trial, N=65. Parent trial primary: 12-month change in total coronary plaque volume by coronary CT angiography.
Localized intermediate- or high-risk prostate cancer, receiving RT + ADT, no prior ADT.
Relugolix oral daily vs leuprolide injection every 3 months, each with RT.
Relugolix favored on IPSS and EPIC-CP total at 12 mo; incontinence, irritation, sexual and SHIM did not differ (all P≥.15). Mean testosterone at 12 mo 199.7 vs 142.0 ng/dL (P=.010), higher on relugolix.
| Endpoint | Relugolix + RT | Leuprolide + RT | p |
|---|---|---|---|
| IPSS | 5.66 | 9.22 | 0.039 |
| EPIC-CP total | 12.25 | 17.25 | 0.02 |
HERO compared relugolix with leuprolide in advanced prostate cancer; this analysis extends the comparison to the curative RT setting, but only on PROs and testosterone, not disease control.
Open route difference (oral vs injection) could bias self-reported outcomes. Whether pts were still on ADT at 12 mo is not stated, so the testosterone and PRO gaps may reflect recovery timing rather than on-treatment tolerability.
The urinary and global PRO advantage aligns with faster testosterone recovery on relugolix. Whether that recovery trades against biochemical control after RT is the unanswered question.
Post hoc QoL analysis of a trial powered for coronary plaque, N=65; PRO differences not a prespecified endpoint and route of administration unblinded.
- Does faster testosterone recovery on relugolix affect biochemical control after RT?
- Do PRO differences hold in a prespecified, larger trial? n=110 · primary completion 2027-07 · relugolix vs leuprolide, 6 mo ADT, QoL as stated aim
📚 Sources · 🐦 1 tweet
Relugolix vs Leuprolide + RT for Localized PCa: PROs in the REVELUTION RCT @urotoday #ASTRO26
— Zach Klaassen (@zklaassen_md) September 30, 2026
Relugolix vs Leuprolide:
📌T @ 12 mos: 199.7 vs 142.0 ng/dL; p=0.01
📌@ 12 mos:
- ⬇️ IPSS (5.66 vs 9.22; p=0.039)
- ⬇️ EPIC-CP total (12.25 vs 17.25; p=0.02)
- ⬇️ EPIC-CP bowel… pic.twitter.com/Ek2xLZsl3u
RTOG 3506 (STEEL)
ForPost-RP BCR with ≥1 high-risk feature, receiving SRT + 24mo ADT
HR 0.62
80% CI 0.42-0.91, one-sided p=0.052
TL;DRPFS HR 0.62 (80% CI 0.42-0.91, one-sided p=0.052) adding enzalutamide to SRT + 24mo ADT in high-risk post-RP BCR; BF at 2y 11% vs 19%.
Both arms received SRT + 24 months GnRHa, so the trial isolates ARSI intensification, not the RT contribution; SRT dose and field are not reported in source. BF at 2y dropped 19% to 11%, but Gr 3-4 lymphopenia rose 15% vs 5%, worth weighing if pelvic nodal fields are in the plan.
In post-RP BCR with Gleason 8-10, SVI, pN1, persistent PSA or PSA ≥0.7 already planned for SRT + 24 months ADT, this supports discussing enzalutamide as investigational intensification; it does not extend to lower-risk BCR or shorter ADT courses.
RT was fixed across arms, so this informs what to pair with SRT, not dose or field; technique is not reported in source. BF at 2y 11% vs 19% suggests the SRT + 24mo ADT backbone still leaves room for intensification in high-risk BCR.
Enzalutamide 160 mg on top of 24 months GnRHa cut PFS hazard (HR 0.62, 80% CI 0.42-0.91) in a screening design. Gr 3-4 lymphopenia 15% vs 5% and hypertension 8% vs 5% are the toxicity trade to weigh pending phase III.
| Arm | PFS HR (80% CI) | p |
|---|---|---|
| SRT+ENH ADT | 0.62 (0.42, 0.91) | one-sided p=0.052 |
| SRT+STD ADT | Referent | n/a |
+2 more figures
| AE (all grades) | SRT + enhanced AR suppression (N=89) | SRT + standard ADT (N=98) |
|---|---|---|
| Lymphocyte count decreased | 19 (21%) | 11 (11%) |
| Hot flashes | 72 (81%) | 69 (70%) |
| WBC decreased | 15 (17%) | 8 (8%) |
| Anemia | 23 (26%) | 11 (11%) |
| Diarrhea | 44 (49%) | 57 (58%) |
| Urinary incontinence | 15 (17%) | 24 (24%) |
| Hyperglycemia | 11 (12%) | 3 (3%) |
8 details
Randomized phase II, 1:1, n=188, final results. Median follow-up 33.1 mos. Designed with a one-sided type I error of 0.10.
BCR after RP with PSA ≥0.2 ng/mL (or ≥0.1 ng/mL ultrasensitive) plus ≥1 aggressive feature: Gleason 8-10, SVI, pN1, persistently elevated post-RP PSA >0.1 ng/mL, or PSA ≥0.7 ng/mL.
Control: 24 months GnRHa. Experimental: 24 months GnRHa + enzalutamide 160 mg.
Salvage RT in both arms. Dose, fractionation and target volume (prostate bed vs pelvic nodes) are not reported in source.
Primary: PFS. Secondary: biochemical failure, hormone-refractory disease, distant metastasis, cause-specific and overall mortality, physician- and patient-reported toxicity, fatigue (PROMIS-F SF 7a), global QoL (EQ-5D-5L).
PFS HR 0.62 (80% CI 0.42-0.91), one-sided p=0.052. BF at 2 yrs 11% vs 19%.
More Gr 3-4 lymphopenia with enza, 13 (15%) vs 5 (5%), and Gr 3-4 hypertension 7 (8%) vs 5 (5%). All-grade hot flashes 81% vs 70%.
RTOG 9601, GETUG-AFU 16 and SPPORT established adding ADT to SRT; STEEL asks the next question, whether an ARSI on top of long-course ADT adds further. EMBARK tested enzalutamide in high-risk BCR without RT, a different setting.
SRT technique not reported, so RT transferability can't be judged. PFS definition and blinding not stated in source. The 24-month ADT control is itself intensified relative to many current practices.
The signal clears the trial's own screening threshold, but no OS or metastasis data in source, so the cost in lymphopenia and hypertension is set against a surrogate benefit only. The question is now phase III-ready, not practice-ready.
Randomized phase II screening design: one-sided α 0.10, 80% CI, surrogate PFS endpoint, 33mo median f/u. Needs phase III confirmation before ARSI intensification with SRT.
- Does PFS gain translate to MFS or OS?
- Phase III confirmation of ARSI intensification with salvage RT
- Role of pelvic nodal RT alongside enhanced AR suppression
📚 Sources · 🐦 1 tweet
Final Results from RTOG 3506 (STEEL): Randomized Ph II -- 24 mos of Enza + ADT vs ADT in HR Pts with BCR Undergoing Salvage RT @EdwinPosadasMD @urotoday #ASTRO26
— Zach Klaassen (@zklaassen_md) September 29, 2026
📌n=188, mFU 33.1 mos
📌Enza + ADT vs ADT, PFS: HR 0.62, 80%CI 0.41-0.91; p = 0.052
📌BF @ 2 yrs: 11% vs 19% pic.twitter.com/fkHw8hzOri
Testosterone Treatment in Prostate Cancer Survivors (Bhasin RCT) NCT03716739
ForHypogonadal men post-RP, pT2 Gleason 3+3/3+4, undetectable PSA ≥2 yr
TL;DRSexual activity +0.91 daily events vs placebo (95% CI 0.56-1.26, P<.001), zero biochemical recurrences, 12wk TRT in hypogonadal men post-RP for Gleason 3+3/3+4.
Men treated with RT or ADT were excluded, so the zero-BCR signal does not transfer to post-RT survivors, the hypogonadal population a radiation oncologist actually follows. Post-RT pts retain prostate tissue, and this trial offers no data on TRT against that background.
In hypogonadal men with undetectable PSA ≥2 years after RP for pT2 Gleason 3+3 or 3+4 disease, this supports short-term TRT as an evidence-backed option for sexual symptoms; it does not extend to post-RT, post-ADT, or higher-grade survivors. The longer read
For the urologist following hypogonadal men after RP for pT2 Gleason 3+3/3+4 disease, this provides the first randomized efficacy data for TRT, with an effect above the stated MCID. It does not settle oncologic safety: 0 vs 0 BCR over 12 wk plus 3 mo in a near-zero-risk cohort cannot rule out harm.
10 details 1 trial watching
Randomized, placebo-controlled, double-blind, parallel-group phase 2 (SPIRIT), 2 academic centers, 1:1, N=136. Enrollment May 2019 to last visit May 2025; target revised from 142 to 134 with DSMB concurrence.
Men ≥40 post-RP for organ-confined pT2N0M0, Gleason 3+3 or 3+4, preop PSA <10, undetectable PSA ≥2 yr. Hypogonadal (T <275 ng/dL and/or free T ≤70 pg/mL) plus low libido, ED, or fatigue. Mean age 68.6; 38% Gleason 6, 62% Gleason 7.
Testosterone cypionate 100 mg IM weekly × 12 wk vs placebo. Total T rose 349 ng/dL (95% CI 283-415) more than placebo; adherence 95% vs 94%.
Primary efficacy: change in sexual activity (PDQ question 4). Primary safety: biochemical recurrence (≥2 consecutive PSA ≥0.2 ng/mL). Secondary: desire, erectile function, affect, body composition, VO2 peak, stair-climb power.
No biochemical recurrence in either arm. Erythrocytosis in 3 TRT pts; SAEs 1 vs 3; no MACE or VTE. One TRT pt had detectable PSA 0.1 to <0.2 ng/mL during treatment.
Described by the authors as the first randomized placebo-controlled trial of TRT in prostate cancer survivors; prior support for TRT after RP rested on observational series. Many guidelines still list prostate cancer history as a TRT contraindication.
Baseline recurrence risk in this cohort is so low that 0 vs 0 BCR carries little information about harm. Erectile function did not move despite EPIC-26 gains, and no P value adjustment was made across secondaries.
The efficacy case for TRT in this population is now randomized and exceeds the MCID. The safety case remains a short-horizon absence of events, which justifies a larger long-term trial rather than settling the contraindication.
| Endpoint | Treatment effect (95% CI) | P |
|---|---|---|
| Sexual activity (PDQ-4), 1° EP | 0.91 (0.56 to 1.26) | <.001 |
| Sexual desire (DISF-SD) | 2.96 (1.46 to 4.45) | <.001 |
| EPIC-26 sexual domain | 5.35 (1.63 to 9.07) | .005 |
| Erectile function (IIEF) | 0.93 (−0.43 to 2.29) | .18 |
| Energy | 1.43 (−0.53 to 3.40) | .15 |
| PANAS positive affect | 0.60 (−0.85 to 2.04) | .42 |
| PANAS negative affect | −1.39 (−2.53 to −0.25) | .02 |
| Event | Placebo | Testosterone |
|---|---|---|
| Biochemical recurrence | 0 | 0 |
| ≥1 AE, pts (events) | 47 (138) | 49 (160) |
| SAEs, pts (events) | 1 (1) | 3 (3) |
| Erythrocytosis (Hb >18 g/dL) | 0 | 3 (3) |
| MACE | 0 | 0 |
| VTE | 0 | 0 |
| Bone fractures | 3 (3) | 0 |
CONSORT flow
Efficacy primary met in a clean double-blind RCT, but the question that gates practice (oncologic safety) is untestable at N=136 and 12 wk; authors frame it as proof-of-concept.
- Long-term oncologic safety of TRT after RP recruiting Impact of Peri-operative tEstosterone Levels on oNcological and Functional Outcomes in RadiCal prostatEctomy Phase 3n=140 · primary completion 2027-12 · phase 3 TRT gel vs placebo post-RP, oncologic outcomes
- TRT safety in post-RT or higher-grade survivors
- Durability of benefit beyond 12 weeks
📚 Sources · 📄 1 paper
Abstract
Testosterone recovery post-ADT discontinuation (podcast review)
TL;DRReview of two datasets: 25% of real-world pts recovered T within 12mo; 54% relugolix vs 3% leuprolide at 90d in HERO.
HERO
For short-course ADT with RT, the recovery question is now quantified: only 25% of real-world pts on injectable ADT had documented T >280 ng/dl within 12mo of stopping, and testing happened in only about 40% at all. The authors position relugolix for short-term or intermittent regimens, not continuous long-term ADT.
In men finishing a defined course of ADT, especially short-term ADT with RT or an intermittent strategy, these data support checking testosterone after discontinuation rather than assuming recovery; they do not inform men on continuous long-term ADT.
Short-course ADT with definitive or salvage RT is exactly the setting the authors name as where recovery matters, and the real-world number is sobering: 25% recovery to >280 ng/dl within 12mo, in a cohort where only about 40% were tested at all. That argues for scheduling a post-ADT testosterone check rather than assuming recovery.
The choice between an oral GnRH antagonist and a depot agonist carries a recovery consequence in this post hoc read: 54% vs 3% at 90 days, median 86 vs 112 days. Relevant when planning intermittent or defined-duration ADT, not continuous therapy.
10 details 4 trials watching
Sponsored podcast article (Pfizer with Sumitomo Pharma), reviewing two published papers: a retrospective real-world Optum EHR/oncology cohort (2020-2021 data) and a post hoc subgroup of the phase 3 HERO trial. No new analysis is presented here.
Real-world cohort: 3875 men who initiated and discontinued injectable ADT, of whom 1553 (about 40%) had at least one testosterone test within 12 months of stopping. HERO subgroup: 184 men who completed 48 weeks of ADT, 137 relugolix and 47 leuprolide.
Relugolix 360 mg loading dose then 120 mg orally once daily; leuprolide IM every 12 weeks. The real-world cohort predates relugolix availability, so it covers injectable formulations only.
Recovery thresholds differ between the two sources. Real-world: testosterone >280 ng/dl on any test within 12 months. HERO subgroup: >280 ng/dl or >80% of baseline, assessed to 90 days post discontinuation.
Real-world recovery was 25% (390/1553) at 12 months, with lower adjusted risk of new-onset diabetes (HR 0.47, 0.27-0.79). HERO 90-day cumulative incidence was 54% relugolix vs 3% leuprolide (nominal p=.002), median time to recovery 86 vs 112 days.
| Outcome | HR | 95% CI |
|---|---|---|
| New-onset diabetes | 0.47 | 0.27-0.79 |
| New-onset depression | 0.58 | 0.33-1.02 |
| Treatment for sexual dysfunction | 1.33 | 0.99-1.78 |
| Subgroup | Relugolix | Leuprolide |
|---|---|---|
| Overall cumulative incidence | 54% | 3% |
| Baseline T at/above pretreatment median | 71% | 6% |
| Age ≤65 | 78% | 13% |
| Age >65 | 47% | 0% |
| Biochemical recurrence | 57% | 0% |
In the HERO post-discontinuation window, any AE and grade 3+ AE were 96% and 15% in both groups over 30 days; serious AEs 12% relugolix vs 11% leuprolide. Day-90 PSA rose slightly more with relugolix (0.39 vs 0.06 ng/ml), with no correlation between rising testosterone and rising PSA.
The two sources are not comparable on their own terms: different recovery definitions, different windows (12 months vs 90 days), and no relugolix in the real-world arm, so the cross-source read is descriptive only. The 86 vs 112 day medians come from a window that ends at 90 days, so the leuprolide median sits beyond the observation period.
The clinically usable claim is the testing-behaviour one: recovery is rarely documented because testosterone is rarely measured after ADT stops. Whether faster biochemical recovery translates into the bone, metabolic and mood outcomes cited as the motivation is untested here.
- Does faster testosterone recovery improve bone, metabolic or cardiovascular outcomes n=110 · primary completion 2027-07 · relugolix vs leuprolide: cholesterol, glucose, QoLrecruiting REVELUTION-2: Relugolix+Abiraterone Acetate (AA) Versus Leuprolide+AA Cardiac Trial Phase 3n=72 · primary completion 2029-07 · phase 3 cardiac endpoints, relugolix vs leuprolide + AA
- Recovery rates beyond 90 days with relugolix not yet Relugolix in Combination With Radiation Therapy for Treating Patients With High Risk Prostate Cancer Phase 2n=90 · primary completion 2025-10 · relugolix duration comparison with DXA + RT
- Recovery after longer ADT durations than 48 weeks active Comeback From Long coursE Androgen Deprivation Therapy (ADT) With RElugolix and Darolutamide (CLEARED) Phase 2n=33 · primary completion 2028-11 · T recovery rate after 2y relugolix + darolutamide
📚 Sources · 📄 1 paper
HERO
ForAdvanced prostate cancer, completing 48wk ADT, no ongoing ADT planned
TL;DR90-day testosterone recovery to ≥280 ng/dL 53.9% with relugolix vs 3.2% with leuprolide after 48wk ADT.
Reported via UroToday →
For intermediate-risk prostate cancer treated with RT plus short-course ADT, the recovery kinetic is the deliverable: median 86.0 days to normal T on relugolix vs 2 of 47 recovering on leuprolide by day 90. That gates the choice of agent when ADT is a fixed 4 to 6 month adjunct to RT and the goal is off-treatment hypogonadism time, not depth of suppression.
In men finishing a defined short-course ADT with RT and no plan for ongoing suppression, this informs agent choice on recovery speed; it does not apply to men continuing ADT indefinitely or to those where prolonged suppression is the therapeutic aim. The longer read
When ADT is a defined 4 to 6 month adjunct to definitive RT, agent choice can be made on recovery speed rather than suppression depth. Median 86.0 days to normal testosterone (95% CI 65.0, 92.0) on relugolix is a concrete planning figure for counselling on off-treatment hypogonadism.
Relevant only where ADT is time-limited by design. The parent trial's depth advantage (96.7% vs 88.8% sustained castration) and this recovery signal point the same way, but neither is tied to an oncologic endpoint, so sequencing and continuous-suppression decisions are untouched.
8 details
Subset analysis of the phase 3 HERO trial, which randomized 934 men with advanced prostate cancer 2:1 to relugolix or leuprolide for 48 weeks. This report covers a 90-day recovery period after treatment discontinuation.
184 men who completed 48 weeks of assigned therapy and had no plan to start alternative ADT within the next 12 weeks (24 weeks after a last leuprolide 3-month depot). 137 had received relugolix, 47 leuprolide.
Relugolix 120 mg orally once daily after a single 360 mg loading dose on Day 1, versus leuprolide injections every 12 weeks, each for 48 weeks.
Time to testosterone recovery to ≥280 ng/dL by Kaplan-Meier, PSA during the recovery phase, and adverse events during recovery. No oncologic efficacy endpoint in this analysis.
During recovery, 96% of men had at least one adverse event and 15% had a grade ≥3 event, similar in both groups.
The 90-day window sits inside the pharmacologic tail of a 3-month leuprolide depot, so part of the 53.9% vs 3.2% gap is measurement timing rather than a durable biologic difference. The leuprolide median of 112.0 days derives from 2 recovery events.
Consistent in direction with the parent HERO result, where relugolix gave deeper sustained castration (96.7% vs 88.8%, difference 7.9%, 95% CI 4.1 to 11.8, P<0.001). The trade the two readings define is depth of suppression on-treatment against speed of recovery off-treatment, both favoring the oral antagonist.
This settles a kinetic question, not a clinical one: no recurrence, quality-of-life, or cardiometabolic endpoint is tied to the faster recovery here. Whether restoring normal testosterone months earlier translates into measurable benefit, or into a PSA that reflects recovering physiology rather than disease, remains untested.
| Metric | Relugolix | Leuprolide |
|---|---|---|
| n in recovery subset | 137 | 47 |
| Baseline T entering recovery (mean±SD) | 427±142 ng/dL | 404±127 ng/dL |
| Recovered T | 74 | 2 |
| Median time to recovery | 86.0 d (95% CI 65.0, 92.0) | 112.0 d (95% CI 112.0, NE) |
| Median PSA at day 90 | 0.39 ng/mL (0 to 233.1) | 0.06 ng/mL (0 to 14.0) |
Post-hoc subset of a phase 3 trial, non-randomised entry criterion, 137 vs 47 arms; recovery kinetics are a pharmacologic expectation, not a new clinical outcome.
- Does faster testosterone recovery change QoL or cardiometabolic outcomes
- Is higher day-90 PSA on relugolix physiologic or disease-driven
- Recovery kinetics after short-course ADT with definitive radiotherapy
📚 Sources · 📄 1 paper
Abstract
STAMPEDE abiraterone ± enzalutamide in high-risk non-metastatic prostate cancer (meta-analysis) NCT00268476
ForHigh-risk non-metastatic prostate cancer (N+ or high-risk N0) starting ADT
HR 0.53
95% CI 0.44-0.64, p<0.0001; 6-yr MFS 82% vs 69%
TL;DRMFS HR 0.53 (0.44-0.64) and OS HR 0.60 (0.48-0.73) adding 2yr abiraterone ± enzalutamide to ADT in high-risk non-metastatic prostate cancer.
The MFS benefit held whether or not RT was planned: HR 0.54 (0.44-0.67) with RT vs 0.51 (0.34-0.76) without, interaction p=0.67. So abiraterone adds to prostate RT and does not stand in for it. The RT was 74 Gy/37 fx to prostate + SVs, and the source does not describe pelvic nodal fields for the 39% who were N+.
In N+ or high-risk N0 non-metastatic prostate cancer starting long-course ADT with prostate RT, this supports 2 yr of abiraterone + prednisolone without enzalutamide. It does not extend to men treated with prostatectomy, who were not studied. The longer read
The abiraterone benefit is independent of planned RT (MFS HR 0.54 with vs 0.51 without, interaction p=0.67), and RT was mandated for N0. It stacks on 74 Gy/37 fx to prostate + SVs with 3 yr ADT. The source does not describe pelvic nodal fields, and only 71% of N+ pts had RT planned.
Two years of abiraterone + prednisolone added to 3 yr ADT improved OS (HR 0.60). Adding enzalutamide gave no extra MFS benefit (interaction HR 1.02) and raised grade 3+ AEs to 58% vs 32%. Enzalutamide adds cost and toxicity without added efficacy.
Also covered Oct 24
11 details 4 trials watching
Prespecified IPD meta-analysis of two open-label, randomised (1:1) phase 3 trials in the STAMPEDE platform, run at 113 UK and Swiss sites. N=1974, randomised 2011-2016, with no overlapping controls. Median follow-up was 72 mo.
High-risk non-metastatic prostate cancer on conventional imaging: N+, or N0 with at least two of T3/T4, Gleason 8-10, or PSA ≥40 ng/mL. Pts relapsing with high-risk features were also eligible. Median age was 68, and 774 (39%) were node-positive. Clinically significant cardiovascular disease was excluded.
All pts received 3 yr ADT. The combination arm added abiraterone 1000 mg + prednisolone 5 mg daily for 2 yr, and the second trial also added enzalutamide 160 mg. If RT was omitted, treatment could continue until progression.
Per local guidelines: 74 Gy/37 fx to prostate + SVs or a hypofractionated equivalent. RT was mandated for N0 and encouraged for N+. RT was planned in 85% overall: 99% of N0, 71% of N+ and 7% of previously treated pts.
Primary: MFS, which was changed from OS before any efficacy inspection and approved by the steering committee on Dec 2, 2019. Secondary endpoints were OS, prostate cancer-specific survival, biochemical failure-free survival, PFS and toxicity.
Both trials showed the benefit on their own: MFS HR 0.54 in the abiraterone trial and 0.53 in the abiraterone + enzalutamide trial, with no between-trial heterogeneity (I² p=0.90).
| Endpoint | Combination | Control | HR (95% CI) |
|---|---|---|---|
| MFS (1°) | 6-yr 82% | 6-yr 69% | 0.53 (0.44-0.64), p<0.0001 |
| OS | 6-yr 86% | 6-yr 77% | 0.60 (0.48-0.73), p<0.0001 |
| Prostate cancer-specific survival | median not reached | median not reached | 0.49 (0.37-0.65), p<0.0001 |
| Biochemical failure-free survival | median not reached | median 86 mo | 0.39 (0.33-0.47), p<0.0001 |
| PFS | median not reached | median not reached | 0.44 (0.36-0.54), p<0.0001 |
| Subgroup | HR (95% CI) | p interaction |
|---|---|---|
| RT planned: yes | 0.54 (0.44-0.67) | 0.67 |
| RT planned: no | 0.51 (0.34-0.76) | 0.67 |
| N0 | 0.60 (0.46-0.78) | 0.22 |
| N+ | 0.49 (0.38-0.64) | 0.22 |
| WHO PS 0 | 0.47 (0.38-0.58) | 0.00656 |
| WHO PS 1-2 | 0.86 (0.58-1.28) | 0.00656 |
| NSAID/aspirin: no | 0.62 (0.51-0.77) | 0.0052 |
| NSAID/aspirin: yes | 0.32 (0.21-0.48) | 0.0052 |
| AE | Abi trial: combo | Abi trial: control | Abi+enza trial: combo | Abi+enza trial: control |
|---|---|---|---|---|
| Any grade 3+ | 37% | 29% | 58% | 32% |
| Hypertension | 5% | 1% | 14% | 2% |
| ALT increase | 6% | <1% | 13% | 1% |
Grade 3+ AEs in the first 24 mo were 37% vs 29% in the abiraterone trial and 58% vs 32% in the abiraterone + enzalutamide trial. The main drivers were hypertension and ALT elevation. There were 7 grade 5 events, all in the combination arms.
The backbone is long-course ADT with prostate RT, which the authors frame as standard for this population. Adding enzalutamide to abiraterone also gave no extra benefit here, consistent with the modest rPFS gains and absent OS benefit the authors cite from that combination in mCRPC.
Staging used conventional imaging only. Toxicity was reported only for the first 2 yr, and data on subsequent therapy are unreliable. Heterogeneity by PS 1-2 (HR 0.86, 0.58-1.28) makes the benefit less certain in less fit men.
Abiraterone intensification improved MFS and OS on top of ADT whether or not RT was planned. Enzalutamide added toxicity without extra efficacy. Open questions are the right duration, the benefit after prostatectomy, and the benefit in PSMA-staged disease, none of which were tested.
Pooled IPD from two randomised phase 3 trials, 72-mo f/u, with both MFS and OS improved. The OS→MFS switch was prespecified before efficacy was seen. Authors call it a new standard.
- Is 2 years the optimal abiraterone duration? recruiting Reduced Length of ADT and ARTA With XRT in High-Risk Prostate Cancer (RELAX): A Randomised Trial Phase 2n=206 · primary completion 2035-01 · 9mo ADT + 6mo ARTA vs 2y ADT with RT, high-risk N0M0
- Benefit after radical prostatectomy untested recruiting Treating Prostate Cancer That Has Come Back After Surgery With Apalutamide and Targeted Radiation Based on PET Imaging Phase 3n=804 · primary completion 2032-12 · post-RP BCR: apalutamide+abiraterone added to SRT+ADT
- Benefit in relapse after prior local therapy underrepresented active Finite Androgen Ablation With or Without Abiraterone Acetate and Prednisone in Treating Patients With Recurrent Prostate Cancer Phase 2n=310 · primary completion 2027-02 · recurrent PCa: finite ADT ± abiraterone, randomisedrecruiting Treating Prostate Cancer That Has Come Back After Surgery With Apalutamide and Targeted Radiation Based on PET Imaging Phase 3n=804 · primary completion 2032-12 · phase 3 ARSI intensification in post-RP BCR
📚 Sources · 📄 1 paper
REVELUTION
ForNon-metastatic intermediate/high-risk prostate cancer receiving definitive RT + ADT
68.9 mm³ adjusted mean difference
Leuprolide vs relugolix; crude 56 vs 25 mm³. CI/p not reported in source
TL;DRAdjusted 12-mo total plaque volume rose 68.9 mm³ more with leuprolide vs relugolix in men getting prostate RT.
Reported via UroToday →
Every man here got prostate ± pelvic nodal RT, so this is an RT-clinic decision, not a med-onc one: for the 6-month ADT course you prescribe alongside definitive RT, the agonist added 68.9 mm³ of adjusted total plaque volume at 12 months, driven by non-calcified plaque. A radiation-alone control cohort was enrolled in parallel, though its comparison was not reported in source.
For the intermediate/high-risk man starting definitive prostate RT with 6+ months of concurrent ADT, particularly with elevated ASCVD 10-year risk, this supports weighing agent choice on cardiovascular grounds; it says nothing about ADT duration or about men on ADT without RT. The longer read
The entire cohort received prostate ± pelvic nodal RT, so this is your ADT prescription, not someone else's: the agonist added 68.9 mm³ of adjusted total plaque volume at 12 months, driven by non-calcified plaque. It moves agent selection for the 6-month course accompanying definitive RT, particularly in men with elevated baseline ASCVD risk.
This supplies the missing mechanism under HERO's MACE difference: comparable testosterone suppression, divergent coronary plaque trajectory, with the signal in non-calcified rather than calcified plaque. It argues the agonist-antagonist cardiovascular gap is pharmacologic rather than an artifact, though the population here is non-metastatic and radiotherapy-treated.
Also covered Sep 30
11 details 4 trials watching
Single-institution, parallel-cohort, open-label randomized trial across four Emory-affiliated centers, enrolling June 2020 to 2024. ADT-eligible pts randomized 1:1 relugolix vs leuprolide, stratified by ASCVD 10-year risk score; a parallel prospective RT-alone cohort was enrolled as control.
94 men with non-metastatic prostate cancer, intermediate and high risk, all treated with pelvic radiotherapy to the prostate with or without pelvic nodes. Lower-risk men eligible for definitive RT alone without planned ADT formed the parallel arm.
Relugolix 360 mg day 1, then 120 mg daily; leuprolide in 3-month depots. ADT given for at least six months, longer by cancer risk tier.
All pts received pelvic radiotherapy to the prostate with or without the pelvic lymph nodes. Dose, fractionation and technique are not reported in source.
Primary: change in total plaque volume. Secondary: changes in plaque subtypes (non-calcified, calcified, low-attenuation). Serial CCTA at baseline (within 7 days of treatment start) and 12 months, blinded to arm, quantified by the automated HeartFlow tool; 12-month mean difference by ANCOVA adjusted for age, statin use and baseline plaque volume.
The adjusted total-plaque-volume difference of 68.9 mm³ favouring relugolix was driven mainly by non-calcified plaque; calcified and low-attenuation plaque showed no significant difference with low absolute change. Per-arm CIs and p-values are not reported in source.
| Measure | Leuprolide | Relugolix |
|---|---|---|
| Total plaque volume, crude difference | 56 mm³ | 25 mm³ |
HERO (2020) showed a lower MACE rate with relugolix vs leuprolide and drove the FDA approval, but offered no mechanism, since both agents suppress testosterone comparably and share the hypogonadal metabolic profile. REVELUTION supplies the candidate mechanism, accelerated coronary atherosclerosis under GnRH agonism, consistent with the 2010s observational signal that agonists carry higher cardiovascular risk than orchiectomy.
The imaging endpoint is validated as a predictor of MACE, not a substitute for it, and 12 months is short for plaque trajectories. The parallel RT-alone cohort was not randomized against either ADT arm, so the no-hormone comparison is observational and cannot isolate radiotherapy's own contribution to plaque change.
If the agonist-antagonist difference is real and mechanistic, the decision it moves is which ADT agent accompanies definitive RT in a man with baseline cardiovascular risk, not whether to give ADT at all. It does not establish that changing agent prevents events; that inference still rests on HERO.
Small single-institution randomized trial with an imaging surrogate (plaque volume), not clinical MACE. Supplies a mechanism for HERO rather than independent outcome evidence.
- Does the plaque difference translate to fewer clinical cardiovascular events recruiting Effects of Relugolix vs Leuprolide on Cardiac Function in Patients With Prostate Cancer Phase 2n=70 · primary completion 2027-12 · relugolix vs leuprolide, cardiac MRI + performancerecruiting REVELUTION-2: Relugolix+Abiraterone Acetate (AA) Versus Leuprolide+AA Cardiac Trial Phase 3n=72 · primary completion 2029-07 · relugolix vs leuprolide + AA, cardiac CTA, pelvic RT
- Plaque trajectory beyond 12 months and after ADT completion n=100 · primary completion 2026-12 · randomised CCTA vs usual care, ADT >12mo planned
- Does pelvic radiotherapy itself contribute to coronary plaque change n=200 · primary completion 2029-11 · ADT cardiotox cohort enrolls with and without RT
📚 Sources · 📄 1 paper
Abstract
DeLLphi-304
For2L SCLC after platinum, with or without baseline brain metastases
TL;DRPost hoc CNS analysis: median CNS PFS NE vs 7.2mo, HR 0.54 (0.39-0.75) favoring 2L tarlatamab in SCLC.
For an RT reader the actionable number is the brain-met subset: CNS PFS 6.5 vs 4.2mo, HR 0.40 (0.24, 0.66) by mRANO-BM BICR, with CNS CR 14.9% vs 5.4%. But >70% had prior CNS-directed treatment and no RT exposure or intracranial-failure pattern is reported, so this informs surveillance interval rather than deferring SRS.
In relapsed SCLC with treated, asymptomatic brain metastases entering 2L, this supports tarlatamab as systemic therapy with meaningful intracranial activity; it does not address untreated or symptomatic CNS disease, where local therapy remains the studied path. The longer read
The brain-met subset read by mRANO-BM BICR gives CNS PFS 6.5 vs 4.2mo, HR 0.40 (0.24, 0.66), which is the number to hold against a systemic-only strategy. But >70% had prior CNS-directed therapy and neither RT exposure nor in-field versus out-of-field failure is reported, so it moves the surveillance interval, not the decision to offer SRS.
Intracranial activity is now a differentiator for tarlatamab in 2L SCLC rather than an unknown: CNS CR 14.9% vs 5.4% and CNS disease control 77.6% vs 71.4%, with median duration of CNS disease control 8.2 vs 5.2mo. That supports keeping a pt with treated, stable brain metastases on the bispecific rather than defaulting to chemotherapy for CNS coverage.
| Arm | n | Median CNS PFS (95% CI) | HR (95% CI) |
|---|---|---|---|
| Tarlatamab | 67 | 6.5 (4.3, 13.7) | 0.40 (0.24, 0.66) |
| Chemotherapy | 56 | 4.2 (2.9, 5.5) | n/a |
+2 more figures
| Arm | n | Median CNS PFS (95% CI) | HR (95% CI) |
|---|---|---|---|
| Tarlatamab | 254 | NE (13.7, NE) | 0.54 (0.39, 0.75) |
| Chemotherapy | 255 | 7.2 (5.6, NE) | n/a |
| CNS outcome | Tarlatamab (n=67) | Chemotherapy (n=56) |
|---|---|---|
| Complete response, n (%) | 10 (14.9) | 3 (5.4) |
| Non-CR/non-PD, n (%) | 42 (62.7) | 37 (66.1) |
| Progressive disease, n (%) | 13 (19.4) | 16 (28.6) |
| CNS disease control rate, n (%) | 52 (77.6) | 40 (71.4) |
| Median duration of CNS disease control, mo | 8.2 (1.2+, 16.7+) | 5.2 (1.2+, 7.0) |
10 details 1 trial watching
Post hoc intracranial analysis of the randomised DeLLphi-304 trial of second-line tarlatamab versus chemotherapy in SCLC. Two assessment frameworks: investigator RECIST in the ITT population and mRANO-BM by BICR in pts with baseline brain metastases. Data cutoff January 29, 2025; median follow-up 11.4 mo (tarlatamab) and 11.5 mo (chemotherapy).
ITT n=254 tarlatamab versus n=255 chemotherapy. The brain-metastasis cohort was n=67 versus n=56, defined as ≥1 brain metastasis at baseline per mRANO-BM by BICR plus ≥1 post-baseline scan. More than 70% had already received CNS-directed treatment, which is why the response categories were CR, non-CR/non-PD and PD rather than a conventional ORR.
This analysis reports time to CNS progression or death (CNS PFS) in the ITT population and in the brain-metastasis subset, plus best overall CNS response, CNS disease control rate, duration of CNS complete response and duration of CNS disease control. None of these was the trial's registered primary endpoint.
Both CNS PFS comparisons favor tarlatamab, and the effect is larger in the brain-metastasis subset (HR 0.40) than in the ITT population (HR 0.54). Intracranial complete response was 14.9% versus 5.4%, and CNS tumor shrinkage ≥30% occurred in 9/16 versus 5/13 pts with measurable lesions ≥10mm.
Brain metastases develop in the majority of SCLC pts, and second-line systemic options have historically been judged on extracranial disease with CNS control assumed to be the province of SRS, WBRT or prophylactic cranial irradiation. A bispecific T-cell engager showing an intracranial complete response rate of 14.9% is the notable part, because the working assumption for large-molecule agents has been limited intracranial penetration.
The ITT median CNS PFS was not estimable at 11.4 months of follow-up, so the ITT curve rests on the early portion of the data and the point estimate can still move. The two populations were also read with different tools and different models (stratified Cox for ITT, unstratified for the subset), so the ITT and subset HRs are not strictly comparable to each other.
The result establishes that intracranial disease does not progress faster under tarlatamab than under chemotherapy, and probably progresses more slowly. What it does not establish is whether that activity is sufficient to defer local therapy in a patient who would otherwise be referred for SRS, since the source reports no radiotherapy exposure data and no in-field versus out-of-field failure pattern.
Post hoc intracranial analysis of a randomised trial; CNS endpoints were not the registered primary, and the brain-met subset HR comes from an unstratified model.
- Does intracranial activity permit deferral of SRS in untreated brain mets
- Activity in CNS-treatment-naive or symptomatic brain metastases n=35 · primary completion 2029-02 · phase 2 tarlatamab, active asymptomatic brain mets
- Durability of CNS control beyond 12 months follow-up
📚 Sources · 🐦 1 tweet
Dr. @g_mountzios #ASCO26 presents CNS outcomes with 2L tarlatamab in DeLLphi-304. Improved time to CNS progression overall (HR 0.54). In pts with brain nets, tarlatamab vs chemo CNS CR rate 15% vs 5% with DCR 78% vs 71% and time to CBS progression 6.5m vs 4.2m, HR 0.40 pic.twitter.com/5i8jL1zlKW
— Stephen V Liu, MD (@StephenVLiu) June 1, 2026
PROTEUS
TL;DRNo primary effect size in source; most distant mets were PSMA PET-detected (53.0% apalutamide group, 60.7% in the other group).
MFS here is largely a PET endpoint: most distant metastases were identified by PSMA PET (53.0% apalutamide group, 60.7% in the other group). Any MFS difference needs reading against conventional-imaging MFS endpoints with that ascertainment shift in mind.
The MFS read hinges on how events were detected: most distant metastases were PSMA PET-identified (53.0% apalutamide group, 60.7% in the other group). Whether adding apalutamide to ADT moves a conventional-imaging metastasis endpoint cannot be judged from source tweets; no effect size reported.
9 details 1 trial watching
Design not stated in source. Commentary frames the comparison as an ADT + apalutamide arm vs ADT alone; results published in NEJM alongside ASCO 2026.
Source names EFS and MFS. Primary endpoint and its effect size are not reported in source tweets.
Most distant metastases were identified by PSMA PET: 53.0% of those in the apalutamide group and 60.7% in the second group (label truncated in source).
The BCR counts (60 vs 50 per 100) come from a hypothetical thought experiment, not trial data. The arm attribution of the 60.7% figure is truncated in the source tweet.
A PET-dominated MFS event mix means the endpoint is not interchangeable with conventional-imaging MFS. Whether the result is a benefit or a negative trial, as the commentator frames the debate, cannot be settled from the source.
Source tweets give no primary endpoint result, design, phase or population; only the imaging mode of distant-met detection is stated.
- Primary endpoint effect size pending full presentation
- Does an MFS difference hold by conventional imaging alone? n=1503 · primary completion 2027-03 · apalutamide + RT in high-risk; conventional-imaging MFS
- Does PSMA PET-detected MFS track overall survival?
📚 Sources · 🐦 3 tweets
#ASCO26
— Daniel E Spratt (@DrSpratticus) May 31, 2026
The PROTEUS trial results are now online...buckle up as we wait to see the full presentation. This is going to be a trial that is likely highly controversial until the full results are published.
Some may call this a homerun, others may call this the largest negative…
Thought experiment:
— Sean McBride (@seanmmcbride) May 31, 2026
Let's take a very simple hypothetical trial involving 100 patients in the APA arm and 100 patients in the ADT alone arm. Pulling from PROTEUS EFS data, assume that, by 5 years, 60 patients in the ADT arm have had a BCR compared to 50 in the ADT+APA arm.… pic.twitter.com/WJaiDlJnQs
#ASCO26
— Daniel E Spratt (@DrSpratticus) May 31, 2026
Talk about real-time updates. NEJM paper now online and my predictions and inferences appear true.
Majority of MFS events were by PET not conventional imaging. "Most distant metastases were identified by PSMA PET (53.0% of those in the apalutamide group and 60.7% in the… https://t.co/Yz4myY0flq
RASolute 302
ForPreviously treated metastatic pancreatic cancer, RAS G12-mutant
TL;DRMedian OS 13.2 vs 6.6 mo, HR 0.40 (95% CI 0.30-0.54), P<0.001, daraxonrasib over chemo in previously treated RAS G12 metastatic pancreatic cancer.
In previously treated metastatic pancreatic cancer with a RAS G12 mutation, this supports daraxonrasib over investigator's choice chemotherapy on OS; it does not extend to treatment-naive or non-metastatic disease.
| Population | Arm | N | Events, n (%) | mOS, mo (95% CI) | HR for death (95% CI) |
|---|---|---|---|---|---|
| RAS G12 | Daraxonrasib | 228 | 72 (32) | 13.2 (10.0-NR) | 0.40 (0.30-0.54), P<0.001 |
| RAS G12 | Chemotherapy | 231 | 127 (55) | 6.6 (5.4-8.2) | ref |
| Overall | Daraxonrasib | 248 | 79 (32) | 13.2 (10.0-NR) | 0.40 (0.30-0.53), P<0.001 |
| Overall | Chemotherapy | 252 | 141 (56) | 6.7 (5.8-8.0) | ref |
8 details 2 trials watching
Phase, randomization and primary endpoint not stated in source. HRs came from a stratified Cox model and P values from a stratified log-rank test. Presented at ASCO as abstract LBA5.
Previously treated metastatic pancreatic cancer. OS reported in a RAS G12 population (228 vs 231) and an overall population that also includes G13 or Q61 mutations or no RAS mutation identified (248 vs 252).
Daraxonrasib vs investigator's choice chemotherapy. Dose, schedule and the chemo options allowed are not stated in source.
OS favored daraxonrasib in both populations with HR 0.40, P<0.001; per-arm values are in the figure table.
Second-line metastatic pancreatic cancer has been a chemotherapy space, with NAPOLI-1 establishing a nal-IRI based option. An OS benefit for a RAS-directed agent over chemo is a different class of result; no cross-trial numbers are reported in source.
Safety and follow-up duration not reported in source; the daraxonrasib median OS upper CI is not reached. Composition of the investigator's-choice control is unknown, which bears on comparator strength.
The identical HR 0.40 in both populations reflects that the overall population is almost entirely RAS G12, not a demonstrated benefit beyond G12. Events of 32% vs 55% and 56% mean the daraxonrasib median of 13.2 mo rests on fewer events and may move with maturity.
OS HR 0.40 vs investigator's-choice chemo, P<0.001, consistent in RAS G12 and overall populations; source frames it as historic. Tweet omits phase and design.
- Benefit in RAS G13, Q61, or no-RAS-mutation tumors?
- Durability of OS benefit with longer follow-up
- Role in first-line metastatic pancreatic cancer recruiting Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma Phase 3n=900 · primary completion 2028-06 · phase 3 daraxonrasib ± GnP vs chemo, 1L metastatic PDACn=400 · primary completion 2029-03 · phase 3 zoldonrasib + daraxonrasib vs GnP, 1L KRAS G12D
📚 Sources · 🐦 1 tweet
#ASCO26
— Nicholas Hornstein (@GIMedOnc) May 31, 2026
This one is special.
This is the hottest paper of 2026 and potentially in the history of pancreatic cancer.
Let’s dive in.
RASolute 302: Daraxonrasib vs investigator’s choice chemotherapy in previously treated metastatic pancreatic cancer
Abstract LBA5 (soon!)… pic.twitter.com/Lq7PEjOWAo
Management After pCR in MIBC (Panel)
TL;DRPanel review: sandwich immunotherapy regimens continue planned adjuvant therapy regardless of pCR, with de-escalation still unanswered.
SWOG 8710ABACUSCHECKMATE-274KEYNOTE-905VOLGANIAGARAVESPERKEYNOTE-B15
In MIBC pts who reach pT0N0 at cystectomy on a sandwich regimen, this supports completing planned adjuvant therapy rather than stopping on pathologic response; after cisplatin-based chemo alone, surveillance remains the presented standard.
+2 more figures
| Setting | Trial | Reported outcome |
|---|---|---|
| Cisplatin-ineligible | KEYNOTE-905 | Periop EVP now standard |
| Cisplatin-ineligible | VOLGA | EV + durva/treme improved EFS (press release) |
| Cisplatin-eligible | NIAGARA | 24-mo OS 82.2% vs 75.2% |
| Cisplatin-eligible | VESPER | 5-yr OS 66% vs 57%, ddMVAC > gem/cis |
| Cisplatin-eligible | KEYNOTE-B15 | OS improved vs gem/cis, under FDA review |
11 details
ASCO 2026 GU education session, not a trial. Synthesizes SWOG 8710, NIAGARA, VESPER, KEYNOTE-905, KEYNOTE-B15 and VOLGA into a position on what to do after pCR.
The practice answer presented is continue: resume durvalumab for 8 months post-cystectomy on the NIAGARA regimen, resume EVP post-cystectomy on perioperative EVP. Surveillance after pCR is standard only for cisplatin-based chemo alone.
The continue-vs-stop question has never been randomized. Not all pts in the source trials completed adjuvant therapy, often for toxicity, so the observed benefit reflects a mixed delivered dose rather than the full planned course.
The session names the two open questions itself: the relative contribution of the pre- versus postoperative components, and whether adjuvant therapy can be de-escalated on pCR or another biomarker. Neither is answerable from an intention-to-treat perioperative design.
- Relative contribution of pre- vs postoperative components
- Can adjuvant therapy be de-escalated based on pCR or biomarkers
📚 Sources · 🐦 1 tweet
#ASCO26 GU Oncology Spotlight 🚨
— Dra. María Natalia Gandur Quiroga (@nataliagandur) May 30, 2026
🔬 Management in Bladder Cancer After Pathologic Complete Disease Response
Presented by Brendan J. Guercio, MD@OncoAlert@ASCO
In muscle-invasive bladder cancer, pCR after neoadjuvant therapy is one of the most powerful prognostic signals we… pic.twitter.com/sMd2In7X3p
A-DREAM
FormHSPC, PSA <0.2 after 18-24mo ADT + ≥12mo ARPI
41.0% (32/78)
80% CI 33.1-48.9%, one-sided p 0.0249
TL;DR41% treatment-free with eugonadal T at 18mo after stopping ADT+ARPI in responding mHSPC (80% CI 33.1-48.9%, one-sided p 0.0249).
The RT-relevant detail is baseline burden: 51.3% had prostate RT and 29.5% had RT to metastatic sites, so the cohort that tolerated interruption was heavily locally treated, and 4 pts (5.1%) took RT as their non-protocol next step off ADT. Metastasis-directed RT is not tested here, but this is the population where a de-intensification question meets it.
In mHSPC with PSA under 0.2 after 18-24 months of ADT plus at least 12 months of ARPI, this supports discussing a protocolized interruption with PSA and testosterone monitoring; it does not extend to pts with persistent PSA or to unselected metastatic disease. The longer read
The cohort was RT-heavy before interruption: 51.3% had prostate radiation and 29.5% had radiation to metastatic sites, and 4 (5.1%) took radiation as their non-protocol next step off ADT. Metastasis-directed RT to extend time off systemic therapy is the randomizable question this describes but does not test.
The composite splits usefully: 57.7% stayed treatment-free for 18 months but only 66.7% recovered testosterone (median 9.0 months), so gonadal recovery, not disease control, is the rate limiter in a median-age-70 cohort. Counsel the two risks separately before interrupting.
+3 more figures
| Characteristic | Value |
|---|---|
| Median age | 70 (49-90) |
| High volume (CHAARTED) | 27 (35.1%) |
| Low volume (CHAARTED) | 50 (64.9%) |
| Prostate RT as local therapy | 40 (51.3%) |
| RT to metastatic sites | 23 (29.5%) |
11 details 5 trials watching
Alliance single-arm phase 2, N=75 planned, 78 eligible enrolled 07/2022-03/2024. Median follow-up 26.9 months. Monitoring PSA and testosterone q3mo, scans at least q6mo (q3mo with rising PSA), QOL q6mo.
mHSPC on ADT + ARPI with PSA <0.2 stable or falling after 18-24 months of ADT and at least 12 months of ARPI. Median age 70 (49-90), 84.6% White, 64.9% low volume by CHAARTED, 35.1% high volume. Median PSA prior to starting ADT+ARPI 18.99 ng/mL.
Not an intervention, but the cohort was RT-heavy at baseline: 40 (51.3%) had radiation as local therapy, 31 (39.7%) had no local therapy, 7 (9.0%) prostatectomy +/- RT. 23 (29.5%) had radiation to metastatic sites. Dose and fractionation not reported in source.
Primary: treatment-free with eugonadal testosterone (T ≥150 ng/dL) at 18 months. Secondary: time to eugonadal T, duration off treatment, QOL. Exploratory: rPFS, TTNT, OS (CSS/NCSS), cost. Re-initiation triggered by PSA ≥5 ng/mL, PCWG3 radiographic change, or prostate-cancer-related symptoms.
Primary endpoint met: 32/78 (41.0%), 80% CI 33.1-48.9%, one-sided p 0.0249. Testosterone recovered in 52 (66.7%) by 18 months with median time to eugonadal T 9.0 months (95% CI 8.4-12.4); 45 (57.7%) stayed treatment-free for 18 months. rPFS 15/78 events, median NE; OS 4/78 events, median NE.
The 18-month primary readout is short for a de-intensification question whose real risk is late: 4 of 29 pts who resumed per protocol later progressed and discontinued the original ARPI, so re-treatment did not uniformly restore control. Deaths (4) included non-prostate causes (myelodysplastic syndrome, influenza, myocardial infarction), and with no continuous-treatment arm the OS curve carries no comparative information.
Intermittent ADT has been tested before in metastatic disease (SWOG 9346 could not exclude an OS decrement with intermittent therapy in mHSPC), but A-DREAM asks the question in the modern ARPI-intensified era with a molecularly deeper response gate, which is why the cohort's off-treatment rate looks better than the older intermittent literature suggests. That comparison is a rationale, not a result: A-DREAM has no randomised arm.
The number that matters clinically is not 41% but its two components: testosterone recovery is the rate limiter (66.7% recovered, median 9.0 months), while disease control off treatment was more common (57.7% treatment-free at 18 months). A trial that de-intensifies successfully on disease grounds can still miss its endpoint on gonadal recovery in an older cohort, and that distinction determines who to counsel.
Single-arm phase 2, no continuous-treatment control, 18mo primary readout in a deeply selected responder cohort. Interruption safety needs a randomised comparator.
- Does interruption cost overall survival vs continuous ADT+ARPI active A Study of an Intermittent ADT Approach With Apalutamide Monotherapy in Participants With mCSPC Phase 3n=420 · primary completion 2026-10 · phase 3 intermittent vs continuous, rPFS non-inferiorityrecruiting Optimal PSA Triggered Individual Management of Androgen Sensitive Prostate Cancer Phase 2n=160 · primary completion 2030-10 · randomised intermittent relugolix+ARPI after PSA response
- Which responders recover testosterone and which do not active Comeback From Long coursE Androgen Deprivation Therapy (ADT) With RElugolix and Darolutamide (CLEARED) Phase 2n=33 · primary completion 2028-11 · 1° EP is T recovery rate after 2y relugolix+darolutamidenot yet Clinical Trial to Observe the Effects of Tamoxifen on Testosterone Recovery in Medically Castrated Prostate Cancer Patients Phase 2n=96 · primary completion 2030-10 · tamoxifen vs no tamoxifen for T recovery post-ADT
- Can metastasis-directed RT extend time off systemic therapy n=254 · primary completion 2031-08 · PSMA-guided SBRT added after 6mo darolutamide+ADT
📚 Sources · 🐦 1 tweet
Can treatment be safely stopped in selected patients with mHSPC?
— MJosé Juan (@mjuanfi81) May 30, 2026
Phase II A-DREAM trial, 41% of responders remained treatment-free with testosterone recovery 18m after stopping ADT/ARPI. At a median FU of 21 months, 35% of patients required treatment re-initiation.@OncoAlert pic.twitter.com/iW2VDBWWhN
ENZAMET + Decipher
FormHSPC on ADT + enzalutamide, Decipher score available
TL;DRDecipher >0.85 predicts docetaxel benefit in mHSPC on ADT+enza: HR(OS) 0.75 (0.43-1.33) vs 1.94 (0.95-3.96) if ≤0.85, interaction p=0.04.
In mHSPC starting ADT + enzalutamide with a Decipher score available, this offers hypothesis-level support for weighing docetaxel intensification above the 0.85 cut and for questioning it below; it does not extend to patients on other ARSIs or to those without genomic testing. The longer read
| Analysis | Lower Decipher (≤0.85) | Higher Decipher (>0.85) | Interaction p |
|---|---|---|---|
| Unweighted HR (95% CI) | 2.78 (1.49, 5.21) | 1.13 (0.71, 1.79) | 0.02 |
| Unweighted p-value | 0.001 | 0.60 | |
| IPTW weighted HR (95% CI) | 1.94 (0.95, 3.96) | 0.75 (0.43, 1.33) | 0.04 |
| IPTW weighted p-value | 0.07 | 0.33 |
+2 more figures
8 details
Post-hoc genomic-classifier analysis of the ENZAMET ADT + enzalutamide cohort, N=320, testing whether Decipher (DPMC) predicts docetaxel benefit. Docetaxel receipt was investigator-elected, not randomised, so a propensity-score IPTW model carries the comparison.
mHSPC on an ADT + enzalutamide backbone with an evaluable Decipher score, split at the prespecified 0.85 cut. A separate panel restricts to low-volume disease.
Overall survival, read two ways: prognostic (Decipher stratum on ADT + enza) and predictive (docetaxel-by-Decipher interaction).
Prognostic signal is the cleanest number on the slide deck: HR 3.02 (1.50-5.76) for DPMC >0.85 on ADT + enza. The predictive claim rests on the interaction, p=0.02 unweighted and p=0.04 after IPTW, not on either stratum reaching significance.
Docetaxel was not randomised within this cohort, so IPTW is doing the causal work and the authors concede residual imbalance after propensity scoring. Low-volume panel numbers are small (n at risk 14 and 13 in the reported strata) with a CI of 1.70 (0.32, 8.06), wide enough to be uninformative.
Presented as level 1B evidence consistent with CHAARTED and STAMPEDE, where docetaxel benefit concentrated in high-volume disease. This analysis proposes a genomic rather than volumetric selector for the same decision.
The strongest defensible claim is the prognostic one: DPMC >0.85 marks worse OS on ADT + enza. The predictive claim (add docetaxel above 0.85, omit it below) is directionally consistent across unweighted and weighted models but is not established by a single non-randomised interaction.
Post-hoc biomarker subgroup with non-randomised docetaxel use; both stratum HRs non-significant after weighting, residual imbalance conceded. Read rests on an interaction p=0.04.
- Prospective validation of Decipher-guided docetaxel selection in mHSPC
- Does the 0.85 cut hold on ARSI backbones other than enzalutamide
- Whether low Decipher predicts docetaxel harm or only absent benefit
📚 Sources · 🐦 1 tweet
#ASCO26 GU Oncology Spotlight 🚨
— Dra. María Natalia Gandur Quiroga (@nataliagandur) May 30, 2026
🔬 ENZAMET + Decipher | Part 2
Can genomics guide docetaxel intensification in mHSPC?
Outstanding presentation by @ChrisSweeney1.@OncoAlert@ASCO
After Part 1, the key question was:
➡️ Can a genomic classifier identify which patients with… pic.twitter.com/nJYMxuXelV
ARACOG (AFT-47)
ForAdvanced prostate cancer (mHSPC, nmCRPC, mCRPC) starting an ARSI
daro -15.8 vs enza -36.1
median % change in MCCD at 24 wks, P=0.009
TL;DREnzalutamide MCCD decline -36.1 vs -15.8 for darolutamide at 24wks (P=0.009) in randomized phase 2, N=111.
The comparison is between each pt's own worst-hit domain, and those differed by arm (PALFAM for daro, SWM for enza), so the read is how far the worst domain falls, not which one. Crossover before 24wks was scored at crossover inside the randomized arm, which attenuates rather than widens the gap. Moves ARSI selection when cognitive burden matters, not efficacy.
In a man starting an ARSI for mHSPC or nmCRPC where cognitive burden is a live concern, this supports darolutamide over enzalutamide on measured cognition; it does not speak to disease control, which was never compared head-to-head. The longer read
For ARSI selection where the two drugs are treated as equivalent on disease control, this puts a measured number on the cognitive difference (median MCCD -15.8 vs -36.1, P=0.009) instead of an AE-table impression. It moves drug choice, not sequencing or line of therapy.
| Metric | Darolutamide (N=48) | Enzalutamide (N=47) |
|---|---|---|
| Maximally changed module | PALFAM | SWM |
| Domain | Visual memory / executive function | Working memory / executive function |
| Median change, baseline to 24 wks | -15.8 | -36.1 |
| Between-arm P | P=0.009 | P=0.009 |
+2 more figures
8 details
Randomized open-label phase 2 from the Alliance for Clinical Trials in Oncology, N=111, stratified by age (<65, 65-80, >80). Enrolled 8/17/2021 to 3/11/2025, with CANTAB modules, PROMs and timed-up-and-go collected at 12 and 24 weeks.
Men with mCRPC, nmCRPC or mHSPC. Randomization was stratified by age across three bands (<65, 65-80, >80), so the design anticipated an older population. Baseline cognitive eligibility criteria not reported in source.
Darolutamide was provided by the study; enzalutamide was given through standard of care, so the two arms differed in drug supply as well as drug. Doses and concurrent ADT not reported in source.
Primary: % change from baseline to 24 weeks in the Maximally Changed Cognitive Domain (MCCD), drawn from 5 remotely delivered CANTAB modules (SWM, PALFAM, OTS, SSP, RVP) covering executive function, visual memory, attention and working memory. Blood for polygenic hazard score and AR testing, PROMs and timed-up-and-go were collected alongside.
Median MCCD change -15.8 with darolutamide (PALFAM) vs -36.1 with enzalutamide (SWM), P=0.009, across 48 and 47 pts in the primary analysis. No oncologic endpoint was reported in source.
The two drugs have never been compared head-to-head for efficacy, and cognition in ARAMIS and ARASENS (darolutamide) and PROSPER and ARCHES (enzalutamide) was captured as clinician-graded adverse events against placebo, not measured with a battery. Mild executive dysfunction is exactly the harm an AE table structurally misses.
Pts crossing over before 24 weeks carried their crossover score into the randomized arm, which should attenuate the gap rather than widen it. CANTAB is a research battery, not a clinical diagnostic, and no link to function, falls or discontinuation is reported in source. 24 weeks says little about years of therapy.
This shifts an argument that has run on mechanism and on AE tables onto measured performance. Where the two drugs are treated as interchangeable for disease control, cognition becomes a defensible tiebreaker. What it does not settle is whether an MCCD gap of this size is felt by the pt.
Randomized, prespecified primary endpoint met against a named comparator; open-label design and the composite MCCD construct temper it. Consistent with darolutamide's known limited CNS penetration.
- Whether the MCCD difference translates to function, falls, or discontinuation
- Durability of cognitive divergence beyond 24 weeks
- Whether apalutamide differs from enzalutamide on the same testing
📚 Sources · 🐦 2 tweets
#ASCO26 GU Oncology Spotlight 🚨
— Dra. María Natalia Gandur Quiroga (@nataliagandur) May 30, 2026
🔬 Abstract 5005 | ARACOG / AFT-47
Cognitive effects of darolutamide vs enzalutamide
Presented by Alicia K. Morgans, MD, MPH, FASCO@CaPsurvivorship @OncoAlert@ASCO
In prostate cancer, we often discuss AR pathway inhibitors through the lens… pic.twitter.com/vpZr1w6kc6
ARACOG (AFT-47) met its primary endpoint: enzalutamide caused significantly greater cognitive decline than darolutamide at 24 weeks in advanced prostate cancer.
— Katy Beckermann (@katy_beckermann) May 30, 2026
Randomized open-label phase 2, 111 pts (mHSPC, mCRPC, nmCRPC), DAR vs ENZ.
Cognition was measured with CANTAB, a… pic.twitter.com/kj4vfGRVyp
TALAPRO-3
ForHRR-deficient metastatic hormone-sensitive prostate cancer, enzalutamide/ADT candidates
HR 0.48
95% CI 0.36-0.65, P<0.001; 3yr rPFS 77% vs 56%
TL;DR3yr rPFS 77% vs 56%, stratified HR 0.48 (0.36-0.65), p<0.001, adding talazoparib to enzalutamide in HRR-deficient mCSPC.
In HRR-deficient metastatic prostate cancer starting enzalutamide plus ADT, this supports considering talazoparib upfront rather than reserving it, including for non-BRCA HRR alterations; it does not speak to HRR-proficient disease, which the trial excluded. The longer read
| Panel | Arm | Events/N | Median rPFS (95% CI), mo | HR (95% CI) |
|---|---|---|---|---|
| A ITT | Talazoparib+enzalutamide | 67/300 | NC (NC-NC) | 0.48 (0.36-0.65), P<0.001 |
| A ITT | Placebo+enzalutamide | 126/299 | 45.8 (37.7-NC) | |
| B BRCA | Talazoparib+enzalutamide | 22/104 | NC (NC-NC) | 0.37 (0.22-0.61) |
| B BRCA | Placebo+enzalutamide | 49/103 | 35.1 (18.6-NC) | |
| C Non-BRCA | Placebo+enzalutamide | 77/196 | NC (40.5-NC) | 0.57 (0.39-0.82) |
8 details 4 trials watching
Randomised, placebo-controlled phase 3 of talazoparib plus enzalutamide vs placebo plus enzalutamide, with ADT in both arms. ITT N=599 (300 vs 299), analysed as ITT with prespecified BRCA and non-BRCA subgroups.
HRR-deficient metastatic prostate cancer; the BRCA subgroup was 104 vs 103 and non-BRCA 196 vs 196, so BRCA carried roughly a third of the trial. Detailed eligibility and stratification factors are not reported in source.
Talazoparib added to an enzalutamide/ADT backbone that both arms received, so the comparison isolates the PARP inhibitor's contribution rather than the androgen-signaling backbone. Doses not reported in source.
Primary: imaging-based rPFS. Overall survival, safety and response endpoints are not reported in the source tweet or figure.
Landmark 3yr rPFS 77% vs 56%; median rPFS not reached in the talazoparib arm against 45.8 mo on placebo. Effect held in both molecular subgroups, numerically larger in BRCA (HR 0.37) than non-BRCA (HR 0.57).
| Population | Events/N talazoparib | Events/N placebo | Median placebo arm | HR (95% CI) |
|---|---|---|---|---|
| ITT | 67/300 | 126/299 | 45.8 (37.7-NC) | 0.48 (0.36-0.65) stratified |
| BRCA | 22/104 | 49/103 | 35.1 (18.6-NC) | 0.37 (0.22-0.61) unstratified |
| Non-BRCA | 45/196 | 77/196 | NC (40.5-NC) | 0.57 (0.39-0.82) unstratified |
TALAPRO-2 tested the same combination in first-line mCRPC across all comers; here the population is HRR-selected and the HR is numerically stronger. PROpel and MAGNITUDE established the PARP-plus-ARSI question in mCRPC, with MAGNITUDE's benefit confined to HRR-altered pts, which is the population this trial enrolled outright.
The talazoparib arm's median rPFS is NC (NC-NC) in both ITT and BRCA panels, so the absolute duration of benefit is unmeasured and the curves may still converge. No OS signal is available in source, and toxicity of the doublet (the practical cost of adding a PARP inhibitor to lifelong ARSI) is entirely absent from what was published in the thread.
The non-BRCA HR of 0.57 is the number that decides how wide this goes: if it holds, the case extends past BRCA to the broader HRR panel rather than collapsing to a BRCA-only result as earlier PARP trials did. What it does not settle is whether an rPFS gain of this size converts to survival, or whether the same result would follow sequential rather than upfront talazoparib.
CONSORT flow
Randomised double-blind phase 3, prespecified 1° rPFS hit with HR 0.48 in a biomarker-defined population, consistent across BRCA and non-BRCA. OS immature.
- Does the rPFS gain convert to overall survival n=1054 · primary completion 2022-10 · TALAPRO-2 mCRPC, mature OS readout of same combon=599 · primary completion 2026-02 · TALAPRO-3 itself; OS is a secondary endpoint
- Upfront combination vs sequential talazoparib after progression recruiting Talazoparib Plus Enzalutamide After Progression to Abiraterone in Metastatic Prostate Cancer: (TEAM PC) Phase 2n=78 · primary completion 2026-01 · talazoparib + enza 1L mCRPC after abiraterone PDrecruiting A Study of Talazoparib With or Without Enzalutamide in People With Prostate Cancer Who Have Previously Received Abiraterone Acetate Phase 2n=126 · primary completion 2029-03 · talazoparib +/- enza post-abiraterone, HRR-mutated
- Toxicity cost of indefinite PARP plus ARSI
📚 Sources · 🐦 1 tweet
JUST In: TALAPRO-3 published in @NEJM
— Toni Choueiri, MD (@DrChoueiri) May 30, 2026
Adding #talazoparib to enzalutamide/ADT
=>3-year rPFS: 77% vs 56% in HRR-deficient metastatic prostate cancer !
Looking forward to full presentation by @neerajaiims who keeps changing SOC, one trial at a time. @ASCO #ASCO26 @OncoAlert pic.twitter.com/nXiPk4DIXg
CHRYSALIS-2
ForTreatment-naive advanced NSCLC with atypical (uncommon) EGFR mutation
TL;DRMedian OS 41.0 mo (95% CI 27.7-NE) with 1L amivantamab + lazertinib in atypical EGFR-mutant NSCLC, single-arm n=49.
In treatment-naive advanced NSCLC with an atypical EGFR mutation, this supports amivantamab plus lazertinib as a prospectively benchmarked option where none is established; it does not extend to classical exon 19del/L858R disease or exon 20 insertions. The longer read
+1 more figure
8 details 3 trials watching
Single-arm expansion cohort of the CHRYSALIS-2 program, n=49, 1L atypical EGFR-mutated advanced NSCLC. Median follow-up 31.3 mo. No randomised comparator arm.
Treatment-naive advanced NSCLC harbouring an atypical (uncommon) EGFR mutation. Baseline strata shown on the swimmer plot include age ≥65y, Asian ancestry and CNS involvement; per-stratum counts are not reported in source.
IV amivantamab (EGFR/MET bispecific) plus lazertinib (third-generation EGFR TKI). No chemotherapy backbone. Median duration of treatment 13.3 months (range <0.1-53.2), with 39% of 1L participants still on treatment beyond 2 years.
Median OS 41.0 mo (95% CI 27.7-NE), described by the presenters as roughly 3.5 years. The upper CI bound is not estimable, so the point estimate is anchored on the lower bound of 27.7 mo.
Reported only as consistent with prior reports, no new safety signals with longer follow-up. No grade 3+ rates, infusion-reaction rates or dermatologic AE rates appear in the source.
The atypical EGFR label pools biologically distinct alterations (G719X, S768I, L861Q and compound variants) whose single-agent TKI sensitivity differs; n=49 cannot resolve per-variant benefit, and the curator's read of no variant-outcome association is an absence of signal in a small cohort, not evidence of uniformity. No comparator, so the 41.0 mo median cannot be positioned against afatinib or osimertinib series in the same population.
Atypical EGFR is the part of the EGFR-mutant space where no regimen is settled, so a 41.0 mo median in 49 pts is meaningful as a benchmark even without randomisation. The practical question this leaves open is whether the bispecific's added toxicity and IV schedule are justified over an oral TKI alone, which this design cannot answer.
Single-arm n=49 expansion cohort, no randomised comparator against afatinib or osimertinib in atypical EGFR. Maturity gate: single-arm never reaches confirmatory.
- Doublet vs single-agent osimertinib or afatinib in atypical EGFR n=480 · primary completion 2029-02 · phase 3 firmonertinib vs osimertinib/afatinib, PACC 1L
- Which atypical EGFR variants drive the durable-response tail
- Whether subcutaneous amivantamab preserves efficacy with less infusion burden n=418 · primary completion 2024-01 · phase 3 SC vs IV ami + lazertinib, randomisedrecruiting A Study of Amivantamab in Participants With Advanced or Metastatic Solid Tumors Including Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small Cell Lung Cancer Phase 2n=520 · primary completion 2027-08 · SC co-formulation activity + safety cohorts
📚 Sources · 🐦 1 tweet
Amivantamab + lazertinib achieved a median OS of 41.0 months in treatment-naïve atypical EGFR-mutant NSCLC, with no clear association between EGFR variant subtype and outcome. A compelling option. Meanwhile, amivantamab continues evaluation across multiple tumor types. #ASCO26 pic.twitter.com/aWn3Ja60Ji
— Chul Kim (@chulkimMD) May 29, 2026
ESAONA
For1L EGFR-mutant NSCLC with brain metastases
95.5% vs 79.6%
p = 0.0004
TL;DRiORR 95.5% vs 79.6% (p=0.0004) and intracranial PFS HR 0.46 favoring asandeutertinib in 1L EGFR-mutant NSCLC with brain mets.
The RT-relevant number is intracranial PFS: median not reached vs 17.5 mo, HR 0.46. If a first-line TKI holds CNS disease that long, the deferral-of-brain-RT window widens, but the source reports no prior-RT stratification, no CNS-RT use by arm, and no lesion size or symptom criteria, so this cannot yet gate an SRS-versus-defer decision.
In treatment-naive EGFR-mutant NSCLC with asymptomatic brain metastases, this supports the case for TKI-first CNS control as a hypothesis, not a change in practice; it says nothing about symptomatic or large lesions where local therapy is already indicated.
Intracranial PFS median not reached vs 17.5 mo, HR 0.46, is the number that touches the SRS-timing decision in asymptomatic brain mets. The source gives no prior-RT stratification and no salvage-RT rates by arm, so the deferral question stays open rather than answered.
The intracranial effect (HR 0.46) is roughly double the systemic one (HR 0.64), so the case for asandeutertinib rests on CNS penetration rather than broad potency. Serious TRAEs run 10.8% vs 7.1%, a real but modest trade against a phase II endpoint with no OS.
| Endpoint | Asandeutertinib (n=111) | Osimertinib (n=113) | Effect |
|---|---|---|---|
| Intracranial ORR (BICR) | 95.5% (89.8-98.5) | 79.6% (71.0-86.6) | p = 0.0004 |
| Intracranial PFS (BICR) | Median not reached | 17.5 mo (15.18-NA) | HR 0.46, p = 0.0020 |
| Overall PFS (BICR) | Median not reached | 17.2 mo (15.18-19.55) | HR 0.64, p = 0.0473 |
| Any TRAE | 99.1% | 95.6% | n/a |
| Serious TRAE | 10.8% | 7.1% | n/a |
7 details 4 trials watching
Randomised phase II, N=224, asandeutertinib (n=111) vs osimertinib (n=113). Endpoints read by BICR. Follow-up duration, stratification factors and alpha allocation are not reported in the source slide.
First-line EGFR-mutated NSCLC with brain metastases. The source does not state lesion number, size, symptom status, or whether prior CNS radiotherapy was permitted, which is the eligibility gate an RT reader needs.
Intracranial ORR by BICR is the headline, with intracranial PFS and overall PFS reported alongside. No overall survival data in source.
Any TRAE 99.1% vs 95.6%; serious TRAE 10.8% vs 7.1%. The excess serious-event rate is small in absolute terms but sits on a phase II denominator, and no organ-level breakdown is given in source.
The intracranial separation (HR 0.46) is larger than the systemic one (HR 0.64), which points at CNS penetration rather than a general potency gain as the mechanism. For radiation oncology the question is whether that CNS margin is durable enough to defer SRS in asymptomatic pts; a phase II with unreached medians and no OS cannot answer it.
CONSORT flow
Phase II, conference-slide source only; no OS, borderline overall-PFS p, and no reported CNS-RT or prior-RT stratification. Needs phase III before displacing osimertinib.
- Does intracranial PFS benefit translate to overall survival
- Salvage brain RT and SRS rates by arm recruiting Observation or Upfront Cranial RT in Oncogene Mutated NSCLC With Asymptomatic BM: A Phase III RCT Phase 3n=190 · primary completion 2025-12 · randomises upfront SRS/WBRT vs TKI alone, asx BMrecruiting A Study of Stereotactic Radiosurgery (SRS) and Standard Treatment in People With Lung Cancer That Has Spread to the Brain Phase 2n=56 · primary completion 2027-12 · SRS after 3mo osimertinib vs osimertinib alonerecruiting Early or Delayed Intervention of Brain Radiotherapy Combined With Almonertinib in EGFR Mutated NSCLC With Brain Metastases Phase 3n=232 · primary completion 2028-12 · early vs delayed SRS timing on 3G TKI, phase 3
- Activity in symptomatic or leptomeningeal CNS disease recruiting A Clinical Trial of Furmonertinib Combined With Anlotinib as First-line Treatment for Advanced NSCLC With EGFR-sensitive Mutations and Brain Metastasis Phase 2n=146 · primary completion 2027-09 · 1L 3G TKI + anlotinib, brain/LM mets at dx
📚 Sources · 🐦 1 tweet
#ASCO26 🧠🌍
— Dr Rishabh Jain (@DrRishabhOnco) May 30, 2026
Could a next-generation EGFR TKI outperform osimertinib in patients with brain metastases?
The phase II ESAONA trial suggests the answer may be yes.
🧪 LBA2007 | ESAONA
1L EGFR-mutated NSCLC with brain metastases
👥 n=224
⚔️ Asandeutertinib vs Osimertinib
Key… https://t.co/mEOKGNKgf7 pic.twitter.com/pUQuH6i2cV
OptiTROP-Lung05 NCT06448312
For1L stage IIIB-IV NSCLC, PD-L1 TPS ≥1%, EGFR/ALK wild-type, ECOG 0-1
HR 0.35
95% CI 0.26-0.47, p<0.0001; NR vs 5.7 mo
TL;DRmPFS NR vs 5.7mo, HR 0.35 (0.26-0.47) for sac-TMT + pembro in 1L PD-L1+ NSCLC.
In treatment-naive PD-L1 TPS ≥1% advanced NSCLC without EGFR/ALK alteration, this supports a TROP2 ADC plus pembro as a chemo-free option worth watching; it does not address pts already committed to pembro plus platinum chemo, nor PD-L1-negative disease. The longer read
| Arm | PFS events, n (%) | Median PFS, mo (95% CI) | HR (95% CI) |
|---|---|---|---|
| Sac-TMT + Pembro (n=208) | 66 (31.7) | NR (13.6, NE) | 0.35 (0.26, 0.47), p<0.0001 |
| Pembro (n=205) | 128 (62.4) | 5.7 (4.3, 7.0) | n/a |
+3 more figures
| PD-L1 stratum | Sac-TMT + Pembro median, mo | Pembro median, mo | HR (95% CI) |
|---|---|---|---|
| TPS ≥50% | NR (NE, NE) | 9.5 (6.9, 13.8) | 0.47 (0.29, 0.77) |
| TPS 1-49% | NR (11.1, NE) | 4.3 (2.9, 5.5) | 0.28 (0.19, 0.41) |
| Arm | OS events, n (%) | Median OS, mo (95% CI) | HR (95% CI) |
|---|---|---|---|
| Sac-TMT + Pembro (n=208) | 33 (15.9) | NR (NE, NE) | 0.55 (0.36, 0.85) |
| Pembro (n=205) | 54 (26.3) | NR (NE, NE) | n/a |
13 details 3 trials watching
Randomized, multicenter, open-label phase 3 (NCT06448312), 1:1, N=413. Stratified by histology (squamous vs non-squamous), PD-L1 TPS (1-49% vs ≥50%), and ECOG (0 vs 1). Median follow-up 10.5 months at this analysis.
Locally advanced stage IIIB/IIIC or metastatic stage IV NSCLC with no prior systemic antitumor therapy. Required PD-L1 TPS ≥1% by IHC 22C3 central lab, no sensitizing EGFR or ALK alteration, ECOG 0 or 1.
Sac-TMT 4 mg/kg Q2W plus pembrolizumab 400 mg versus pembrolizumab 400 mg Q6W alone, until progression or unacceptable toxicity. Pembro was capped at a maximum of 18 cycles in both arms. One pt in the pembro group never received assigned treatment.
PFS by BICR. Key secondary: OS. Other secondary: investigator-assessed PFS, ORR, DCR, DOR, safety. The updated efficacy boundary at the actual 194 PFS events was 0.0174 (2-sided).
PFS crossed its boundary at p<0.0001. OS was descriptive at the PFS interim, HR 0.55 (0.36, 0.85) with both medians not reached and only 33 vs 54 deaths.
The pembro-alone control performed as expected for an all-comers TPS ≥1% population, with the TPS ≥50% arm reaching 9.5 mo and the TPS 1-49% arm 4.3 mo, consistent with the KEYNOTE-042 signal that low-expressors gain least from single-agent IO. This is the setting where chemo-IO has historically been chosen, so the trial tests whether an ADC can occupy that slot instead of platinum doublet chemotherapy.
No toxicity data in the source, which is the decisive missing piece for a doublet whose entire premise is avoiding chemotherapy. The comparator is pembro monotherapy rather than the chemo-IO most oncologists actually give at TPS 1-49%, so the PFS gap partly measures a weak control rather than a strong experimental arm.
An HR of 0.35 with a median not reached is a large PFS effect, and the OS point estimate moves in the same direction, but neither settles whether sac-TMT plus pembro beats the regimen it would actually replace. The larger effect in TPS 1-49% (HR 0.28) than TPS ≥50% (HR 0.47) is the expected pattern when the control arm is weakest in the low-expressors, not evidence of a biomarker-selected ADC effect.
CONSORT flow
PFS interim of an open-label phase 3; OS descriptive at 10.5 mo f/u with both medians NR. No safety data in source, and no comparison vs pembro + chemo.
- Benefit vs pembrolizumab plus platinum chemotherapy, the real-world comparator n=614 · primary completion 2028-01 · phase 3 sac-TMT + pembro vs pembro alone, TPS >=50%, OSrecruiting Pembrolizumab With or Without Maintenance Sacituzumab Tirumotecan (Sac-TMT; MK-2870) in Metastatic Squamous Non-small Cell Lung Cancer (NSCLC) [MK-2870-023] Phase 3n=851 · primary completion 2029-01 · 1L sq NSCLC: pembro + platinum backbone, sac-TMT maint
- Safety and ILD rates of sac-TMT combined with pembrolizumab n=30 · primary completion 2026-12 · phase 1 safety/tolerability of sac-TMT + pembro
- Whether the OS signal holds at the final prespecified analysis
📚 Sources · 🐦 2 tweets
Right patient. Right treatment. Right timing.
— Yakup Ergün (@dr_yakupergun) May 30, 2026
The result: curves like these👇#ASCO26 https://t.co/72KByLKz90
🔁REVIEW #ASCO26 #LCSM Oral
— Hidehito HORINOUCHI (@HHorinouchi) May 30, 2026
🔥OptiTROP-Lung05: 1L Sac-TMT + Pembro vs Pembro in PD-L1+ NSCLC
✅mPFS NR vs 5.7m (HR 0.35)
✅ORR 70.2% vs 42.0%
✅OS HR 0.55 (95%CI 0.36-0.85, immature)
🎙️Dr. Caicun Zhou
🔗 https://t.co/DcbK1dGrhO@OncoAlert @Larvol @ASCO @IASLC https://t.co/512k6dZviW pic.twitter.com/Vdo86N50h9
NRG/RTOG 9804 + E5194 combined analysis (tamoxifen after lumpectomy, DCIS)
ForGood-risk DCIS, lumpectomy without RT, low/int grade, ≤2.5 cm, margins ≥3 mm
TL;DR15-yr IBR 11.4% vs 19.0% with vs without tamoxifen in good-risk DCIS treated by lumpectomy without RT; invasive IBR HR 0.43.
The association was confined to invasive events (DCIS-IBR p=0.089), which made up 65 of 117 IBRs. For the RT-omission discussion, the 11.4% 15-yr IBR on tamoxifen has no RT arm in this analysis to benchmark against, and which good-risk subgroups drive it sits in Fig 3, with subgroup HRs not in source text.
In low/intermediate-grade DCIS ≤2.5 cm with margins ≥3 mm managed without RT after lumpectomy, this supports tamoxifen as an invasive-IBR risk-reduction option in the omission discussion; it does not extend to high-grade DCIS or pts receiving RT. The longer read
For RT omission in good-risk DCIS, tamoxifen alone still left 15-yr IBR at 11.4%, and this analysis has no RT arm to benchmark it against. The reduction tracked invasive IBR (HR 0.43), while DCIS-IBR did not separate (p=0.089).
In good-risk DCIS managed without RT, tamoxifen associated with lower invasive IBR (HR 0.43, 0.24-0.77) but not DCIS-IBR (p=0.089). Dose, duration and adherence are not reported, and contralateral breast event results, the other half of the endocrine rationale, are not in source text.
9 details 1 trial watching
Ancillary exploratory analysis combining the non-RT arm of NRG/RTOG 9804, which randomized good-risk DCIS to RT or no RT, with the good-risk E5194 cohort observed without RT. Tamoxifen was optional and not randomized in either trial. Univariate and multivariable Fine-Gray models; median follow-up 14.85 yr.
N=878 (317 RTOG 9804, 561 E5194); median age 59 (28-88). Good-risk: low- or intermediate-grade, ≤2.5 cm, excision margins ≥3 mm, lumpectomy without RT.
Tamoxifen, optional per trial; used by 43.1% overall (65.6% RTOG 9804 vs 30.3% E5194). Dose, duration and adherence not reported in source.
No RT in the analyzed population. The RTOG 9804 RT arm is not part of this analysis, so tamoxifen alone is not compared against RT here.
IBR (any), invasive IBR, DCIS-IBR, contralateral breast event and overall survival. CBE and OS results are not reported in the source text.
117 IBRs (65 invasive, 52 DCIS). The reduction tracked invasive IBR, not DCIS-IBR.
| Endpoint | Tamoxifen | No tamoxifen | Effect |
|---|---|---|---|
| Any IBR, 15-yr estimate | 11.4% (7.9-15.5) | 19.0% (15.3-22.9) | p=0.001 |
| Any IBR, multivariable | n/a | n/a | HR 0.54 (0.35-0.83), p=0.0045 |
| Invasive IBR | not reported | not reported | p=0.0048; MVA HR 0.43 (0.24-0.77), p=0.0042 |
| DCIS-IBR | not reported | not reported | p=0.089 |
| Characteristic | Tamoxifen | No tamoxifen | p |
|---|---|---|---|
| Enrolled on NRG/RTOG 9804 | 55.0% | 21.8% | <0.0001 |
| Non-white | 13.8% | 9.2% | 0.034 |
| Negative re-excision | 27.2% | 10.6% | <0.0001 |
| Pathologic size ≤5 mm | 57.0% | 41.3% | <0.0001 |
NSABP B-24 randomized tamoxifen after lumpectomy plus RT, and the UK/ANZ DCIS trial randomized tamoxifen and RT in a factorial design. Here tamoxifen is examined only in good-risk pts managed without RT, and without randomization.
Multivariable covariates are not listed in source, and trial membership also differs in follow-up (13.87 vs 16.15 yr). The DCIS-IBR result (p=0.089) rests on 52 events and does not exclude an effect.
Tamoxifen use tracked lower invasive recurrence in good-risk DCIS managed without RT, consistent in direction with randomized tamoxifen data. It does not settle whether tamoxifen alone approaches RT, or how much of the gap reflects the lower-risk profile of users.
Exploratory ancillary analysis; tamoxifen optional, not randomized, and imbalanced by trial, re-excision and size. Parent RCT tested RT, not tamoxifen, so residual confounding limits causal read.
- Does tamoxifen alone approximate RT for IBR control in good-risk DCIS? recruiting Omission of Adjuvant Radiotherapy in Low- and Intermediate-Risk Ductal Carcinoma In Situ After Breast-Conserving Surgery Phase 3n=636 · primary completion 2031-06 · ph3 NI RT omission in ER+ low/int-grade DCIS, tamoxifen
- Which good-risk DCIS subgroups gain enough to justify tamoxifen?
- Is the lack of DCIS-IBR reduction real or underpowered?