2026-05-31

GI Lower

RT-first sequencing before chemo-IO in MSS metastatic rectal cancer, single-arm and with responses that fade (1-yr DOR 20%).

Early signal

MIRACLE-2

ForMSS rectal ca ≤10cm from anal verge, synchronous unresectable mets, 1L

Early tumor shrinkage (≥20% target lesion reduction at 8 weeks) surrogate

ETS 76.0%

95% CI 62.4%-86.8%; single-arm, no comparator

TL;DRORR 68%, mOS 23.2mo with upfront HFRT/SBRT then chemo + tislelizumab in MSS unresectable metastatic rectal ca; 18% reached NED.

Why it mattersRadiation oncology

The RT-relevant claim rests on sequencing: HFRT to primary AND HFRT/SBRT to metastases delivered BEFORE any systemic therapy, with 18% (9/50) converting to NED. Dose and fractionation are not reported in source, which blocks transfer to practice. G3/4 lymphopenia 36.7% is the cost of irradiating primary plus mets ahead of cytotoxics.

Monday clinic

In 1L MSS rectal cancer with synchronous unresectable liver or lung mets, this supports enrolling on a conversion-intent RT-first protocol rather than changing off-trial practice; it does not extend to resectable disease, MSI-high tumors, or non-rectal colon primaries.

The longer read

MIRACLE-2 — Outcome n (%) 95% CI

CR 1 (2.0%) n/a
PR 33 (66.0%) n/a
ORR 34 (68.0%) 53.6%-80.0%
DCR 44 (88.0%) 76.0%-95.2%
ETS 38 (76.0%) 62.4%-86.8%

Outcome	n (%)	95% CI
CR	1 (2.0%)	n/a
PR	33 (66.0%)	n/a
ORR	34 (68.0%)	53.6%-80.0%
DCR	44 (88.0%)	76.0%-95.2%
ETS	38 (76.0%)	62.4%-86.8%

10 details 3 trials watching

Design

Prospective single-arm phase I study at Fudan University Shanghai Cancer Center with a Fujian Cancer Hospital branch. Efficacy data available for N=50 as of Dec 31, 2025, median follow-up 19.9 months (95% CI 16.4-23.4). Reassessment every 8 weeks.

Population & inclusion

MSS rectal cancer with primary ≤10 cm from anal verge on MRI and synchronous unresectable metastases. 38 males (76.0%), median age 57 (range 30-73). Liver mets 52.0%, lung 8.0%, both 40.0%; RAS/BRAF mutant in 56.0%.

Radiotherapy

Hypofractionated RT to the primary and HFRT or SBRT to metastases, delivered first, before systemic therapy. Dose, fractionation and target volumes are not reported in source, so the RT prescription cannot be reproduced from this abstract.

Regimen

After RT: FOLFOX-bevacizumab-tislelizumab for RAS/BRAF-mutant pts, FOLFIRI-cetuximab-tislelizumab for wild-type. Tislelizumab 200mg Q2W. Median eight treatment courses (range 3-12). Resectable disease went to primary resection plus metastasectomy or local ablation; watch-and-wait was considered for cCR where sphincter preservation was not possible.

Endpoints

Primary: ETS rate (≥20% target lesion reduction at 8 weeks post systemic initiation). Secondary: DCR, DOR, OS, PFS, safety. Note the headline ORR and OS circulating with this abstract are secondary, not the registered primary.

Safety

No grade 5 TRAEs. All-grade lymphopenia 95.9%, anemia 91.8%, leukopenia 69.4%. G3/4: lymphopenia 36.7%, neutropenia 26.5%, leukopenia 20.4%. The marrow and lymphoid toxicity dominates, which is the expected signature of irradiating a pelvic primary plus liver/lung mets ahead of FOLFOX or FOLFIRI.

Applies to

first-line MSS rectal cancer with a low-lying primary and synchronous unresectable liver or lung metastases

Does not represent MSI-high tumors, resectable metastatic disease, colon primaries above 10 cm from the anal verge, or pts previously treated with systemic therapy.

Limitations

The RT prescription is absent from the abstract, so the intervention cannot be replicated. DOR median 8.0 months with a 1-year DOR rate of 20% sits awkwardly under a 68% ORR, and PFS 9.3 months against OS 23.2 months means most of the survival curve is post-progression, where subsequent lines rather than the studied regimen are acting.

Discussion

The trial's own conclusion claims only a high ETS rate and manageable safety, not an immune-resistance mechanism. Whether RT contributed anything beyond debulking is untestable in a single-arm design where every patient also received chemotherapy plus a PD-1 antibody.

Results

Endpoint	Median	95% CI	1-yr rate
OS	23.2 mo	15.1-31.3	93.3%
PFS	9.3 mo	7.1-11.5	33.4%
DOR (n=34 CR/PR)	8.0 mo	5.2-10.8	20%

Rationale

Single-arm phase I, N=50, no randomised comparator; median f/u 19.9mo with OS still immature. Hard maturity gate: single-arm never reaches confirmatory.

Open questions

Does RT add anything over chemo plus PD-1 alone in MSS mCRC?

recruiting Regorafenib Alone or in Combination With Hypofractionated/Low-dose Radiotherapy Plus Toripalimab for Metastatic Colorectal Cancer Phase 2

n=108 · primary completion 2025-04 · randomised: regorafenib +/- HFRT/LDRT + toripalimab

not yet A Combination Therapy Including Anti-PD-1 Immunotherapy in MSS Rectal Cancer With Resectable Distal Metastasis Phase 2

n=52 · primary completion 2027-09 · SCRT then tislelizumab combo, MSS rectal w/ mets
Durability beyond 1 year given 20% 1-yr DOR rate
Optimal RT dose and fractionation for primary plus metastases

recruiting Standard Systemic Therapy Combined With High/Low-dose Radiotherapy Plus Toripalimab for Metastatic Colorectal Cancer Phase 2

n=96 · primary completion 2026-12 · TORCH-M: high vs low-dose RT + toripalimab, MSS mCRC

Sourced from @NiuSanford

📚 Sources · 🐦 1 tweet

MIRACLE-2: RT to primary/mets -> chemo + tislelizumab in MSS unresectable met rectal ca (N=50): 68% ORR & median OS 23 mo.

Early, single-arm data, but ~1 in 5 pts reached NED.

Suggests RT + systemic + PD1 blockade could overcome immune resistance in MSS mCRC. #ASCO26 @OncoAlert pic.twitter.com/sjnUW8x7f3
— Dr. Nina Niu Sanford (@NiuSanford) May 31, 2026

Combined Palliative Phase 1 Early signal

Prostate

Three RT-relevant reads in one day: a positive local-control add-on, a negative AR-intensification trial, and a proton-vs-photon comparison where the spacer, not the beam, moved GI toxicity.

Confirmatory

COMPPARE

ForDe novo localized prostate cancer, excluding very high risk and metastatic

Patient-reported bowel urgency (EPIC) safety

5.7% vs 6%

P=0.28, hypothesized 7% vs 15%

TL;DRProton vs IMRT: no difference in bowel urgency (5.7% vs 6%), ≥G2 GI toxicity (5.2% vs 5.6%), or 3yr disease control.

Why it mattersRadiation oncology

The spacer table is the actionable finding, not the modality comparison: 2yr GI G2+ fell to 4.4% (IMRT) and 4.7% (proton) with a spacer vs 7.2% and 8.7% without, P=0.009. Rectal separation, available at any IMRT center, delivered what particle therapy did not.

Monday clinic

In de novo localized prostate cancer outside very high risk, this argues the rectal-sparing decision sits with spacer placement rather than referral to a proton center; it says nothing about late GU endpoints or very high risk disease.

The longer read

COMPPARE — Outcome Hypothesized IMRT Hypothesized PT Actual IMRT Actual PT P-value

Bowel urgency 15% 7% 6% 5.7% 0.28
Bowel frequency 10% 4% 4% 3.5% 0.43
GI toxicity CTCAEv5 ≥2 29% 20% 5.6% 5.2% 0.60
Freedom from progression 3yr 89% 91% 97.9% 98.0% 0.90

Outcome	Hypothesized IMRT	Hypothesized PT	Actual IMRT	Actual PT	P-value
Bowel urgency	15%	7%	6%	5.7%	0.28
Bowel frequency	10%	4%	4%	3.5%	0.43
GI toxicity CTCAEv5 ≥2	29%	20%	5.6%	5.2%	0.60
Freedom from progression 3yr	89%	91%	97.9%	98.0%	0.90

+2 more figures

Group	2yr cumulative CTCAE v5 GI G2+	P
IMRT, no spacer	7.2% (5.0%, 9.9%)	0.009
Proton, no spacer	8.7% (5.0%, 14%)
IMRT, spacer	4.4% (2.8%, 6.4%)
Proton, spacer	4.7% (3.6%, 6.0%)

Study schema: 2524 accrued, proton cohort 1500, photon cohort 1000, 51 centers, July 2018 to October 2022.

8 details 4 trials watching

Design

Prospective nonrandomised comparative-effectiveness cohort study funded by PCORI, comparing proton therapy and IMRT across 51 centers. Accrual 2524 pts from July 2018 to October 2022, allocated to a proton cohort (1500) and a photon cohort (1000).

Population & inclusion

All de novo prostate cancer except very high risk and metastatic. The exclusion is the boundary that matters: the pts in whom elective nodal coverage and integral dose arguments are strongest were never enrolled.

Endpoints

Primary: patient-reported bowel urgency and bowel frequency (EPIC) and CTCAE v5 ≥G2 GI toxicity, each powered at 90%. Freedom from disease progression at 3 years (PSA) was exploratory, not powered.

Results

Every prespecified comparison was null. The more telling result is that observed rates undershot the design assumptions in both arms: ≥G2 GI toxicity 5.6% IMRT and 5.2% proton against 29% and 20% hypothesized.

Safety

Rectal spacer use separated the toxicity curves where modality did not. 2yr cumulative ≥G2 GI toxicity was 4.4% (2.8%, 6.4%) IMRT with spacer and 4.7% (3.6%, 6.0%) proton with spacer, vs 7.2% (5.0%, 9.9%) and 8.7% (5.0%, 14%) without, P=0.009 by Gray's test.

Applies to

de novo localized prostate cancer treated at a proton or IMRT center between 2018 and 2022, with spacer available

Does not represent very high risk or metastatic disease, and does not speak to endpoints beyond 3 years.

vs leading data

The ≥G2 GI rates here are far below the toxicity burden that motivated the proton hypothesis, and align with the modern IMRT plus spacer experience rather than the older photon series the 29% assumption was drawn from.

Limitations

Cohort allocation, not randomisation, so the arms differ by referral pattern, geography, and insurance in ways baseline adjustment cannot fully absorb. The unequal cohort sizes (1500 vs 1000) reflect enrollment at proton-capable centers, not a design ratio.

Discussion

A null comparative-effectiveness result in a low-event setting is weak evidence of equivalence and strong evidence that the toxicity target moved. The question the field now needs answered is late toxicity and second malignancy, which 3 years cannot address.

Rationale

Nonrandomised prospective cohort comparison; residual confounding unaddressable. Null on every prespecified endpoint, but 3yr follow-up cannot capture the late toxicity protons are argued to prevent.

Open questions

Late GI and GU toxicity beyond 3 years

active Mild Hypofractionation With Proton Therapy or IMRT for Intermediate-Risk Prostate Cancer

n=303 · primary completion 2026-12 · proton vs IMRT hypofx registry, f/u to 2026

recruiting Protons Vs. Photons for High-risk Prostate Cancer Phase NA

n=400 · primary completion 2027-03 · randomised proton vs photon, late GI primary EP

recruiting Reduction of Gastrointestinal Toxicity in Prostate Cancer by Proton Spot Placement Phase NA

n=500 · primary completion 2030-01 · proton LET vs rectal/bladder toxicity, n=500
Second malignancy risk from integral dose
Whether protons add anything once a spacer is placed

recruiting Rectal Spacers Use in Prostate Cancer Radiation Therapy Phase NA

n=50 · primary completion 2025-09 · 2-arm spacer trial in pts planned for proton

Sourced from @QianJanieQin

📚 Sources · 🐦 1 tweet

#COMPPARE early results: in localized #ProstateCancer, #proton therapy vs #IMRT showed no sig difference in pt-reported bowel urgency/frequency, ≥G2 GI toxicity, or 3-year biochemical control. Longer follow-up needed for late toxicity/long term outcomes #ASCO2026 pic.twitter.com/yli4l8nEOY
— QianJanieQin (@QianJanieQin) May 31, 2026

Radiation Curative Real-world evidence Confirmatory

Early signal

CAN-2409 NCT01436968

ForIntermediate or high-risk localised prostate, planned definitive EBRT, ECOG 0-2

TL;DRDFS median NR vs 86.1mo, HR 0.70 (0.52-0.94), p=0.016, adding intraprostatic gene therapy to definitive EBRT.

Why it mattersRadiation oncology

The RT read is local persistence: 2yr post-Rx biopsy positivity 19.6% vs 36.4% (p=0.0015), the mechanism behind the DFS curve. That sits in the same range dose intensification already buys (FLAME crude local failure 2.7% vs 7.7%), and ADT was optional and unreported by arm, so whether the gain survives a modern 78Gy-plus-boost, ADT-intensified plan is untested.

Monday clinic

In intermediate or high-risk localised prostate going to definitive EBRT, this supports an added intraprostatic strategy for local persistence but competes with dose intensification the trial did not use; it says nothing about pts already receiving a brachy or SIB boost.

The longer read

Endpoint CAN-2409 Placebo Effect

DFS (median) NR 86.1 mo HR 0.7 (0.52-0.94), p=0.0155
2yr post-Rx biopsy pCR 80.4% 63.6% n/a
2yr local persistence/recurrence 19.6% 36.4% p=0.0015
Overall survival Not significantly different Not significantly different median f/u 50.3mo
PCSM 1 event 1 event Not significantly different

Endpoint	CAN-2409	Placebo	Effect
DFS (median)	NR	86.1 mo	HR 0.7 (0.52-0.94), p=0.0155
2yr post-Rx biopsy pCR	80.4%	63.6%	n/a
2yr local persistence/recurrence	19.6%	36.4%	p=0.0015
Overall survival	Not significantly different	Not significantly different	median f/u 50.3mo
PCSM	1 event	1 event	Not significantly different

+1 more figure

Trial	Comparison	Local endpoint	Control	Experimental
RTOG 9408	RT 66.6Gy +/- 4m ADT	2yr post-Rx biopsy positive	40%	20%
ASCENDE-RT	RT 46Gy + DE-EBRT 23Gy vs RT 46Gy + LDR-BT (I-125)	10y local failure	7.1%	1.5%
FLAME	RT 77Gy vs RT 77Gy + SIB 95Gy	Crude local failure	7.7%	2.7%
CAN-2409	RT 78Gy + placebo vs RT 78Gy + CAN-2409	2yr post-Rx biopsy positive	36.4%	19.6%

11 details 3 trials watching

Design

Phase 3, randomised 2:1, double-blind, placebo-controlled across 51 US and Puerto Rico centres (26 community, 25 institutional or military). Enrolment ran Feb 21, 2012 to Sept 9, 2021; median follow-up 50.3 months (IQR 35.2-63.3).

Population & inclusion

Men aged 18+ with intermediate or high-risk localised prostate cancer planning EBRT, ECOG 0-2. N=745 (496 aglatimagene, 249 placebo); 591 (79%) White, 121 (16%) Black. Randomisation stratified by risk category and ADT use.

Regimen

Three courses of intraprostatic aglatimagene besadenovec 5 × 10^11 viral particles plus oral valacyclovir prodrug, versus placebo plus valacyclovir. ADT was optional in both arms.

Radiotherapy

Standard-of-care EBRT at investigator discretion: 78 Gy in 2 Gy fractions, or hypofractionated 60 Gy in 3 Gy or 70 Gy in 2.5 Gy. No boost strategy (brachytherapy or SIB) was specified, and target volume was not reported in source.

Endpoints

Primary: disease-free survival, time from randomisation to prostate cancer recurrence or death, ITT. Safety assessed in all who received at least one injection. Discussant flagged MFS and biochemical recurrence as not reported.

Results

Median DFS not reached (95% CI 121.78 to NR) versus 86.1 months, HR 0.70 (0.52-0.94), p=0.016. Two-year post-treatment biopsy positivity 19.6% vs 36.4% (p=0.0015). OS and PCSM showed no significant difference, with one PCSM event per arm.

Event	Aglatimagene (n=479)	Placebo (n=232)
Grade 3+ TEAE	40 (8%)	17 (7%)
Acute kidney injury G3+	9 (2%)	4 (2%)
Serious AE	28 (6%)	17 (7%)
Treatment-related SAE	8 (2%)	5 (2%)

Safety

Grade 3+ TEAEs 40/479 (8%) vs 17/232 (7%); most common was acute kidney injury in both arms (9 [2%] vs 4 [2%]). Treatment-related serious AEs in eight (2%) versus five (2%). No treatment-related deaths.

vs leading data

The discussant set the biopsy signal against the field's established local-control levers: RTOG 9408 (2yr biopsy positive 40% to 20% with 4mo ADT), ASCENDE-RT (10y local failure 7.1% to 1.5% with an LDR boost) and FLAME (crude local failure 7.7% to 2.7% with a 95Gy SIB). Each buys local control the reader can already deliver.

Applies to

intermediate and high-risk localised prostate treated with definitive EBRT to 60-78 Gy with optional ADT

Does not represent pts staged with PSMA PET, receiving a brachytherapy or SIB boost, or receiving ARSI intensification.

Limitations

The nine-and-a-half-year accrual window straddles the field's move to hypofractionation, PSMA PET staging and ARSI intensification, so the control arm's 86.1-month DFS reflects an older standard. ADT use was a stratification factor but is not reported by arm in source, leaving the interaction between the viral therapy and hormonal control unresolved.

Discussion

The result establishes that intraprostatic immunotherapy can reduce residual local disease at two years, which is a real mechanistic finding. What it does not settle is whether that reduction is additive to, or merely duplicative of, the local control a modern boost already delivers, and whether it converts to survival: OS and PCSM sit at one event per arm.

Enrolment

CONSORT flow

Randomized 745

↓

Aglatimagene + valacyclovir

allocated 496

Median DFS not reached

Placebo + valacyclovir

allocated 249

Median DFS 86.1 mo

Rationale

DFS driven by a 2yr biopsy endpoint; OS and PCSM immature (1 event per arm). Accrual spanned 9.5yr of changing RT dose intensification and staging.

Open questions

Additive value over brachytherapy or SIB dose intensification

active A Study of MRI-guided High-dose Radiation Therapy in Prostate Cancer Phase 2

n=91 · primary completion 2026-08 · phase 2 MRI-guided DIL boost, recurrence endpoint

recruiting Evaluation of Tumor Control Based on Serial Multiparametric MRI and Post-Treatment Biopsies For Patients Treated With Dose Intensification to the Dominant Intra-Prostatic Lesion (DIL) Using Ultra-Hypofractionated, MR-Guided Radiotherapy Phase NA

n=91 · primary completion 2027-12 · DIL boost read out by post-treatment biopsy control

recruiting PRO-BOOST-LC: Whole-Gland Boost Strategies Versus SBRT Monotherapy in PSMA-Staged Localized and Locally Advanced Prostate Cancer Phase 2/3

n=1000 · primary completion 2033-12 · randomises HDR/LDR brachy or SBRT boost vs SBRT alone
Whether DFS gain converts to OS or PCSM benefit
Effect in ADT-treated versus ADT-free strata

Sourced from @MikeSerzanMD, DeWeese, Theodore L et al.

📚 Sources · 🐦 1 tweet · 📄 1 paper

🗣️Prostate Oral Abstract #ASCO25

👉Dr @angela_jia_ discusses "Better Treatments, Better Selection: Improving Patient Outcomes in Localized Prostate Cancer"

🔑 KEY TAKE AWAYS
- #CAN2409 improves DFS and 2yr PathCR however PCSM and OS remain immature.
❓How to integrate with… pic.twitter.com/WamsneYBI1
— Michael Serzan, MD (@MikeSerzanMD) June 3, 2025

📄 PAPER DeWeese, Theodore L; Manzanera, Andrea; Sylvester, John et al. · The Lancet Oncology (2026-06)

Aglatimagene besadenovec (CAN-2409) with radiotherapy for patients with localised prostate cancer: a phase 3, multicentre, randomised, double-blind, placebo-controlled trial

doi

Abstract

Background About 30% of men with localised prostate cancer undergoing radiotherapy with curative intent have disease recurrence associated with progression-related symptoms and substantial toxicity of salvage therapies. Previous studies with aglatimagene besadenovec (CAN-2409, hereafter referred to as aglatimagene) showed synergy with radiation and immune-mediated cytotoxicity in patients with prostate cancer. We aimed to assess whether addition of aglatimagene plus prodrug (valacyclovir) to standard-of-care external beam radiation therapy (EBRT) could improve disease-free survival in this population. Methods We conducted a phase 3, randomised, double-blind, placebo-controlled trial at 51 medical centres (26 community and 25 institutional or military) across the USA and Puerto Rico in patients with intermediate or high-risk prostate cancer. Patients aged at least 18 years who were planning to undergo EBRT and with an Eastern Cooperative Oncology Group score of 0-2 were eligible. Patients were randomly assigned (2:1) via central block-randomisation to receive either three courses of intraprostatic aglatimagene (5 × 10 11 viral particles) plus valacyclovir or placebo plus valacyclovir, with randomisation stratified by risk category and androgen deprivation therapy (ADT) use. Patients received standard-of-care EBRT (78 Gy in 2 Gy fractions) or hypofractionated EBRT (60 Gy in 3 Gy fractions or 70 Gy in 2·5 Gy fractions) with optional ADT. The primary endpoint was disease-free survival, defined as time-from-randomisation to prostate cancer recurrence or death in the intent-to-treat population (all randomly assigned patients). Safety was assessed in all individuals who received at least one injection. The trial is registered at ClinicalTrials.gov, NCT01436968, and long-term follow-up is ongoing. Findings Between Feb 21, 2012, and Sept 9, 2021, 745 men (591 [79%] White, 121 [16%] Black) were randomly assigned to receive aglatimagene plus valacyclovir (n=496) or placebo plus valacyclovir (n=249). After a median follow-up of 50·3 months (IQR 35·2-63·3), median disease-free survival was not reached (95% CI 121·78 to not reached) in the aglatimagene plus valacyclovir group versus 86·1 (IQR 29·7-143·0) months in the placebo plus valacyclovir group (hazard ratio 0·70, 95% CI 0·52-0·94; p=0·016). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 40 (8%) of 479 patients in the aglatimagene group and 17 (7%)of 232 patients in the placebo group. The most common TEAE of grade 3 or worse was acute kidney injury in both the aglatimagene group (nine [2%] of 479 patients) and the placebo group (four [2%] of 232 patients). Serious adverse events occurred in 28 (6%) of 479 patients in the aglatimagene group and 17 (7%) of 232 in the placebo group. Treatment-related serious adverse events occurred in eight (2%) patients in the aglatimagene group (four acute kidney injury, two pyrexia, and one each influenza-like symptoms and urinary retention) and five (2%) in the placebo group (four acute kidney injury, and one each increased creatinine levels and skin rash; one patient reported two serious adverse events). No treatment-related deaths were reported. Interpretation Aglatimagene plus valacyclovir was associated with longer disease-free survival than placebo plus valacyclovir when added to standard of radiotherapy for the treatment of localised prostate cancer, offering a meaningful benefit without increasing clinically significant toxicity. Funding Candel Therapeutics and US National Institutes of Health.

📝 https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(26)00071-9/fulltext

Combined Curative Phase 3 RCT Early signal

Unclear

PROTEUS

TL;DRMost distant metastases were PSMA PET-detected (53.0% apalutamide, 60.7% comparator); no EFS or MFS effect size in source.

Why it mattersRadiation oncology

53.0% of distant mets in the apalutamide group were PSMA PET-detected vs 60.7% in the comparator, so the arms differ in how events were found, not only how often. MFS surrogacy was built in the conventional-imaging era, which is the read this complicates. No effect size in source.

Also covered Aug 29

8 details

Endpoints

MFS event ascertainment was PSMA PET-dominant: 53.0% of distant metastases in the apalutamide group and 60.7% in the comparator were identified by PET rather than conventional imaging. EFS is named in the thread, but no effect size for either endpoint appears in the source.

Discussion

The contested question is whether a PET-detected metastasis is the same event MFS was built to count. A commentator's hypothetical, explicitly not trial data, models 100 pts per arm with 60 BCRs on ADT alone and 50 on apalutamide plus ADT to show how differential detection alone can widen an apparent gap.

Limitations

The NEJM sentence quoted in the thread is truncated, so the 60.7% figure's arm label is inferred from a two-arm comparison rather than read directly. The full presentation has not occurred, and the source gives no phase, N, follow-up, or eligibility.

Rationale

Results online but the source thread carries no EFS or MFS effect size, so no strength bucket is defensible; ascertainment concern noted, not adjudicated.

Open questions

Whether the MFS separation holds under conventional-imaging-only ascertainment
Does the EFS signal translate to overall survival
How PSMA PET stage migration should be handled in MFS endpoints

Sourced from @DrSpratticus, @seanmmcbride

📚 Sources · 🐦 3 tweets

#ASCO26
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…
— Daniel E Spratt (@DrSpratticus) May 31, 2026

📝 Note until the trial is released later this is preview

Thought experiment:

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
— Sean McBride (@seanmmcbride) May 31, 2026

📝 note add commentary to proteus discussion

#ASCO26
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
— Daniel E Spratt (@DrSpratticus) May 31, 2026

📝 add to proteus data

Systemic Unclear

GI Upper

A systemic result with no RT component: daraxonrasib roughly doubles 2L mOS in RAS G12 pancreatic.

Practice-changing

RASolute 302

ForPreviously treated metastatic pancreatic adenocarcinoma, RAS G12-mutant

Overall survival (RAS G12 population)

13.2 vs 6.6 mo

HR 0.40 (95% CI 0.30-0.54), P<0.001

TL;DRmOS 13.2 vs 6.6mo, HR 0.40 (0.30-0.54), P<0.001 for daraxonrasib vs chemo in RAS G12 2L metastatic pancreatic.

Monday clinic

In previously treated metastatic pancreatic cancer with a RAS G12 mutation, this supports RAS(ON) multi-selective inhibition over investigator's choice chemotherapy in the second line; it does not speak to untreated disease, to RAS wild-type tumors, or to any role alongside radiotherapy.

The longer read

RASolute 302 — Population / arm N Events (%) Median OS (95% CI), mo 12-mo OS HR (95% CI) P

RAS G12 · daraxonrasib 228 72 (32) 13.2 (10.0-NR) 53.3 0.40 (0.30-0.54) <0.001
RAS G12 · chemotherapy 231 127 (55) 6.6 (5.4-8.2) 8.7 n/a n/a
Overall · daraxonrasib 248 79 (32) 13.2 (10.0-NR) 53.2 0.40 (0.30-0.53) <0.001
Overall · chemotherapy 252 141 (56) 6.7 (5.8-8.0) 17.3 n/a n/a

Population / arm	N	Events (%)	Median OS (95% CI), mo	12-mo OS	HR (95% CI)	P
RAS G12 · daraxonrasib	228	72 (32)	13.2 (10.0-NR)	53.3	0.40 (0.30-0.54)	<0.001
RAS G12 · chemotherapy	231	127 (55)	6.6 (5.4-8.2)	8.7	n/a	n/a
Overall · daraxonrasib	248	79 (32)	13.2 (10.0-NR)	53.2	0.40 (0.30-0.53)	<0.001
Overall · chemotherapy	252	141 (56)	6.7 (5.8-8.0)	17.3	n/a	n/a

9 details 4 trials watching

Design

Randomised comparison of daraxonrasib against investigator's choice chemotherapy in previously treated metastatic pancreatic cancer, reported as ASCO 2026 Abstract LBA5. Two co-reported populations: RAS G12 (n=459) and an overall population (n=500) that adds G13, Q61 and tumors with no RAS mutation identified. Hazard ratios from a stratified Cox model, P values from stratified log-rank.

Population & inclusion

Previously treated metastatic pancreatic cancer. The G12 population carried RAS G12 mutations; the overall population also admitted G13, Q61, and patients in whom no RAS mutation was identified. Line of prior therapy, performance status and prior regimen are not given in the source.

Endpoints

Primary read here is overall survival, reported separately for the RAS G12 and overall populations. No PFS, response or safety endpoint appears in the source figure.

Results

OS 13.2 vs 6.6 mo in RAS G12, HR 0.40 (0.30-0.54), P<0.001; the overall population is nearly identical at 13.2 vs 6.7 mo, HR 0.40 (0.30-0.53). Only 32% of daraxonrasib patients had died versus 55-56% of chemotherapy patients, and the experimental median's upper CI bound is not reached, so the estimate can still move.

Applies to

previously treated metastatic pancreatic cancer with a RAS G12 mutation

Does not represent untreated or locally advanced disease, and the source gives nothing on RAS wild-type tumors analysed separately.

vs leading data

Second-line metastatic pancreatic cancer has sat near six months' median OS since NAPOLI-1, and the 6.6 mo control arm here reproduces that benchmark rather than undercutting it. The experimental arm roughly doubles it, which is a larger step than any second-line systemic result in this disease to date.

Limitations

The whole read rests on one OS figure from a conference thread: crossover, chemotherapy-arm composition and the safety profile are absent, and any of the three could change how the survival curve should be read. The 12-mo OS gap between the two control populations (8.7% vs 17.3%) is wide enough to deserve explanation when the full report lands.

Discussion

The result's strength is its concordance: an identical HR 0.40 in the mutation-selected and all-comers populations means the benefit is not an artefact of subgroup selection. What it does not settle is durability, since the experimental median is immature, nor whether the effect holds in patients without an identified RAS mutation, who were pooled into the overall population rather than reported on their own.

Rationale

Randomised, OS primary, HR 0.40 with concordant effect in G12 and all-comers. Source is a conference OS figure only; safety and PFS unverified here.

Open questions

Durability beyond the immature 13.2mo median

active Phase 3 Study of Daraxonrasib (RMC-6236) in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC) Phase 3

n=500 · primary completion 2026-06 · the same phase 3, primary completion 2026-06

recruiting Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma Phase 3

n=900 · primary completion 2028-06 · daraxonrasib +/- GnP moved to 1L metastatic

recruiting Study of Daraxonrasib (RMC-6236) in Patients With Resected Pancreatic Ductal Adenocarcinoma (PDAC) Phase 3

n=500 · primary completion 2029-05 · daraxonrasib vs observation after R0/R1 resection
Activity in tumors with no identified RAS mutation

not yet A Pan-RAS Inhibitor in Combination With Anti-Tumor Therapy in Participants With Advanced Pancreatic Cancer Phase 1/2

n=80 · primary completion 2028-08 · pan-RAS HRS-2329, RAS mutation OR amplification
Safety and tolerability profile, absent from source

Sourced from @GIMedOnc

📚 Sources · 🐦 1 tweet

#ASCO26

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
— Nicholas Hornstein (@GIMedOnc) May 31, 2026

Systemic Palliative Phase 3 RCT Practice-changing

Thoracic / Lung

Registry data putting sequential ahead of concurrent iRT in advanced NSCLC, with no RT dose, target or pneumonitis data to transfer it to a plan.

Early signal

OCEANUS

ForAdvanced or refractory NSCLC receiving both RT and an ICI

Real-world overall survival

20.3 vs 16.0 mo

aHR 0.68, 95% CI 0.47-0.99, P=.045 (sequential vs concurrent)

TL;DRSequential iRT beat concurrent for OS in newly diagnosed advanced NSCLC (20.3 vs 16.0 mo, aHR 0.68, P=.045); territory-wide cohort.

Why it mattersRadiation oncology

For an RT reader the actionable variable is timing, and the only signal here favors giving RT sequentially rather than concurrently with ICI (20.3 vs 16.0 mo, aHR 0.68). But the source reports no dose, fractionation, target volume or pneumonitis rate, so the parameter that would let you transfer this to a plan is absent.

Monday clinic

In newly diagnosed advanced NSCLC already going on an ICI who also need thoracic or palliative RT, this weakly supports separating RT from the ICI start rather than overlapping them; it says nothing about stage III unresectable chemoRT-plus-durvalumab, where the concurrent-then-consolidation standard is randomized.

The longer read

13 details 3 trials watching

Design

Territory-wide retrospective cohort (OCEANUS) using the Hong Kong Hospital Authority CDARS, covering more than 90% of the population. Propensity score overlap weighting was the primary method with IPTW for sensitivity; analysis ran December 2024 to April 2025. Landmark analysis was applied, and refractory pts had to survive at least 90 days.

Population & inclusion

NSCLC diagnosed January 1, 2010 to December 31, 2021 who subsequently received iRT for advanced or refractory disease. Of 3522 pts who received ICIs, 335 received RT: 155 newly diagnosed advanced and 180 refractory. 247 (73.7%) male, median age 64 (range 34-90).

Radiotherapy

The exposure is RT timing relative to ICI, sequential vs concurrent, in newly diagnosed disease, and RT with vs without ICI maintenance in refractory disease. Dose, fractionation, modality, target volume and irradiated site are not reported in the source, which is the gap that limits transfer to a specific plan.

Endpoints

Primary: real-world OS after landmark, estimated with weighted Kaplan-Meier and Cox models. Where proportional hazards were violated per Schoenfeld residuals, effects were summarized with restricted mean survival time.

Results

Sequential iRT carried longer OS than concurrent in newly diagnosed advanced disease, aHR 0.68 (0.47-0.99), P=.045. In refractory disease the ICI-maintenance difference was not significant (P=.20), and added chemotherapy showed no significant OS association there.

vs leading data

PACIFIC established consolidation durvalumab after concurrent chemoRT in stage III unresectable disease, and PEMBRO-RT and MDACC randomized data tested RT added to pembrolizumab in metastatic disease, but none of these randomize sequential against concurrent iRT in advanced NSCLC. That question has no randomized answer, which is why a 155-pt weighted cohort is currently among the larger reads on it.

Applies to

advanced or refractory NSCLC pts in a Hong Kong territory-wide system who received both an ICI and RT between 2010 and 2021

Does not represent stage III unresectable pts treated on the PACIFIC paradigm, nor pts whose RT dose, site or intent would differ from an unreported and heterogeneous real-world mix.

Limitations

Timing was clinician-assigned, so pts pushed to concurrent RT plausibly had more urgent, symptomatic or bulky disease, an indication bias that overlap weighting on recorded covariates cannot remove. The 2010-2021 window also mixes ICI eras, agents and lines, and the source reports no toxicity, so the pneumonitis risk that motivates avoiding concurrency is unmeasured here.

Discussion

The result argues that separating RT from ICI administration does not cost survival and may favor it, which is the opposite of the abscopal-synergy rationale often used to justify concurrency. It does not establish causality, define an interval, or identify which pts the timing matters for.

Rationale

Retrospective propensity-weighted registry cohort, 155 pts in the primary comparison, P=.045 with CI touching 1.0. Authors themselves call it hypothesis generating.

Open questions

Optimal interval between RT and ICI administration

active Concurrent or Sequential Immunotherapy and Radiation Therapy in Patients With Metastatic Lung Cancer Phase 1

n=78 · primary completion 2026-12 · randomises seq vs concurrent SBRT + nivo/ipi in stage IV
Whether concurrent iRT increases pneumonitis in advanced NSCLC

recruiting Predictive Biomarkers for Pneumonitis After Chemoradiotherapy and Immunotherapy in Patients With Non-small Cell Lung Cancer

n=150 · primary completion 2027-02 · biomarker cohort tracking pneumonitis after CRT then ICI
Which pts, if any, benefit from concurrent rather than sequential timing

active Concurrent or Sequential Immunotherapy and Radiation Therapy in Patients With Metastatic Lung Cancer Phase 1

n=78 · primary completion 2026-12 · same SBRT dose levels in each timing arm, stage IV NSCLC

Sourced from Zhou et al.

📚 Sources · 📄 1 paper

📄 PAPER Zhou; Wang; Lee et al. · JAMA oncology (2026-05)

Combination of Radiotherapy and Immunotherapy in Advanced Non-Small Cell Lung Cancer.

PMID 41885834 → doi full text (PMC)

Abstract

IMPORTANCE: The optimal sequencing of radiotherapy (RT) combined with immunotherapy (iRT) and the value of chemotherapy remain undefined for advanced non-small cell lung cancer (NSCLC), where randomized data are limited. OBJECTIVE: To compare real-world overall survival (OS) between sequential and concurrent iRT in newly diagnosed advanced NSCLC, assess the effect of immune checkpoint inhibitor (ICI) maintenance after RT in refractory disease, and evaluate the association of chemotherapy with survival. DESIGN, SETTING, AND PARTICIPANTS: This is a territory-wide study (OCEANUS) based on the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System (more than 90% population coverage). Patients with NSCLC diagnosed from January 1, 2010, to December 31, 2021, who subsequently received iRT for advanced or refractory disease were included. Overlap weighting was the primary propensity score-weighted method, with inverse probability of treatment weighting used for sensitivity analysis. Data were analyzed from December 2024 to April 2025. EXPOSURES: Sequential vs concurrent iRT for newly diagnosed advanced NSCLC; RT with vs without ICI maintenance for refractory NSCLC; receipt of chemotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was real-world OS after landmark, estimated with weighted Kaplan-Meier and Cox models. When proportional hazards were violated (per Schoenfeld residuals), treatment effects were summarized using restricted mean survival time. RESULTS: Of 3522 patients who received ICIs, 335 received RT, including 155 with newly diagnosed advanced and 180 with refractory NSCLC. Of these, 247 (73.7%) were male, and the median (range) age was 64 (34-90) years. In newly diagnosed NSCLC, patients treated with sequential iRT had significant longer real-world OS than those treated with concurrent iRT (median, 20.3 months [95% CI, 13.3 to not reached] vs 16.0 months [95% CI, 8.3-30.0]; adjusted hazard ratio, 0.68; 95% CI, 0.47-0.99; P = .045). Chemotherapy was also associated with longer survival in patients with newly diagnosed advanced NSCLC. In refractory NSCLC, RT with ICI maintenance was associated with a numerically longer median real-world OS (11.2 months [95% CI, 7.9-20.6] vs 6.7 months [95% CI, 4.4-17.4]; P = .20). Addition of chemotherapy was not significant for real-world OS. Inverse probability of treatment weighting analyses produced similar estimates. CONCLUSIONS AND RELEVANCE: In this cohort study, sequential iRT was associated with longer survival than concurrent iRT in patients with newly diagnosed advanced NSCLC, and chemotherapy was associated with longer survival. In patients with refractory NSCLC who survived at least 90 days, RT with ICI maintenance resulted in nonsignificantly longer survival and an unclear association with chemotherapy. These findings are hypothesis generating and support prospective randomized studies to define optimal sequencing of iRT and use of systemic treatment partners.

📝 https://jamanetwork.com/journals/jamaoncology/fullarticle/2847148?guestAccessKey=6284363c-f1dd-46da-aa0e-8528e5ecca06&utm_source=twitter&utm_medium=social_jamaonc&utm_term=20674463146&utm_campaign=article_alert&linkId=952727864

Combined Palliative Real-world evidence Early signal

🌀 GI Lower

MIRACLE-2

🌰 Prostate

COMPPARE

CAN-2409 NCT01436968

PROTEUS

🍽️ GI Upper

RASolute 302

🫁 Thoracic / Lung

OCEANUS

GI Lower

Prostate

GI Upper

Thoracic / Lung