FDA Approves Olaparib for HRR Gene-Mutated mCRPC


The FDA approved olaparib for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer.

The FDA has approved olaparib (Lynparza) for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone (Zytiga), according to AstraZeneca and Merck, the joint developers of the agent.

The FDA recommended a dose of 300 mg of olaparib, taken orally twice daily, with or without food. 

“Prostate cancer has lagged behind other solid tumors in the era of precision medicine,” Maha Hussain, MD, one of the principle investigators of the trial and deputy director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said in a press release. “I am thrilled by the approval of (olaparib), which now brings a molecularly targeted treatment for this patient population in the US. The PROfound trial was an international effort and I want to thank the patients, their families, the investigators, and their teams involved in making it possible.”

Patients will be selected for therapy based on an FDA-approved companion diagnostic for olaparib. Foundation Medicine announced that they have received FDA approval for the FoundationOne CDx to be used in this space.2 The BRACAnalysis CDx had already been approved for use. 

The approval of olaparib was based on positive results from the prospective, multicenter, randomized, open-label, phase III PROfound trial, which was designed to evaluate the safety and efficacy of olaparib versus enzalutamide or abiraterone in patients with mCRPC who have progressed on prior treatment with a new hormonal anticancer treatment and have a qualifying tumor mutation in 1 of 15 genes involved in the HRR pathway, including BRCA1/2, ATM and CDK12.

Overall, 256 patients were randomized to 300 mg of olaparib twice daily and 131 patients to investigator’s choice of enzalutamide or abiraterone acetate.3 All patients received a GnRH analog or had prior bilateral orchiectomy. Patients were divided into 2 cohorts based on their HRR gene mutation status. Patients with mutations in either BRCA1, BRCA2, or ATM were randomized to cohort A (n = 245), patients with mutations among 12 other genes involved in the HRR pathway were randomized to cohort B (n = 142), and those with co-mutations (cohort A gene and a cohort B gene) were assigned to cohort A.

The primary outcome of the trial was radiological progression-free survival (PFS) in cohort A. Key secondary outcomes included confirmed objective response rate (ORR) in cohort A with measurable disease, radiological PFS in cohorts A and B, and overall survival (OS) in cohort A. 

Results from the PROfound trial demonstrated that olaparib reduced the risk of disease progression or death by 66% (HR, 0.34; 95% CI, 0.25-0.47; P < 0.0001). Moreover, olaparib was found to have improved radiographic PFS to a median of 7.4 months vs 3.6 months with enzalutamide or abiraterone in men with mCRPC selected for BRCA1/2 or ATM gene mutations.

Additional results announced in April 2020 also showed a statistically significant improvement in OS with olaparib. Results demonstrated that olaparib reduced the risk of death by 31% (HR, 0.69; 95% CI, 0.50-0.97; P = 0.0175) and improved OS to a median of 19.1 months vs 14.7 months for patients treated with enzalutamide or abiraterone. 

“Today marks the first approval of (olaparib) in prostate cancer. In the PROfound trial, (olaparib) more than doubled the median radiographic progression-free survival and is the only PARP inhibitor to improve overall survival versus enzalutamide or abiraterone for men with BRCA or ATM mutations,” Dave Frederickson, executive vice president and head of the oncology business unit at AstraZeneca, said in a press release. “These results further establish that genomic testing for HRR mutations should be considered a critical step for the diagnosis and determination of treatment options for men with advanced prostate cancer.” 

Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients who received olaparib plus androgen deprivation therapy (ADT), compared to 3.1% of those receiving enzalutamide or abiraterone plus ADT in the PROfound study. Further, patients receiving olaparib and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. 

The most common adverse events (AEs) observed in the PROfound trial (≥10%) for olaparib compared to enzalutamide or abiraterone were anemia (46% vs 15%, respectively), nausea (41% vs 19%), fatigue (including asthenia; 41% vs 31%), decreased appetite (30% vs 18%), diarrhea (21% vs 7%), vomiting (18% vs 12%), thrombocytopenia (12% vs 3%), cough (11% vs 2%), and dyspnea (10% vs 3%). In addition, dose interruptions due to an AE occurred in 45% of patients receiving olaparib and dose reductions due to an AE occurred in 22% of those receiving olaparib. Discontinuation due to AEs occurred in 18% of patients.

Fatal AEs occurred in 4% of patients treated with olaparib. These included pneumonia (1.2%), cardiopulmonary failure (0.4%), aspiration pneumonia (0.4%0, intestinal diverticulum (0.4%), septic shock (0.4%), Budd-Chiari Syndrome (0.4%), sudden death (0.4%), and acute cardiac failure (0.4%). 

Serious AEs occurred in 36% of patients receiving olaparib. The most frequent serious AEs (≥2%) were anemia (9%), pneumonia (4%), pulmonary embolism (2%), fatigue/asthenia (2%), and urinary tract infection (2%).

Currently, olaparib is under regulatory review in the European Union and other jurisdictions as a treatment for men with HRR gene-mutated mCRPC.

AstraZeneca and Merck indicated that they are also exploring additional trials in metastatic prostate cancer, including the ongoing phase III PROpel trial, which is evaluating olaparib as a first-line therapy in combination with abiraterone acetate for patients with mCRPC vs abiraterone acetate alone.


1. LYNPARZA® (olaparib) Approved by FDA for Treatment of HRR Gene-Mutated Metastatic Castration-Resistant Prostate Cancer That Has Progressed Following Prior Treatment with Enzalutamide or Abiraterone [news release]. Kenilworth, NJ. Published May 20, 2020. mrknewsroom.com/news-release/oncology/lynparza-olaparib-approved-fda-treatment-hrr-gene-mutated-metastatic-castratio. Accessed May 20, 2020. 

2. Foundation Medicine Receives FDA Approval for FoundationOne®CDx as the Companion Diagnostic for LYNPARZA® to Identify Patients with HRR-Mutated Metastatic Castration-Resistant Prostate Cancer [news release]. Cambridge, Massachusetts. Published May 20, 2020. biospace.com/article/releases/foundation-medicine-receives-fda-approval-for-foundationone-cdx-as-the-companion-diagnostic-for-lynparza-to-identify-patients-with-hrr-mutated-metastatic-castration-resistant-prostate-cancer-/. Accessed May 20, 2020. 

3. FDA. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA website. Published May 19, 2020. fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer. Accessed May 20, 2020. 

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