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, Andrew J. Armstrong, Neal D. Shore, Daniel J. George, Mototsugu Oya, Mikio Sugimoto, Rana R. McKay, Maha Hussain, Noel W. Clarke
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. 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.