STAMPEDE (abiraterone ± enzalutamide, high-risk non-metastatic) NCT00268476
ForHigh-risk non-metastatic prostate ca (N+ or 2 of T3/T4, Gleason 8–10, PSA ≥40)
HR 0·53
95% CI 0·44–0·64, p<0·0001; 6yr MFS 82% vs 69%
TL;DR6yr MFS 82% vs 69%, HR 0·53 (0·44–0·64), adding 2yr abiraterone to ADT+RT; enzalutamide adds nothing.
The RT-relevant read is that benefit is unchanged by radiotherapy: MFS HR 0·54 (0·44–0·67) with planned RT vs 0·51 (0·34–0·76) without, p interaction 0·67, in a cohort where 85% were planned for 74 Gy/37 fx to prostate and seminal vesicles. Abiraterone is therefore additive to definitive RT plus 3yr ADT, not a substitute for either.
In a man starting 3yr ADT plus 74 Gy prostate RT for node-positive or high-risk node-negative disease, this supports 2yr abiraterone intensification; it does not extend to men relapsing after prior local therapy, who were under-represented, nor to post-prostatectomy combination therapy, which was not tested.
Benefit is unchanged by radiotherapy: MFS HR 0·54 (0·44–0·67) with planned RT vs 0·51 (0·34–0·76) without, p interaction 0·67, in a cohort where 85% were planned for 74 Gy/37 fx to prostate and seminal vesicles. Abiraterone is additive to definitive RT plus 3yr ADT, not a reason to omit either.
The regimen question is duration and partner, not whether to intensify: 2yr abiraterone 1000 mg plus prednisolone on a 3yr ADT backbone gives MFS HR 0·53, and adding enzalutamide 160 mg buys nothing (interaction HR 1·02) while raising G3+ AEs from 37% to 58%. Node-positive pts derived HR 0·49 (0·38–0·64).
14 details 5 trials watching
Two open-label phase 3 randomised comparisons within the STAMPEDE MAMS platform, run at 113 UK and Swiss sites, with no overlapping controls, pooled by individual patient data meta-analysis. Recruitment Nov 15, 2011 to March 31, 2016; N=1974; median follow-up 72 months (85 months in the abiraterone trial, 60 months in the abiraterone and enzalutamide trial). The switch of the non-metastatic primary outcome from overall survival to metastasis-free survival was made before any efficacy inspection by randomised group and published as a prespecified declaration.
High-risk non-metastatic prostate adenocarcinoma: node positive, or if node negative, at least two of T3/T4, Gleason 8–10, PSA ≥40 ng/mL; or relapsing with high-risk features (PSA ≥4 with doubling time <6 months, PSA ≥20, or nodal relapse). WHO PS 0–2, no age limit, clinically significant cardiovascular disease excluded. Median age 68 (IQR 63–73), median PSA 34 ng/mL, 774 (39%) node positive, 1563 (79%) of 1968 Gleason 8–10.
ADT for 3 years in all arms, started no more than 12 weeks before randomisation. Combination arms added abiraterone acetate 1000 mg + prednisolone 5 mg daily for 2 years, with enzalutamide 160 mg daily in the second trial only. Median time from randomisation to starting combination therapy 1·4 weeks; when RT was omitted, treatment could continue to progression.
Local RT was mandated for node-negative disease unless contraindicated and encouraged for node-positive disease, per local guidelines at 74 Gy in 37 fractions to prostate and seminal vesicles or a hypofractionated equivalent. Planned RT covered 1684 (85%) of 1974 pts: 99% of newly diagnosed node-negative, 71% of node-positive, and only 7% of previously treated pts.
Primary: metastasis-free survival in the pooled intention-to-treat population, powered for a target HR of 0·75 at 90% power with a one-sided type 1 error of 1·25%, requiring roughly 315 control-group events. Secondary: overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity.
G3+ AEs in the first 24 months were 169 (37%) of 451 vs 130 (29%) of 455 in the abiraterone trial, but 298 (58%) of 513 vs 172 (32%) of 533 once enzalutamide was added. Hypertension (14% vs 5%), fatigue (10% vs 2%) and raised aminotransferases (13% vs 5%) account for most of the gap between the two combination arms. Seven grade 5 events occurred, none in a control group.
Trials of abiraterone combined with enzalutamide or apalutamide in metastatic castration-resistant disease had already shown modest radiographic PFS gains with no overall survival gain, and the interaction HR of 1·02 (0·70–1·50) here reproduces that in the hormone-sensitive non-metastatic setting. The two trials also confirm each other independently, MFS HR 0·54 (0·43–0·68) and 0·53 (0·39–0·71), which is the strongest internal replication available for a result of this size.
Toxicity was captured only during the first 2 years of treatment, so late cardiovascular and metabolic effects of a 2-year ARSI on top of 3 years of ADT are not measured here. Data on subsequent therapy at castration resistance are described as unreliable, and the 2-year combination duration was pragmatic (matched to the ADT-with-RT requirement), not compared against shorter or longer schedules.
The result establishes fixed-duration hormone intensification as additive to definitive local therapy, with the effect size holding across nodal status and across planned RT use. What it does not settle is whether MFS at 72 months translates into a durable cure fraction, or which of the enzalutamide-driven toxicities would be acceptable if a future combination did show separation.
| Endpoint | HR | 95% CI | p |
|---|---|---|---|
| Overall survival | 0·60 | 0·48–0·73 | <0·0001 |
| Prostate cancer-specific survival | 0·49 | 0·37–0·65 | <0·0001 |
| Biochemical failure-free survival | 0·39 | 0·33–0·47 | <0·0001 |
| Progression-free survival | 0·44 | 0·36–0·54 | <0·0001 |
| Subgroup | SOC events/n | Combination events/n | HR (95% CI) | p interaction |
|---|---|---|---|---|
| RT planned | 238/843 | 139/841 | 0·54 (0·44–0·67) | 0·67 |
| No RT planned | 68/145 | 41/145 | 0·51 (0·34–0·76) | 0·67 |
| N0 | 140/598 | 89/599 | 0·60 (0·46–0·78) | 0·22 |
| N+ | 165/389 | 91/385 | 0·49 (0·38–0·64) | 0·22 |
| Event | Abiraterone trial | Abi + enzalutamide trial |
|---|---|---|
| Hypertension | 23 (5%) of 451 | 73 (14%) of 513 |
| Fatigue | 10 (2%) | 49 (10%) |
| Raised aminotransferases | 25 (5%) | 69 (13%) |
CONSORT flow
Two prospectively randomised phase 3 trials, prespecified pooled primary endpoint hit, 72mo follow-up, and the RT-treated majority carries the same effect as the whole.
- Optimal duration of abiraterone: shorter or longer than 2 years 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 · randomised 9mo ADT/6mo ARTA vs 2y ADT with XRT
- Benefit in men relapsing after prior local therapy n=532 · primary completion 2031-02 · ARPI timing with SBRT/salvage XRT in recurrent HSPCrecruiting 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 abi+apa added to salvage RT for post-RP BCR
- Combination therapy in men undergoing prostatectomy n=90 · primary completion 2026-09 · randomised apalutamide ± abiraterone before RPrecruiting Neoadjuvant Intense Endocrine Therapy for High Risk and Locally Advanced Prostate Cancer Phase 2n=900 · primary completion 2026-12 · neoadjuvant ADT + abiraterone arms before RARP
📚 Sources · 📄 1 paper
The longer read
The clinically load-bearing finding here is not that hormone intensification works in non-metastatic disease, which several trials had made plausible, but that the benefit sits on top of definitive radiotherapy rather than substituting for it. Eighty-five percent of this cohort was planned for local RT, essentially all of the node-negative patients, and the metastasis-free survival hazard ratio in that group (0·54, 0·44–0·67) is indistinguishable from the hazard ratio in the small minority who did not receive RT (0·51, 0·34–0·76). A radiation oncologist can read that as reassurance that adding two years of abiraterone does not cannibalise the local therapy effect, and equally that omitting radiotherapy is not licensed by systemic intensification: the no-RT stratum is 290 patients, far too small to support a de-escalation argument, and the protocol mandated RT for node-negative disease precisely so that question would not be asked of these data.
The enzalutamide arm is the more interesting negative. The trial management group made the decision to pool and to report the combination as a single question before looking at efficacy by randomised group, on the reasoning that castration-resistant data had already shown abiraterone plus a second androgen receptor antagonist buying radiographic progression-free survival without survival. That prediction held: an interaction hazard ratio of 1·02 with a confidence interval from 0·70 to 1·50 cannot exclude a modest benefit, but the toxicity ledger settles the question without needing to. Grade 3 or worse events in the first two years went from 37% to 58% when enzalutamide was added, with hypertension, fatigue and transaminitis carrying most of the difference, and four of the seven grade 5 events occurred in that arm. A trial that cannot demonstrate separation while doubling severe toxicity has answered the practical question even if it has not answered the statistical one.
Two features should raise confidence beyond what a single trial of this size would earn. The abiraterone and abiraterone-plus-enzalutamide comparisons ran sequentially with no shared controls, and each reached the same hazard ratio independently (0·54 and 0·53), which is internal replication rather than subgroup consistency. Follow-up is also long enough for a metastasis-free survival readout to have accumulated real events, 486 across both arms, and the proportional hazards assumption held on formal testing.
Two features should lower it. The trials were open label, and the authors concede that control patients could have received second-generation hormone therapy at castration resistance, both in trials and, since 2019, as standard care. That contamination biases the overall survival comparison toward the null, so the OS hazard ratio of 0·60 is if anything conservative rather than inflated, but it also means the survival benefit being quoted reflects a control group with real access to salvage. Toxicity reporting stopped at two years, which is the wrong window for the effects a clinician actually worries about when stacking an androgen receptor pathway inhibitor onto three years of castration in a population with a median age of 68.
The population boundary deserves more weight than it usually gets. The authors state explicitly that patients relapsing after prior local therapy were under-represented, and only 7% of previously treated patients were planned for radiotherapy. The result should not be carried across to biochemical relapse after prostatectomy or to the post-radiation salvage setting, both of which are the populations where the temptation to extrapolate is strongest.