The Food and Drug Administration (FDA) has approved Lynparza® (olaparib; AstraZeneca and Merck) 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 or abiraterone. 

The approval was based on results from the multicenter, open-label phase 3 PROfound trial that evaluated the efficacy and safety of olaparib in 387 adult men with mCRPC who have failed prior therapy with enzalutamide or abiraterone. Patients were randomized 2:1 to receive either olaparib 300mg twice daily or the investigator’s choice of enzalutamide or abiraterone (control). The primary end point of the trial was radiological progression-free survival (rPFS) in those with BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations.

Results showed that among patients with BRCA1/2 or ATM gene mutations, olaparib reduced the risk of disease progression or death by 66% (hazard ratio [HR] 0.34; 95% CI, 0.25-0.47; P <.001); median rPFS was 7.4 months in the olaparib arm vs 3.6 months in the control arm. Among patients in the overall HRR gene-mutated population, olaparib significantly reduced the risk of disease progression or death by 51% (HR 0.49; 95% CI, 0.38-0.63; P <.0001); median rPFS was 5.8 months in the olaparib arm vs 3.5 months in the control arm.

Moreover, olaparib achieved the key secondary end point of improvement in overall survival (OS) in patients with BRCA1/2 or ATM gene mutations with a 31% reduction in the risk of death (HR 0.69; 95% CI, 0.50-0.97, P =.0175); median OS was 19.1 months in the olaparib arm vs 14.7 months in the control arm.

With regard to safety, the most common adverse reactions reported in the olaparib arm included anemia, nausea, fatigue including asthenia, decreased appetite, diarrhea, vomiting, thrombocytopenia, cough and dyspnea. Additionally, patients treated with olaparib plus androgen deprivation therapy (ADT) experienced a higher incidence of venous thromboembolic events, including pulmonary embolism, vs the control arm plus ADT (7% vs 3.1%, respectively).

“In the PROfound trial, Lynparza more than doubled 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,” said Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca. “These results further establish that genomic testing for HRR mutations should be a critical step for the diagnosis and determination of treatment options for men with advanced prostate cancer.”

Additionally, 2 companion diagnostics were approved for use in the selection of mCRPC patients for olaparib treatment: the FoundationOne CDx test (Foundation Medicine, Inc) to identify patients carrying HRR gene alterations and the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc) to identify patients carrying germline BRCA1/2 alterations.

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Lynparza, a poly (ADP-ribose) polymerase (PARP) inhibitor, is also approved for the treatment of ovarian, breast, and pancreatic cancer.

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