Prostate
RT-backbone population: 85% planned prostate RT (74 Gy/37 fx or hypofractionated equivalent), mandated for N0.
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.
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.
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