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

Sep 23, 2026

Treatment strategies for metastatic castration-resistant prostate cancer (mCRPC) are rapidly evolving, with growing focus on DNA damage response inhibition through poly(ADP-ribose) polymerase (PARP) activity. Olaparib was the first approved PARP inhibitor for prostate cancer, first as monotherapy after PROfound and then in combination with abiraterone after PROpel. In intention-to-treat populations, olaparib improved radiographic progression-free survival versus control, with greatest benefit in BRCA1 and/or BRCA2 mutation carriers (BRCAm). Overall survival benefits were also reported, and the article synthesizes clinical efficacy and safety data to support treatment decisions, emphasizing genetic testing to identify patients most likely to benefit from olaparib.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Abstract

Plain Language Summary

Key Clinical Findings and Evidence Base

Biomarker Testing for BRCAm

Summary of Key Phase 3 Trials (PROfound and PROpel)

Targeted Oncology (2025) 20:445–466 [https://doi.org/10.1007/s1](https://doi.org/10.1007/s1) 1523-025-01146-4 Olaparib Monotherapy or in Combination with Abiraterone for the Treatment of Patients with Metastatic Castration‑Resistant Prostate Cancer (mCRPC) and a BRCA Mutation Fred Saad1 · Andrew J. Armstrong2 · Neal Shore3 · Daniel J. George4 · Mototsugu Oya5 · Mikio Sugimoto6 · Rana R. McKay7 · Maha Hussain8 · Noel W. Clarke9 Accepted: 18 April 2025 / Published online: 21 May 2025 © The Author(s) 2025 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 amonotherapy 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

FAQs

What is the main focus of this overview on olaparib in mCRPC?

The document focuses on the utility of olaparib for patients with metastatic castration-resistant prostate cancer (mCRPC) who have BRCA1 and/or BRCA2 mutations, using evidence mainly from PROfound and PROpel and related studies.

How were olaparib monotherapy and olaparib combination therapy evaluated?

Olaparib monotherapy was evaluated in PROfound versus hormonal therapies such as abiraterone or enzalutamide. Olaparib plus abiraterone was evaluated in PROpel versus abiraterone alone to delay cancer progression.

Why is genetic testing emphasized before choosing olaparib treatment?

Genetic testing is emphasized to identify patients with BRCA mutations who may optimally benefit from olaparib, either alone or in combination with abiraterone.

Sep 23, 2026

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