Figure 1. Summary of PROpel results. CI, confidence interval; DCO, data cut-off; HR, hazard ratio; INV, investigator-assessed; OS, overall survival; rPFS, radiographic progression-free survival. DCO1: July 30, 2021, DCO3: October 12, 2022
PROpel (NCT03732820; Figure 1) was the first of the Phase 3 PARP inhibitor and NHA trials to read out and investigate the combination of olaparib with abiraterone in the first-line treatment of patients with mCRPC enrolled irrespective of HRRm status.1 It was initiated based on the results of the Phase 2 Study 8 trial, which demonstrated a statistically significant radiographic progression-free survival (rPFS) benefit with olaparib plus abiraterone versus placebo plus abiraterone in biomarker unselected patients with mCRPC who had progressed on prior docetaxel.2 PROpel met its primary endpoint and demonstrated a statistically significant and clinically meaningful rPFS benefit with olaparib plus abiraterone versus placebo plus abiraterone, a current standard of care (median 24.8 months vs. 16.6 months, respectively; hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.001; data cutoff 1: July 30, 2021; Figure 2).1 Sensitivity analysis of rPFS found a benefit was observed in all prespecified subgroups analyzed.
Figure 2. Kaplan–Meier estimate of investigator-assessed rPFS.1 rPFS by investigator assessment. There were 168 progression or death events in the olaparib plus abiraterone arm and 226 in the placebo plus abiraterone arm. The median (range) duration of follow-up for disease progression in patients with censored data was 19.3 months (0.03–30.59 months) in the olaparib plus abiraterone arm and 19.4 months (0.03–30.16 months) in the placebo plus abiraterone arm. Circle indicates a censored observation. Data cutoff: July 30, 2021. CI, confidence interval; HR, hazard ratio; rPFS, radiographic progression-free survival. From NEJM Evidence, Clarke NW et al, Abiraterone and olaparib for metastatic castration-resistant prostate cancer, 1(9), doi: 10.1056/EVIDoa2200043. Copyright © (2022) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society)
We have now reported the prespecified final overall survival (OS) results, which show that, although the difference between the treatment arms was not statistically significant, median OS in the olaparib plus abiraterone arm was the longest reported to date in an mCRPC trial at 42.1 months, 7.4 months longer than the 34.7 months observed for the placebo plus abiraterone arm (HR 0.81, 95% CI 0.67–1.00; P=0.054; data cutoff 3: October 12, 2022; Figures 1 and 3).3 These data are notable given that PROpel included patients who were symptomatic at baseline (patients who had a Brief Pain Inventory-Short Form item 3 score of ≥4 or were taking opiates), comprising 23% of the total study population.
Figure 3. Kaplan–Meier estimate of OS.3 Kaplan–Meier estimate of OS in the intention-to-treat population. Data cutoff October 12, 2022. Median follow-up for OS in patients with censored data was 36.6 months (IQR 34.1–40.3) for olaparib plus abiraterone and 36.5 months (33.8–40.3) for placebo plus abiraterone. Any patient not known to have died at the time of analysis will be censored on the basis of the last recorded date on which the patient was known to be alive. Circle indicates a censored observation. CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survival. Reprinted from The Lancet, Vol. 24, Issue 10, Saad F et al, Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial, pp.1094–108, Copyright (2023), with permission from Elsevier.
The patient population of PROpel was not selected based on HRRm status; however, tumor tissue and circulating tumor DNA testing were conducted following randomization and prior to primary analysis in order to determine HRRm status, including the presence of BRCA1 and/or BRCA2 mutations (BRCAm). Efficacy was then assessed for the subgroups of patients with and without HRRm. We report numerical rPFS and OS benefits for HRRm, non-HRRm, BRCAm, and non-BRCAm subgroups of patients (Figure 4A and B). The greatest efficacy was observed in the population of patients with BRCAm (rPFS: HR 0.23, 95% CI 0.12–0.43; OS: HR 0.29, 95% CI 0.14–0.56; Figure 4A and B), and a benefit was also observed for patients who did not have BRCAm (rPFS: HR 0.76, 95% CI 0.61–0.94; OS: HR 0.91, 95% CI 0.73–1.13; Figure 4A and B).3 HRRm testing is important to assess relative benefit-risk of intensification of therapy by adding a PARP inhibitor to a NHA, and for assessment of prognosis and familial risk.
Figure 4. Forest plot of rPFS (A) and OS results (B) in the ITT, HRRm, non-HRRm, BRCAm, and non-BRCAm populations. CI, confidence interval; HR, hazard ratio; HRRm, homologous recombination repair mutation; ITT, intention-to-treat; NR, not reached; OS, overall survival; rPFS, radiographic progression-free survival.
Additional secondary and exploratory endpoints including time to first subsequent therapy or death and time to second progression or death in the overall population favored the combination of olaparib plus abiraterone and supported the primary analysis.
Figure 5. Kaplan–Meier estimate of rPFS (A) and OS (B) in the BRCAm population.3 Data cutoff July 30, 2021. A circle indicates a censored observation. Data cutoff: October 12, 2022. Any patient not known to have died at the time of analysis was censored on the basis of the last recorded date on which the patient was known to be alive. Circle indicates a censored observation. CI, confidence interval; HR, hazard ratio; OS, overall survival; rPFS, radiographic progression-free survival. Reprinted from The Lancet, Vol. 24, Issue 10, Saad F et al, Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial, pp.1094–108, Copyright (2023), with permission from Elsevier.
At primary analysis, the safety profile of olaparib plus abiraterone was consistent with the individual safety profiles for each drug. At final analysis, no new safety signals were observed and the most common adverse events were anemia (any grade: 50%, n=198; grade 3/4: 16%, n=64), fatigue/asthenia (39%, n=154; grade 3/4: 3%, n=10), and nausea (31%, n=122; grade 3/4: <1%, n=1) in the olaparib plus abiraterone arm and fatigue/asthenia (30%, n=120; grade 3/4: 2%, n=6), back pain (20%, n=79; grade 3/4: 2%, n=6), and arthralgia (19%, n=77; grade 3/4: 1%, n=2) in the placebo plus abiraterone arm.3 The rate of anemia was lower than has been seen in other trials of PARP inhibitors combined with NHAs; however, this comparison should be treated with caution because of differences in trial design between studies.4,5
No clinically meaningful effect on overall health-related quality of life (HRQoL) based on Functional Assessment of Cancer Therapy-Prostate (FACT-P) Total Score was observed when olaparib was added to standard of care abiraterone treatment.
Understanding the unique treatment goals of individual patients, as well as the benefit-risk profile, including key clinical endpoints, subgroup analyses, HRQoL, and tolerability of different treatments, is essential to support patient-physician discussions and shared decision-making.
Overall, the results of PROpel show that there was clinical benefit with olaparib plus abiraterone versus placebo plus abiraterone in patients with and without HRRm or BRCAm, that the combination treatment did not impact on HRQoL, and that the safety profile was predictable and manageable. These findings support combination treatment with olaparib plus abiraterone as an important new first-line treatment option for patients with mCRPC.
Written by:
- Fred Saad, MD, FRCS, Professor, Department of Surgery, Raymond Garneau Chair in Prostate Cancer, Director of Prostate Cancer Research, Director of GU Oncology, Université de Montréal, University of Montreal Hospital Centers (CHUM), Montréal, QC
- Noel Clarke, MBBS, FRCS, ChM, FRCS, Professor of Urological Oncology, Director GU Research Group Paterson Institute; Director MCRC Pan-Manchester Biobank, The Christie NHS Foundation Trust, Manchester, UK
- Mototsugu Oya, MD, Professor, Keio University School of Medicine, Tokyo, Japan
- Andrew J. Armstrong, MD, MSc, Medical Oncologist, Professor of Medicine, Surgery, Pharmacology and Cancer Biology, Duke Cancer Institute, Center for Prostate and Urologic Cancers, Durham, NC
This study was supported by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who are codeveloping olaparib. Medical writing assistance was provided by Laura Smart, MChem, from Mudskipper Business Ltd, funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
References:
- Clarke N, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evidence 2022;1:DOI: 10.1056/EVIDoa2200043.
- Clarke N, Wiechno P, Alekseev B et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2018;19:975–86.
- Saad F, Clarke NW, Oya M et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol 2023;24:1094–108.
- Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet 2023;402:291–303.
- Chi KN, Rathkopf D, Smith MR et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol 2023;41:3339–51.
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Olaparib plus Abiraterone Versus Placebo plus Abiraterone in Metastatic Castration-Resistant Prostate Cancer (PROpel): Final Prespecified Overall Survival Results of a Randomised, Double-Blind, Phase 3 Trial - Fred Saad