onc brain

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.

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.