Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1 and/or BRCA2 mutations (BRCAm) face worse outcomes compared with patients with mCRPC without BRCAm.1 Therapies that target DNA damage responses in tumor cells by inhibiting poly(ADP-ribose) polymerase (PARP) activity have pioneered a new treatment paradigm in the first-line mCRPC setting for patients with BRCAm. For this subgroup of patients with BRCAm, we reviewed key clinical and safety outcomes for olaparib, the first PARP inhibitor to receive regulatory approval for the treatment of patients with mCRPC and a BRCAm. We focused on both olaparib monotherapy, based on findings from the PROfound trial (NCT02987543), and olaparib in combination with abiraterone, as investigated in the PROpel trial (NCT03732820): two trials that were pivotal in the development and subsequent regulatory approval of olaparib.
The PROfound trial was the first phase III study to demonstrate the efficacy of a PARP inhibitor in a biomarker-selected mCRPC population, who had progressed on androgen receptor pathway inhibitors.2 In cohort A (patients with BRCA1, BRCA2, or ATM mutations), olaparib led to significantly longer radiographic progression-free survival (rPFS) than the control arm, which received physician’s choice of enzalutamide or abiraterone. An rPFS benefit was also observed in the overall trial population, including patients with 15 prespecified homologous recombination repair mutations. In post hoc exploratory analyses of the BRCAm subgroup, consistent with outcomes in cohort A, rPFS was longer for patients receiving olaparib than for those in the control arm (median 9.8 vs 3.0 months; hazard ratio [HR] 0.22; 95% confidence interval [CI] 0.15–0.32).3 Overall survival (OS; 59% maturity) was also longer in the olaparib than the control arm (median 20.1 vs 14.4 months; HR 0.63; 95% CI 0.42–0.95; Figure 1).
Figure 1: Overall survival (OS) in patients with BRCA1 and/or BRCA2 mutations (BRCAm; including co-occurring mutations with other homologous recombination repair genes) from PROfound. Data cut-off: March 20, 2020. Control refers to the physician’s choice of next generation hormonal agent (either abiraterone or enzalutamide). Reproduced with the permission of Wolters Kluwer Health Inc. from Mateo J et al.3
CI, confidence interval; HR, hazard ratio; OS, overall survival.
The PROpel trial assessed olaparib plus abiraterone in a broader, biomarker-unselected first-line mCRPC population.4 The study met its primary endpoint and demonstrated a statistically significant and clinically meaningful rPFS benefit with olaparib plus abiraterone versus placebo plus abiraterone, according to investigator assessment in the intention-to-treat (ITT) population. Post hoc exploratory analyses showed that the combination of olaparib plus abiraterone had a clinically meaningful benefit over placebo plus abiraterone for rPFS and OS in the first-line treatment setting for patients with BRCAm mCRPC: median investigator-assessed rPFS was not reached (NR) for olaparib plus abiraterone versus 8.4 months for placebo plus abiraterone (HR 0.23; 95% CI 0.12–0.43) and median OS (45% maturity) was NR for olaparib plus abiraterone versus 23.0 months for placebo plus abiraterone (HR 0.29; 95% CI: 0.14–0.56; Figure 2).5
Figure 2. Overall survival (OS) in patients with BRCA1 and/or BRCA2 mutations from PROpel. Data cut-off: October 12, 2022. Reproduced with the permission of Elsevier from Saad F et al.5
CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survival. Phase II clinical trials, including TOPARP-B (NCT03012321) and BRCAAway (NCT03012321), reinforced the findings of olaparib in patients with BRCAm mCRPC. Both trials showed high response rates and prolonged rPFS in patients receiving olaparib or olaparib plus abiraterone, respectively; median rPFS in TOPARP-B was 8.3 (95% CI 5.5–13.0) months and in BRCAAway was 39 (95% CI 22–NR) months.6,7
Side effects in patients with BRCAm in both PROfound and PROpel were consistent with the known safety profiles of olaparib and abiraterone when used alone, and those observed in the respective ITT populations.3,8 Anemia was the most common side effect in the olaparib arm of both PROfound and PROpel. Most anemia events occurred during the first 2 months of treatment and were manageable with supportive care, not precluding continued treatment with olaparib in most patients.
In conclusion, our review highlights that in clinical trials, olaparib, both on its own and in combination with abiraterone, resulted in substantial clinical benefits for patients with BRCAm mCRPC, delaying disease progression and improving survival over standard treatments. These findings support the integration of olaparib early in the treatment sequence for patients with BRCAm mCRPC. Our findings also highlight the importance of early and comprehensive genetic testing to identify patients with BRCAm who may derive the greatest benefit from PARP inhibitors such as olaparib.
Written by: Fred Saad,1 Andrew J. Armstrong,2 Neal Shore,3 Daniel J. George,4 Mototsugu Oya,5 Mikio Sugimoto,6 Rana R. McKay,7 Maha Hussain8 and Noel W. Clarke9
- Service d’Urologie, Centre Hospitalier de l’Université de Montréal/CRCHUM, Université de Montréal, Montréal, Canada, QC
- Divisions of Medical Oncology and Urology, Duke Cancer Institute Center for Prostate and Urologic Cancer, Duke University, Durham, NC, USA
- Carolina Urologic Research Center, Myrtle Beach, SC, USA
- Department of Medicine, Duke Cancer Institute, Duke University, Durham, NC, USA
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
- Department of Urology, Kagawa University Hospital, Kagawa, Japan
- Department of Medicine, University of California San Diego, San Diego, CA, USA
- Division of Hem/Onc, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Surgery, The Christie and Salford Royal NHS Foundation Trusts, Manchester, UK
References:
- Olmos D, Lorente D, Alameda D, et al: Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes. Ann Oncol 35:458-472, 2024
- de Bono J, Mateo J, Fizazi K, et al: Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 382:2091-2102, 2020
- Mateo J, de Bono JS, Fizazi K, et al: Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in BRCA1 and/or BRCA2 in the PROfound trial. J Clin Oncol 42:571-583, 2024
- Clarke NW, Armstrong AA, Thiery-Vuillemin A, et al: Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid 1:EVIDoa2200043, 2022
- 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 24:1094-1108, 2023
- Hussain M, Kocherginsky M, Agarwal N, et al: Abiraterone, olaparib, or abiraterone + olaparib in first-line metastatic castration-resistant prostate cancer with DNA repair defects (BRCAAway). Clin Cancer Res 30: 4318-4328, 2024
- Mateo J, Porta N, Bianchini D, et al: Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 21:162-174, 2020
- AstraZeneca: Lynparza® (olaparib) in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer, 2023. https://www.fda.gov/media/167485/download. Last accessed: March 2024