FDA Approves Olaparib for HRR-Mutated Metastatic Castration-Resistant Prostate Cancer


Approximately 20% to 30% of men with metastatic castration-resistant prostate cancer have HRR gene mutation.

Clinical trial

Olaparib (Lynparza, AstraZeneca and Merck) has been approved by the FDA to treat individuals with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC), according to a news release.

Prostate cancer is the second-most common cancer in men; it affected approximately 1.3 million men in 2018, according to AstraZeneca. Five-year survival has remained low despite the uptick in available therapies for mCRPC. Thirty-three percent of men with CRPC diagnosis will develop metastases within 2 years, and 20% to 30% of patients with mCRPC experience HRR deficiency (HRD).

HRD is targeted by poly ADP ribose polymerase (PARP) inhibitors, which have shown to block a rescue DNA damage repair mechanism through trapping PARP bound to DNA single-strand breaks, leading to replication fork stalling, causing their collapse and the development of DNA double-strand breaks, effectively leading to cancer cell death.

The FDA’s approval is based on the phase 3, prospective, multi-center, randomized, open-label PROfound trial. The trial evaluated olaparib’s safety and efficacy compared with enzalutamide or abiraterone. Patients with HRRm genes were placed into 1 of 2 arms. The study’s main objective was to see radiographic progression-free survival (rPFS) in patients with BRCA1/2 or ATM gene mutations, which is a subset of HRRm. The study results showed that olaparib reduced the risk of disease progression or death by 66% and improved rPFS to a median of 7.4 months compared with 3.6 months with enzalutamide or abiraterone.

Results from the PROfound trial additionally reported clinically significant improvement in overall survival (OS), as olaparib use for treatment of individuals with mCRPC and BRCA1/2 or ATM gene mutation showed a 31% reduced risk of death and improved OS to a median of 19.0 months, compared with 14.6 months with enzalutamide or abiraterone.

Results of the phase 3 trial have been published in The New England Journal of Medicine.

AstraZeneca and MSD plan to continue additional trial in metastatic prostate cancer, including the ongoing phase 3 PROpel trial.

“Lynparza is the only PARP inhibitor approved with phase 3 data for men with HRR gene-mutated metastatic castration-resistant prostate cancer,” said Roy Baynes, senior vice president and head of global clinical development, chief medical officer, MSD Research Laboratories. “This approval highlights the importance of genomic testing to help identify treatment options for men in this patient population. We are proud to work in collaboration with AstraZeneca toward our overall goal of improving outcomes for patients.”


1. Lynparza approved in the US for HRR gene-mutated metastatic castration-resistant prostate cancer. News Release. AstraZeneca; May 20, 2020. Accessed May 20, 2020. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/lynparza-approved-in-the-us-for-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer.html

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