Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 May;20(3):445-466.
doi: 10.1007/s11523-025-01146-4. Epub 2025 May 21.

Olaparib Monotherapy or in Combination with Abiraterone for the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) and a BRCA Mutation

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 Hussain  8 , Noel W Clarke  9
Affiliations
Review

Olaparib Monotherapy or in Combination with Abiraterone for the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) and a BRCA Mutation

Fred Saad et al. Target Oncol. 2025 May.

Abstract

Treatment strategies to improve outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) are evolving. Of particular interest are therapies that target DNA damage responses in tumor cells by inhibiting poly(ADP-ribose) polymerase (PARP) activity. Several PARP inhibitors have recently received regulatory approval for the treatment of patients with mCRPC, of which olaparib was the first for prostate cancer. Olaparib received approval as a monotherapy following the PROfound study (NCT02987543) and in combination with abiraterone following the PROpel study (NCT03732820) for mCRPC. Both PROfound (homologous recombination repair mutation biomarker-selected) and PROpel (biomarker unselected) patients demonstrated statistically significant longer radiographic progression-free survival (rPFS) with olaparib versus their respective control arms in the intention-to-treat population. In both studies, the greatest clinical benefit with olaparib was seen in patients with BRCA1 and/or BRCA2 mutations (BRCAm): PROfound rPFS hazard ratio (HR) 0.22 (95% confidence interval [CI] 0.15-0.32); PROpel rPFS HR 0.23 (95% CI 0.12-0.43). Clinical benefit was also observed in terms of overall survival: PROfound HR 0.63 (95% CI 0.42-0.95); PROpel HR 0.29 (95% CI 0.14-0.56). We provide a comprehensive overview of the utility of olaparib for patients with mCRPC harboring a BRCAm. Key clinical and safety data in BRCAm subgroup populations are discussed, predominantly based on findings from PROfound and PROpel, as well as investigator-initiated studies, to help inform treatment decision-making in this patient population. We also discuss the importance of genetic testing to identify patients who may optimally benefit from treatment with olaparib, either as a monotherapy or in combination with abiraterone.

Plain language summary

In the USA, prostate cancer is the most commonly diagnosed cancer in men. It affects approximately one in eight men during their lifetime. Metastatic castration-resistant prostate cancer (mCRPC) occurs when the cancer spreads beyond the prostate gland and the disease progresses despite treatment with standard hormonal therapy. Patients who have cancers with mutations in BRCA1 and/or BRCA2 genes have poor outcomes, and additional life-prolonging treatments are needed. Olaparib is a drug approved to treat certain patients with mCRPC, both alone and in combination with abiraterone. Approval was based on two landmark clinical trials called PROfound and PROpel. PROfound compared olaparib directly with the hormonal therapies abiraterone or enzalutamide. PROpel evaluated whether combining olaparib with abiraterone would delay the progression of cancer compared with just abiraterone. After these two studies were completed, results were analyzed specifically in patients who had a BRCA mutation in their cancer. We have compiled the results in patients with mCRPC with BRCA mutations and show that both olaparib on its own or in combination with abiraterone resulted in substantial clinical benefits in delaying disease progression and improving survival over standard treatments for mCRPC. The side effects that patients with a BRCA mutation experienced were similar to those in the overall patient population originally analyzed. We also discuss the importance of testing men with prostate cancer for these genetic mutations before starting treatment to help identify patients who may benefit the most from olaparib on its own or in combination with abiraterone.

PubMed Disclaimer

Conflict of interest statement

Declarations. Funding: Financial support was provided by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who are codeveloping olaparib. Conflict of interest: Fred Saad has received consultancy and advisory fees from AbbVie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca/MedImmune, Bayer, Janssen Oncology, Knight Therapeutics, Myovant Sciences, Novartis, Pfizer, and Sanofi; honoraria from AbbVie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Knight Therapeutics, Merck, Myovant Sciences, Novartis, Pfizer, and Sanofi; and institutional research funding from Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Merck, Novartis, Pfizer, and Sanofi. Andrew J. Armstrong has received consultancy or advisory fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Dendreon, Exelixis, FORMA Therapeutics, GoodRX, Janssen, Merck, Myovant Sciences, Novartis, and Pfizer; travel and accommodation expenses from Astellas; and institutional research funding from Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Constellation Pharmaceuticals, Dendreon, FORMA Therapeutics, Janssen Oncology, Gilead Sciences, Merck, Novartis, Pfizer, and Roche/Genentech and holds institutional patents, royalties, and other intellectual property for circulating tumor cell novel capture technology. Neal Shore has acted in a consulting or advisory role for AbbVie, Accord, Alessa Therapeutics, Amgen, Antev, Asieris, Astellas, AstraZeneca, Aura Biosciences, Bayer, Bioprotect, Bristol Myers Squibb, Boston Scientific, CGOncology, Clarity, Dendreon, Exact Imaging, Ferring, Fize Medical, Foundation Medicine, Invitae, Janssen, Lantheus, Lilly, Dxhealth, Merck, Minomic, Myriad, Novartis, Pfizer, Photocure, Promaxo, Protara, Sanofi Genzyme, Telix, Tolmar, and Urogen; and in a leadership or fiduciary role for Alessa Photocure and Tuteix. Neal Shore is an editorial board member of Targeted Oncology and as such was not involved in the selection of peer reviewers for the manuscript or any of the subsequent editorial decisions. Daniel J. George has received grants from Calithera, Convergence, and Corvus; grants and personal fees from Astellas, Bristol Myers Squibb, Johnson and Johnson Pharmaceuticals, Merck Sharp & Dohme, Novartis, and Pfizer; personal fees from AstraZeneca, Axess Oncology, Capio Bioscience, Flatiron, Michael J Hennessey Associates, Millennium Medical Publishing, Myovant Sciences Inc, NCI Genitourinary, Nektar Therapeutics, Physician Education Resource, UroGPO, Vizuri Health Sciences, Platform Q, Propella Therapeutics, RevHealth, Seattle Genetics, WebMD, and Xcures; grants, personal fees, and non-financial support from Bayer Healthcare Pharmaceuticals, and Exelixis Inc; personal fees and non-financial support from UroToday; and other support from the American Association for Cancer Research, all outside of the submitted work. Mototsugu Oya has received consultancy or advisory fees from Bayer; honoraria from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb Japan, Chugai, Janssen, MSD, Novartis, Ono Pharmaceuticals, Pfizer, Sanofi, and Takeda and research funding from Astellas Pharma, Novartis, and Pfizer. Mikio Sugimoto has received honoraria from Astellas, AstraZeneca, Janssen Pharmaceuticals, and Takeda; research funding from Astellas, AstraZeneca, Bristol Myers Squibb, Janssen, MSD, and Pfizer; and travel and accommodation expenses from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, and MSD. Rana R. McKay has received institutional grant/research support from AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Oncternal, and Tempus; consultancy fees from Arcus, Ambrx, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Caris, Dendreon, Eisai, Exelixis, Johnson & Johnson, Lilly, Merck, Myovant, NeoMorph, Novartis, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Telix, and Tempus. Maha Hussain has received honoraria from AstraZeneca, Bayer, Convergent, Novartis, and Tango; has served on advisory boards and received honoraria for the following invited educational events/lectures/manuscripts: PROST8 Consensus Conference Steering Committee member and session chair (honorarium received from MJH, RTP Lecture, AACR Satellite Symposium Lecture, Academic CME and travel expenses); South Africa Oncology Society lecture (honorarium received from AstraZeneca); Bayer APEX meeting (travel/accommodation, honorarium); 2nd International Genitourinary Cancer Conference Prostate Cancer Educational program (honorarium received from AstraZeneca); PER/NYGU – co-chair/speaker, RTP, Prostate Cancer Diagnostic Medical Education (Virtual) program (honorarium from AstraZeneca). Maha Hussain has also had clinical trials funding contracts with Arvinas, AstraZeneca, Bayer, and Northwestern University. Noel W. Clarke has received institutional consultancy or advisory fees from Astellas Pharma, Bayer, Ferring, Janssen-Cilag, and Sanofi; speaker bureau fees from Astellas Pharma, AstraZeneca, Bayer, Janssen-Cilag, Pfizer, and Sanofi; and travel and accommodation expenses associated with lectures and advisory board meetings from Astellas Pharma, AstraZeneca, Bayer, Ferring, Ipsen, Janssen-Cilag, and Sanofi. Ethics approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable. Availability of data and material: No new data were generated or analyzed in support of this research. Code availability: Not applicable. Author contributions: All authors contributed to the concept and development of this review article, including drafting and critical revision of the manuscript. All authors have approved the submitted version.

Figures

Fig. 1
Fig. 1
Kaplan–Meier curves for a radiographic progression-free survival (rPFS) by blinded independent central review and b overall survival (OS) in patients with BRCA1 and/or BRCA2 mutations (BRCAm; including co-occurring mutations with other homologous recombination repair genes) from PROfound [5, 43]. Data cut-off for rPFS: June 4, 2019; data cut-off for OS: March 20, 2020. Control refers to investigator’s choice of next-generation hormonal agent (either abiraterone or enzalutamide). a Is reproduced from Mateo et al. [5]. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. b Is reproduced with permission of Wolters Kluwer Health Inc. from Mateo J et al. [43]. CI confidence interval, HR hazard ratio
Fig. 2
Fig. 2
Kaplan–Meier curves for a radiographic progression-free survival (rPFS) and b overall survival (OS) by no prior taxane and prior taxane in patients with a mutation in BRCA1 only or BRCA2 only from PROfound [43]. Data cut-off for rPFS: June 4, 2019; data cut-off for OS: March 20, 2020. Control refers to investigator’s choice of next-generation hormonal agent (either abiraterone or enzalutamide). a Is reproduced with permission of Wolters Kluwer Health Inc. from Mateo et al. [43]. b Is reproduced from Hussain et al. [53]. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. CI confidence interval, HR hazard ratio, NR not reached
Fig. 3
Fig. 3
Best percentage change in a size of target lesions, b prostate-specific antigen (PSA), and c circulating tumor cell (CTC) levels in patients with BRCA1 and/or BRCA2 mutations from PROfound [43]. Data cut-off: June 4, 2019. Analysis of best percentage change from baseline in size of target lesions includes patients with measurable disease at baseline (as assessed by blinded independent central review) and a valid baseline and post-baseline RECIST assessment. The dashed line at + 20 indicates the threshold for progressive disease, and the dashed line at − 30 indicates the threshold for partial response. Analysis of best percentage change from baseline in PSA includes patients with a valid baseline and post-baseline PSA measurement. The dashed line at − 50 indicates the threshold for PSA response. Analysis of best percentage change from baseline in CTC includes patients with ≥ 5 cells/7.5 mL at baseline and a post-baseline CTC measurement. Patients with values lower than − 100% have an imputed value of − 100%. Patients with values > 100% have an imputed value of 100%. Control refers to investigator’s choice of next-generation hormonal agent (either abiraterone or enzalutamide). a–c Are reproduced with permission of Wolters Kluwer Health Inc. from Mateo et al. [43]. bid twice daily, RECIST Response Evaluation Criteria in Solid Tumors
Fig. 4
Fig. 4
Kaplan–Meier curves for a radiographic progression-free survival (rPFS) by investigator assessment (data cut-off [DCO]-1), b rPFS by blinded independent central review (DCO1), and c overall survival (OS) (DCO3) in patients with BRCA1 and/or BRCA2 mutations from PROpel [58, 62]. DCO1: July 30, 2021; DCO3: October 12, 2022. Circles indicate censored observations. Landmark rates, data on file. 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. a and c Are reproduced from Saad et al. [58]. © 2023, with permission from Elsevier. b Is reproduced from Saad F, et al. Poster presented at 2022 annual meeting of European Society for Medical Oncology (ESMO). © The authors. CI confidence interval, HR hazard ratio, NR not reached
Fig. 4
Fig. 4
Kaplan–Meier curves for a radiographic progression-free survival (rPFS) by investigator assessment (data cut-off [DCO]-1), b rPFS by blinded independent central review (DCO1), and c overall survival (OS) (DCO3) in patients with BRCA1 and/or BRCA2 mutations from PROpel [58, 62]. DCO1: July 30, 2021; DCO3: October 12, 2022. Circles indicate censored observations. Landmark rates, data on file. 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. a and c Are reproduced from Saad et al. [58]. © 2023, with permission from Elsevier. b Is reproduced from Saad F, et al. Poster presented at 2022 annual meeting of European Society for Medical Oncology (ESMO). © The authors. CI confidence interval, HR hazard ratio, NR not reached
Fig. 5
Fig. 5
Kaplan–Meier curves for a time to first subsequent therapy (data cut-off [DCO]-3), b time to second disease progression (PFS2; DCO3), and c time to prostate-specific antigen (PSA) progression (DCO3) in patients with BRCA1 and/or BRCA2 mutations from PROpel [58]. DCO3: October 12, 2022. a Time to first subsequent therapy (excluding radiotherapy) was defined as the time from randomization to the start date of the first subsequent anti-cancer therapy after discontinuation of randomized treatment or death from any cause (whichever was earlier). Any patient not known to have died at the time of the analysis and not known to have had a subsequent therapy was censored at the last known time to have not received first subsequent therapy. b Patients who had not had a second disease progression event or died at the time of analysis, or who had second progression or died after two or more missed visits, were censored at the latest evaluable assessment when they were known to be alive and without a second disease progression. c Time to PSA progression was defined as the time from randomization to first PSA progression per the Prostate Cancer Working Group 3 criteria. a–c Are reprinted from Saad et al. [58]. © 2023, with permission from Elsevier. CI confidence interval, HR hazard ratio, NR not reached, TFST time to first subsequent therapy
Fig. 5
Fig. 5
Kaplan–Meier curves for a time to first subsequent therapy (data cut-off [DCO]-3), b time to second disease progression (PFS2; DCO3), and c time to prostate-specific antigen (PSA) progression (DCO3) in patients with BRCA1 and/or BRCA2 mutations from PROpel [58]. DCO3: October 12, 2022. a Time to first subsequent therapy (excluding radiotherapy) was defined as the time from randomization to the start date of the first subsequent anti-cancer therapy after discontinuation of randomized treatment or death from any cause (whichever was earlier). Any patient not known to have died at the time of the analysis and not known to have had a subsequent therapy was censored at the last known time to have not received first subsequent therapy. b Patients who had not had a second disease progression event or died at the time of analysis, or who had second progression or died after two or more missed visits, were censored at the latest evaluable assessment when they were known to be alive and without a second disease progression. c Time to PSA progression was defined as the time from randomization to first PSA progression per the Prostate Cancer Working Group 3 criteria. a–c Are reprinted from Saad et al. [58]. © 2023, with permission from Elsevier. CI confidence interval, HR hazard ratio, NR not reached, TFST time to first subsequent therapy
Fig. 6
Fig. 6
Frequency and severity of the most common adverse events (AEs; frequency ≥ 10% in either treatment arm from the intention-to-treat [ITT] population) or AEs grade 3 or higher (frequency ≥ 2% in either treatment arm from the ITT population), including other hematological AEs in patients with BRCA1 and/or BRCA2 mutations from PROpel [61]. Patients with multiple events were counted once for each preferred term. Includes AEs with onset date or worsening on or after the date of first dose and up to and including 30 days after discontinuation of randomized treatment. Anemia category (data on file) includes anemia, decreased hemoglobin level, decreased red-cell count, decreased hematocrit level, erythropenia, macrocytic anemia, normochromic anemia, normochromic normocytic anemia, and normocytic anemia. Neutropenia category (data on file) includes febrile neutropenia, granulocyte count decreased, neutropenia, neutropenic infection, neutropenic sepsis, neutrophil count decreased, idiopathic neutropenia, and agranulocytosis; other hematological AEs (data on file). ALT alanine aminotransferase, WBC white blood cell
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–63. - PubMed
    1. Moreira DM, Howard LE, Sourbeer KN, Amarasekara HS, Chow LC, Cockrell DC, et al. Predicting time from metastasis to overall survival in castration-resistant prostate cancer: results from SEARCH. Clin Genitourin Cancer. 2017;15(1):60-6.e2. - PMC - PubMed
    1. Shore ND, Laliberte F, Ionescu-Ittu R, Yang L, Mahendran M, Lejeune D, et al. Real-world treatment patterns and overall survival of patients with metastatic castration-resistant prostate cancer in the US prior to PARP inhibitors. Adv Ther. 2021;38(8):4520–40. - PMC - PubMed
    1. Kariburyo-Yay F, George DJ, Aggarwal H, Tepsick JG, Yu R, Li W, et al. Real-world baseline treatment patterns and overall survival (rwOS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in the United States. J Clin Oncol. 2024;42(16 Suppl):5054.
    1. 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):2091–102. - PubMed

MeSH terms

LinkOut - more resources