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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.

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.

Multicenter open-label randomized phase III noninferiority trial, 16 hospitals across 11 provinces of China, accrual August 2015 to August 2018, N=599 randomly assigned 1:1 (TNT 302, CRT 297). Stratified by tumor location, clinical stage and MRF status; median follow-up 35.0 months (range 8.3-63.9).

Age 18-70, ECOG 0-1, rectal adenocarcinoma of the distal or middle third (0-10cm from anal verge), cT3-4 and/or node-positive, no distant metastases, no prior anticancer treatment. Arms were balanced: cT4 15.9% v 12.8%, MRF involvement 56.3% v 56.2%, clinical stage III 85.8% v 83.5%.

TNT arm received 25Gy in 5 fractions over one week; CRT arm 50Gy in 25 fractions over 5 weeks with concurrent capecitabine 825mg/m2 twice daily. All patients received IMRT, a departure from RAPIDO, Polish II and PRODIGE 23. CTV covered mesorectum, presacral space, internal iliac, obturator nodes and ischiorectal fossa; superior border at the sacral promontory, inferior 2-3cm distal to the tumor, external iliacs added only for cT4b; CTV-to-PTV expansion 0.5-1.0cm.

TNT arm: 4 cycles CAPOX (oxaliplatin 130mg/m2 day 1, capecitabine 1,000mg/m2 twice daily days 1-14) starting 7-14 days after radiotherapy, then TME, then 2 further cycles. CRT arm: concurrent capecitabine during radiotherapy, then TME, then 6 cycles CAPOX. Total mesorectal excision was scheduled 6-8 weeks after preoperative treatment in both arms; a watch-and-wait pathway was permitted for clinical complete responders.

Primary: 3-year disease-free survival, noninferiority claimed if the upper bound of the 95% CI of the HR was at or below 1.43 (an 11% absolute margin against an assumed 65% CRT rate). Secondary endpoints were overall survival, metastasis-free survival, locoregional recurrence and surgical complications. Target accrual 600 with at least 194 DFS events for 80% power at one-sided alpha 0.05.

Acute grade III-V toxicity during preoperative treatment was 26.5% with TNT versus 12.6% with CRT (P<.001), driven almost entirely by hematologic events (grade 3-4 15.8% v 2.0%, P<.001) rather than by anything the radiotherapy added. Radiotherapy delivery itself was cleaner in the short-course arm, with no dose reductions at all, and grade III+ surgical complications were comparable (14.0% v 15.7%, P=.625). Grade III-IV toxicity during adjuvant chemotherapy ran lower after TNT (3.3% v 11.8%, P=.003).

STELLAR is the third randomized trial of short-course radiotherapy plus neoadjuvant chemotherapy against long-course CRT, after Polish II and RAPIDO, with PRODIGE 23 addressing the adjacent question of chemotherapy sequencing around long-course CRT. Its 3-year LRR of 8.4% with TNT sits alongside RAPIDO and PRODIGE 23 (4%-8.3%) and well below Polish II (21%-22%), which enrolled a heavier fixed cT3/cT4 population. Unlike RAPIDO and PRODIGE 23, STELLAR showed no reduction in distant metastasis (3-year DM 22.8% v 24.7%), and its OS advantage mirrors the early Polish II signal that later disappeared at 8 years.

The 11% noninferiority margin is wide, and the authors concede in retrospect that a narrower margin or larger sample would have been defensible given how close the arms proved. Distant metastasis, the endpoint short-course TNT was designed to move, did not separate at all (22.8% v 24.7%), which weakens the mechanistic case for the OS difference. Adjuvant chemotherapy completion also differed between arms (60.0% v 48.3%, P=.009), so postoperative treatment intensity is not held constant across the comparison.

The defensible read is the primary endpoint: 25Gy in 5 fractions followed by CAPOX delivers the same 3-year DFS and the same locoregional control as 50Gy in 25 fractions, in one week of radiotherapy instead of five. The 11.4-point OS separation is the number that will be quoted and the one least supported, since neither MFS nor LRR moved and the same pattern in Polish II did not survive longer follow-up. What transfers most reliably is the technique: full elective pelvic coverage with IMRT at 5x5Gy, delivered without a single dose reduction.

Prespecified noninferiority met on 3yr DFS with adequate accrual, but open-label, 35mo follow-up only, and the OS gain is a secondary endpoint unsupported by MFS or LRR.

Multicenter randomized phase III, N=458, accrual June 6, 2017 to December 27, 2023, median follow-up 51 months. Primary endpoint: DFS. Blinding is not reported and the two regimens are not maskable.

Stage II/III LARC aged 18 to 70 with at least one MRI high-risk feature (cT4a-b, cN2, mesorectal fascia involvement, or cT3c-d with EMVI). Baseline burden was heavy: cT4 47.82%, cN2 75.98%, threatened MRF 70.96%, EMVI 54.80%.

Experimental: one cycle induction CAPOX, LCRT with two cycles concurrent CAPOX, three cycles consolidation CAPOX, then surgery, so all cytotoxic therapy precedes resection. Control: LCRT with concurrent capecitabine, surgery, then six cycles adjuvant CAPOX at 4 to 8 weeks.

Long-course RT in both arms, so RT is the fixed element and the randomized variable is chemotherapy timing plus oxaliplatin exposure. Dose, fractionation, technique and target volume are not reported in the source text, nor is whether concurrent doublet chemotherapy altered RT delivery.

Primary: DFS. Secondary results reported here: MFS, pCR, locoregional failure, overall survival, grade ≥3 adverse events, major postoperative complications.

Primary endpoint met, with MFS moving in step and pCR strongly favoring the experimental arm, while locoregional failure and 3-year OS did not separate. See the efficacy table.

Grade ≥3 toxicity front-loads into the neoadjuvant phase with the doublet, but severe toxicity across the entire treatment course and major postoperative complications were comparable. Total mesorectal excision was performed in approximately 87% (TNT) and 90% (nCRT).

Sits alongside RAPIDO, PRODIGE-23 and STELLAR, the trials that established TNT, but keeps long-course chemoradiation as the RT backbone rather than short-course RT. Unlike RAPIDO's longer follow-up, intensification here did not increase locoregional failure.

Control-arm adjuvant CAPOX delivery and completion are not reported, and a TNT advantage partly reflects therapy planned but not received when postoperative chemotherapy under-delivers. Accrual spanned 2017 to 2023, during which TNT became routine, so control-arm contemporaneity drifted. Age was capped at 70.

The gain is distant, not local: MFS tracks DFS while locoregional failure is flat and low in both arms, which says long-course chemoradiation with a fluoropyrimidine is near its local ceiling in this population and the remaining room is systemic. The pCR tripling is the organ-preservation lever, but pCR is a resection-specimen endpoint and this trial did not test nonoperative management.

Randomized phase III, primary DFS met at 51mo median f/u, but TNT is already established by RAPIDO, PRODIGE-23, STELLAR; this refines regimen rather than the paradigm.

Phase 3 international randomised trial, 1:1 central allocation by ICR-CTSU with permuted blocks, stratified by centre and NCCN risk group. Treatment allocation was open-label. Of 874 randomised, 844 formed the analysis population (SBRT=414, CRT=430), median follow-up 85.7 and 85.6 mo.

Men with low-/intermediate-risk localised prostate cancer. Baseline characteristics balanced; baseline PROM data pooled across arms given equivalent pretreatment function.

SBRT 36.25 Gy in five fractions versus CRT 78 Gy in 39 fractions or 62 Gy in 20 fractions. Image-guidance method was not analysed as a variable, and rectal spacer use is not reported in this analysis.

Primary comparison: SBRT vs CRT at 5 yr for each PROM endpoint, using EPIC-26 urinary incontinence, sexual and bowel domains plus the Vaizey faecal incontinence score at baseline, 1, 2 and 5 yr. Binary outcomes by chi-squared with Wilson 95% CIs; continuous by Mann-Whitney.

All predefined between-group differences were nonsignificant. Sexual domain median score fell from 48.7 (IQR 22.2-77.8) to 26.3 (IQR 16.7-57) for SBRT and 54.2 (IQR 27.8-75.0) to 24.3 (IQR 16.7-52.8) for CRT, p=0.89.

Moderate or big urinary leakage problems reached 6% (15/250) SBRT and 4% (9/244) CRT; bowel problems 5% in both arms. Solid stool incontinence never/rarely in 94% (232/248) SBRT and 90% (217/241) CRT; liquid stool 92% in both.

PACE-B previously showed SBRT non-inferior to conventional and moderately hypofractionated RT for efficacy but with higher cumulative GU adverse events; these PROMs argue that excess did not persist to 5 yr. Against TrueNTH's robotic prostatectomy benchmark at 1 yr (42% leak- and pad-free, 6% of baseline-potent men retaining intercourse-adequate erections), the RT curves sit far better, and PACE-A reported pad use of 4.6% after SBRT versus 46.9% after prostatectomy.

The EPIC-26 irritative/obstructive domain was not included, removing the symptom cluster most often attributed to SBRT, though the authors note no 5-yr difference was seen in prior reporting. There is no untreated control arm, so age-related decline is unseparated from treatment effect, and no analysis by image-guidance method.

The clinically useful claim is narrow and real: five fractions buys convenience without a late functional cost relative to 20 or 39 fractions. The cross-modality framing against surgery is the weaker half, comparing separate cohorts at different timepoints with a shared instrument rather than a randomised contrast.

Prespecified 5-yr PROM analysis of a phase 3 RCT; all between-group differences nonsignificant, supporting five-fraction SBRT already in guideline use. Attrition to ~60% limits precision.

Protocol-planned secondary analysis of the TROG 08.03 RAVES phase 3 noninferiority RCT, 166 aRT vs 167 sRT. Median follow-up 6 yr (IQR 4 to 7.1) in both arms. Complete-case analysis, no imputation, chi-square per timepoint.

High-risk features after RP: positive margins, extraprostatic extension, or seminal vesicle invasion. 82% Gleason 7, 3% Gleason 8, 12% Gleason 9. Median age 63.8 vs 63.9 yr (p = 0.9).

64 Gy in 32 fractions to the prostate fossa in both arms, mostly 3D-CRT rather than IMRT. aRT within 6 mo of RP; sRT triggered at PSA 0.20 ng/ml and delivered within 4 mo. Concurrent ADT and pelvic nodal treatment were not permitted.

Primary: proportion with a minimal clinically important change, defined as a >0.5 SD decline from baseline on each QLQ-PR25 domain. MCIC thresholds were 7 points urinary, 2 points bowel, 14 sexual activity, 12 sexual functioning. Global QOL by QLQ-C30.

The RP-to-RT interval regression is the cleanest read: no coefficient approached significance at 3, 4, or 5 yr in any domain, with the largest estimate 0.20 (95% CI -0.29 to 0.70, p = 0.4).

GETUG-AFU 17 and RADICALS reported the same directional late GU penalty for adjuvant RT, though cross-trial comparison is blocked by differing urinary grading. Prior clinician-rated series put CTCAE grade 2 incontinence at 10 to 20%, bracketing the 16% seen here.

The aRT versus never-irradiated comparison is not randomized: those 87 men were selected by not recurring, so comorbidity and baseline continence are unbalanced by construction. The sRT-received group's worse sexual activity at 3 and 4 yr is confounded by higher-risk disease and likely more ADT off-protocol, and the 5-yr sexual functioning cells are as small as n = 10.

The patient-reported bowel signal is invisible on CTCAE (RAVES showed no clinician-rated GI difference), and the patient-reported urinary trend never reached consistent significance despite a 70% vs 54% clinician-rated G2+ GU gap. The two instruments are measuring different things, and neither alone describes what a man experiences.

Protocol-planned secondary analysis of a randomized trial; supports the established early-salvage standard. Exploratory, unadjusted for multiple testing, 3D-CRT era.

Randomized, non-blinded phase III, 1:1, N=698 (MH-IMRT 345, SBRT 353), stratified by Gleason score, PSA, and rectal manipulation. The trial's oncologic primary endpoint sits elsewhere; this analysis reports the patient-reported secondary endpoints.

Localized intermediate-risk prostate cancer, median age 68 (IMRT) and 69 (SBRT). Two patients were ineligible (one high-risk, one PSA out of window). Baseline EPIC domains were balanced across arms, all p≥0.093.

SBRT 36.25 Gy in 5 fractions delivered 2-3 per week, PTV expansion 5mm except 3mm posteriorly and anteriorly, PTV max capped at 38.78 Gy unless the urethra was visualized and contoured (acceptable variation 43.5 Gy). MH-IMRT 70 Gy/28 fx or 60 Gy/20 fx, PTV expansion 8mm except 5mm posteriorly. CTV was prostate ± 1cm proximal seminal vesicles. Rectal manipulation was common: SpaceOAR in 55% overall.

EPIC-26 at baseline, 12 and 24 months. MCID thresholds: >5 points urinary irritative/obstructive, >6 urinary incontinence, >10 sexual, >4 bowel and hormonal. Individual MCID rather than group mean scores was the analytic unit, with an exploratory longitudinal linear model adjusted for baseline score, arm, stratification factors, T-stage, age, and race.

The arm-level MCID and toxicity comparisons are tabulated above. Longitudinal modeling of urinary incontinence gave a least square mean difference of 2.91 (95% CI 0.85-4.97, p=0.0058) favoring SBRT, while sexual and hormonal domains showed no significant treatment effect.

Investigator-reported toxicity favored SBRT across the board: grade ≥3 GU 0.6% vs 2.5% (p=0.04), any-grade rectal hemorrhage 10.5% vs 17.3% (p=0.01), any-grade fatigue 39.2% vs 50.8% (p=0.0025). The GU finding is the one that most often runs the other way in ultrahypofractionation series, so it is worth reading as the trial's own answer to the pre-trial toxicity concern.

PACE-B is the other large randomized SBRT vs moderate hypofractionation comparison, and both trials show lower urinary incontinence decline with SBRT despite differing MCID definitions. Prior patient-level meta-analysis had suggested less clinically meaningful bowel and urinary irritative/obstructive decline at two years with SBRT, and the 1-year bowel result here is directionally consistent.

Differential attrition ran against the IMRT arm: 22 IMRT patients (6.4%) died or withdrew before year 1 versus 4 SBRT patients (1.1%), and 22 IMRT patients never received the assigned RT after withdrawal versus 1 in the SBRT arm. Completion was 79.9% (IMRT) and 84.0% (SBRT) at year 1. The domain-by-timepoint pattern (bowel and sexual at 1yr, incontinence at 2yr) is the kind of scattered significance that multiplicity should temper.

The trial was designed when the open question was whether five fractions cost the patient something. The PRO answer is that it does not, and the investigator-reported toxicity answer is that it may cost less. What the QoL data cannot do is settle whether SBRT is oncologically non-inferior, which is the primary endpoint and is not reported in this source.

Prespecified PRO secondary analysis of a phase III trial, non-blinded with patient-reported endpoints; aligns with PACE-B rather than establishing a new position. Oncologic primary endpoint not reported here.

Randomised phase III, four-group intergroup trial (EORTC/NCIC-CTG/TROG/MRC-CTU), N=478, comparing two single-modality first-line strategies. This is the mature analysis; a post hoc reclassification to 2021 WHO criteria was possible in 73% (351/478) with analyzable tissue.

Clinical high-risk WHO grade 2 low-grade glioma, treatment-naive. Post hoc molecular strata: IDHmt/1p19q non-codeleted astrocytoma n=178, IDHmt/1p19q codeleted oligodendroglioma n=109, IDH wild-type n=64.

Standard fractionation, 28 × 1.8 Gy (50.4 Gy), delivered as the entire assigned treatment. No concurrent or adjuvant systemic therapy in the RT arm, which is the gap between this trial and how grade 2 glioma is treated now.

Dose-dense temozolomide 75 mg/m² once daily, 21 of 28 days, up to 12 cycles, given as sole first-line therapy with RT withheld.

Primary: progression-free survival. Overall survival and differential response by molecular marker were the mature-analysis questions.

No significant difference in PFS or OS between arms, and the null held across every molecular subtype except IDH wild-type, where OS favored TMZ.

RTOG 9802 established RT followed by PCV as the high-risk grade 2 benchmark, and combined-modality therapy is now standard for IDH-mutant astrocytoma. EORTC 22033 tested neither arm of that question: it asked which single modality to lead with, and answered that it does not matter.

Molecular strata are post hoc in 73% of the enrolled population, so subtype comparisons carry both selection and multiplicity risk. The IDH wild-type finding rests on n=64, and under 2021 criteria those tumors would not be enrolled as grade 2 at all.

The durable contribution is prognostic rather than therapeutic: median OS of 12.9-14.9 years in codeleted oligodendroglioma against 6.6-6.7 years in IDH-mutant astrocytoma quantifies how far molecular class outweighs modality choice. The finding that pts ≥40 fared better than <40 undercuts the age-40 cutoff that still gates high-risk definitions.

Mature randomised phase III, primary endpoint negative in both arms and across molecular subtypes; the IDHwt survival difference is post hoc, n=64.

International investigator-initiated phase 3, N=802 from 8 countries, accrued March 2014 to June 2018, median follow-up 8 years. Powered at 80% for an HR 0.67. Primary was changed from OS to MFS during the trial because deaths ran below projection.

High-risk clinically localized or locally-advanced disease suitable for EBRT: 90% Gleason 8-10, 36% PSA >20 ng/ml, 12% cN1 by conventional imaging. 40% planned for pelvic RT and 8% for a brachytherapy boost.

Experimental: enzalutamide 160 mg daily x 24 months plus LHRH agonist x24 months. Control: conventional NSAA x6 months plus LHRH agonist x24 months. The control is an active antiandrogen, not ADT alone.

Prostate to 78Gy, or 46Gy plus brachytherapy boost, starting 16 weeks after hormonal therapy. Pelvic nodal RT required for cN1 (46Gy elective nodes plus boost to gross nodes) and optional for cN0 but declared before randomization. QA was unusually tight: credentialing, benchmarking, real-time review of the first 5 plans per site, then 20% random sampling.

Primary: MFS. Secondary: OS, CSS, PSA PFS, clinical PFS, castration resistance, HRQoL, adverse events, cost-effectiveness. Main effects by unstratified log-rank at alpha=0.05, Cox HRs, all p-values nominal without multiplicity adjustment, five prespecified subgroups tested by interaction.

Primary MFS not met. PFS favored enzalutamide at a nominal p=0.044 and OS was flat; the subgroup detail sits in the table above.

STAMPEDE's abiraterone-based intensification in non-metastatic high-risk disease produced an MFS HR 0.53 against ENZARAD's 0.88, and the ENZARAD cN1 subgroup HR mirrors the STAMPEDE result. The gap plausibly reflects population, not drug: cN1 11% vs 39%, median PSA 14 vs 35 ng/ml, cT3-4 47% vs 92%.

The pelvic-RT subgroup is not a clean randomized comparison of pelvic coverage: it carried 28% N1 and 62% Gleason 9/10 against 0% N1 and 49% Gleason 9/10 in the no-pelvic-RT group, so risk enrichment and biological interaction are entangled. The presenter named both explanations and could separate neither.

Two prespecified subgroups moving together on MFS and OS, with OS HRs tracking MFS HRs as ICECaP surrogacy predicts, is more internally consistent than a lone subgroup blip. It still does not establish that enzalutamide works only when the pelvis is treated.

Adequately powered phase 3 missed its primary MFS endpoint against an active NSAA control; benefit rests on two prespecified subgroups with overlapping risk composition.

Randomized phase III SWOG/NRG cooperative-group trial, accrual 8/13/20 to 9/6/24, 417 randomized / 403 eligible (201 SBRT alone, 202 atezolizumab + SBRT) against an accrual goal of 432. Closed at the first interim analysis for futility on both OS and PFS. Median follow-up in living pts was 12 months (range 0.03-49).

T1-3N0M0 NSCLC ≤7 cm, medically inoperable or declined surgery, with ≥1 recurrence risk factor: tumor diameter ≥2 cm, ≥6.2 (SUV), or moderately/poorly/undifferentiated histology. Median age 73 (41-91), 89% ECOG 0-1, median tumor diameter 2.3 cm. Stratified by location (central vs peripheral), size (<4 vs ≥4 cm) and PS.

SBRT in 3-8 fractions to a BED ≥100 Gy in both arms, i.e. standard definitive dosing rather than a de-escalated backbone. In the experimental arm SBRT began with cycle 3, so radiation was delivered after two neoadjuvant atezolizumab cycles and concurrently with the third.

Atezolizumab 1200 mg IV Q3W for 8 cycles, given neoadjuvantly, concurrently and adjuvantly around SBRT. No protocol treatment was received by 6 pts on S and 8 on AS.

Primary: overall survival, compared by 1-sided stratified log-rank at the 2.5% level. Secondary: PFS, failure patterns, toxicity, QoL.

Neither OS nor PFS favored the IO arm, and local failure ran higher with atezolizumab. See the failure-pattern table and primary endpoint above.

G≥3 AEs 12% on AS vs 2% on S (21 G3, 1 G4, and 1 G5 respiratory failure with atezolizumab; 3 G3 and 1 G4 with SBRT alone). A six-fold excess of high-grade toxicity with no efficacy return is the safety read.

The prior randomized phase II (PMID 37478883) suggested benefit from adding immunotherapy to SBRT; this larger phase III does not reproduce it. It also sits against PACIFIC-era logic, where consolidation IO helps after chemoRT for stage III, and shows that result does not port down to node-negative disease treated with ablative SBRT.

Follow-up is short (median 12 mo alive) and central review of local recurrence events is not complete, so the local-failure imbalance is provisional. The smoker subgroup harm signal was not multiplicity-controlled, and PD-L1 status, QoL and correlative blood/tissue analyses are all still pending.

A negative primary endpoint with a directionally worse PFS, worse local control and six-fold more high-grade toxicity is stronger than a null result: it argues against the abscopal/radiosensitization rationale in this setting. It does not exclude benefit in a biomarker-selected subset, which the pending PD-L1 analysis will test.

Phase III, primary OS endpoint not met, closed at interim for futility. Reaffirms SBRT alone as SoC and refutes the earlier phase II IO signal.