PROfound
Olaparib versus enzalutamide or abiraterone in metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations
Phase 3N = 387NCT02987543
- Population
- Metastatic castration-resistant prostate cancer with progression on enzalutamide or abiraterone and a qualifying alteration in a prespecified homologous recombination repair gene
- Design
- Randomised (2:1), open-label phase 3 trial of olaparib versus the physician's choice of enzalutamide or abiraterone (plus prednisone) in men whose disease progressed on a new hormonal agent. Cohort A (245 patients) had an alteration in BRCA1, BRCA2 or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, determined prospectively and centrally from tumour tissue. Crossover to olaparib was allowed after imaging-based progression. The primary endpoint was imaging-based progression-free survival in cohort A by blinded independent central review.
- Primary endpoint
- rPFS
- Arms
- Olaparib (experimental, n = 256): Olaparib
- Enzalutamide or abiraterone (physician's choice) (control, n = 131): Enzalutamide or abiraterone plus prednisone, physician's choice, as control therapy
- People
- de Bono J
rPFSHR 0.34 (95% CI 0.25–0.47)Δ median rPFS+3.8 monthsΔ median OS+3.4 monthsOSHR 0.69 (95% CI 0.50–0.97)Δ median OS+4.4 monthsΔ median OS+2.6 months
Show the numbers
| Endpoint | Analysis | Olaparib | Enzalutamide or abiraterone (physician's choice) | Effect |
|---|---|---|---|---|
| rPFSCohort A (BRCA1, BRCA2 or ATM alteration; n=245)Imaging-based progression-free survival by blinded independent central review | primaryde 2020 | median 7.4 months | median 3.6 months | HR 0.34 (95% CI 0.25–0.47)P<0.001Hazard ratio for progression or death. |
| OSCohort A (BRCA1, BRCA2 or ATM alteration; n=245) | interimde 2020 | median 18.5 months | median 15.1 months | Medians given in the primary publication without a hazard ratio in its abstract; 81% of control-group patients who had progressed crossed over to olaparib. Labelled interim because the later survival paper reports the final overall survival analysis (its abstract background states that the final analysis had not yet been reported). |
| OSCohort A (BRCA1, BRCA2 or ATM alteration; n=245) | finalHussain 2020 | median 19.1 months | median 14.7 months | HR 0.69 (95% CI 0.50–0.97)P=0.02Final overall survival analysis at a data maturity of approximately 60%. Overall, 86 of 131 control patients (66%) crossed over to olaparib (56 of 83 in cohort A, 67%). A sensitivity analysis adjusted for crossover gave a hazard ratio for death of 0.42 (95% CI 0.19 to 0.91) in cohort A. |
| OSCohort B (alterations in 12 other prespecified genes; n=142) | finalHussain 2020 | median 14.1 months | median 11.5 months | Medians only; no hazard ratio is given in the abstract. Crossover-adjusted hazard ratio for death 0.83 (95% CI 0.11 to 5.98). |
| OSCohorts A and B combined (n=387) | finalHussain 2020 | median 17.3 months | median 14 months | Medians only; no hazard ratio is given in the abstract. Crossover-adjusted hazard ratio for death 0.55 (95% CI 0.29 to 1.06). |
| Endpoint | Analysis | Olaparib | Enzalutamide or abiraterone (physician's choice) | Effect |
|---|---|---|---|---|
| rPFSCohort A (BRCA1, BRCA2 or ATM alteration; n=245)Imaging-based progression-free survival by blinded independent central review | primaryde 2020 | median 7.4 months | median 3.6 months | HR 0.34 (95% CI 0.25–0.47)P<0.001Hazard ratio for progression or death. |
| OSCohort A (BRCA1, BRCA2 or ATM alteration; n=245) | interimde 2020 | median 18.5 months | median 15.1 months | Medians given in the primary publication without a hazard ratio in its abstract; 81% of control-group patients who had progressed crossed over to olaparib. Labelled interim because the later survival paper reports the final overall survival analysis (its abstract background states that the final analysis had not yet been reported). |
| OSCohort A (BRCA1, BRCA2 or ATM alteration; n=245) | finalHussain 2020 | median 19.1 months | median 14.7 months | HR 0.69 (95% CI 0.50–0.97)P=0.02Final overall survival analysis at a data maturity of approximately 60%. Overall, 86 of 131 control patients (66%) crossed over to olaparib (56 of 83 in cohort A, 67%). A sensitivity analysis adjusted for crossover gave a hazard ratio for death of 0.42 (95% CI 0.19 to 0.91) in cohort A. |
| OSCohort B (alterations in 12 other prespecified genes; n=142) | finalHussain 2020 | median 14.1 months | median 11.5 months | Medians only; no hazard ratio is given in the abstract. Crossover-adjusted hazard ratio for death 0.83 (95% CI 0.11 to 5.98). |
| OSCohorts A and B combined (n=387) | finalHussain 2020 | median 17.3 months | median 14 months | Medians only; no hazard ratio is given in the abstract. Crossover-adjusted hazard ratio for death 0.55 (95% CI 0.29 to 1.06). |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| rPFS | 0.34 | 0.25–0.47 |
| OS | 0.69 | 0.5–0.97 |
- Olaparib (experimental)
- Enzalutamide or abiraterone (physician's choice) (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Olaparib | Enzalutamide or abiraterone (physician's choice) |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 5 | 62.6% | 38.2% |
| 9 | 43.0% | 17.7% |
| 14 | 26.9% | 6.8% |
| 19 | 16.9% | 2.6% |
- Olaparib (experimental)
- Enzalutamide or abiraterone (physician's choice) (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Olaparib | Enzalutamide or abiraterone (physician's choice) |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 12 | 63.8% | 57.6% |
| 23 | 42.2% | 34.8% |
| 35 | 26.9% | 20.1% |
| 46 | 17.8% | 12.1% |
Appears in
Sources
de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382(22):2091-2102.
Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;383(24):2345-2357.