Lynparza (Olaparib) Supplemental New Drug Application Granted FDA Priority Review for HRR-Mutated Metastatic Castration-Resistant Prostate Cancer

On January 20, AstraZeneca and MSD announced today that the U.S. Food and Drug Administration has accepted the supplemental New Drug Application for Lynparza (olaparib) and granted it Priority Review designation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) harboring deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutations (HRRm), who have experienced disease progression following prior therapy with novel hormonal agents. The PDUFA date is set for the second quarter of 2020.

The FDA’s priority review was based on the results of the Phase 3 PROfound trial, which were presented at the 2019 ESMO Congress. The PROfound trial results demonstrated that, in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 or ATM mutations, Lynparza significantly reduced the risk of disease progression or death by 66% compared with abiraterone or enzalutamide, with a hazard ratio of 0.34 (p<0.0001); this constituted the primary endpoint of the trial. The trial further showed that, in the overall study population of mCRPC patients with homologous recombination repair (HRR) gene mutations (HRRm), including those with mutations in BRCA1/2, ATM, CDK12, or any of 11 other HRR-related genes, Lynparza reduced the risk of disease progression or death by 51% compared with abiraterone or enzalutamide, with a hazard ratio of 0.49 (p<0.0001); this represented the key secondary endpoint. The safety and tolerability profile of Lynparza observed in the PROfound trial was consistent with that seen in previous clinical trials. PROfound is the first positive Phase 3 trial to evaluate targeted therapy in biomarker-selected patients with prostate cancer.

PROfound is a prospective, multicenter, randomized, open-label Phase 3 trial designed to evaluate the efficacy and safety of Lynparza compared with enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after prior treatment with a novel hormonal anticancer therapy and harbor mutations in one of 15 genes associated with the homologous recombination repair (HRR) pathway, including BRCA1/2, ATM, and CDK12. The primary endpoint was radiographic progression-free survival (rPFS) in mCRPC patients with BRCA1/2 or ATM mutations. The key secondary endpoint was rPFS in the overall HRR-mutated (HRRm) population (including BRCA1/2, ATM, CDK12, and 11 other HRRm genes). The results demonstrated that Lynparza significantly improved rPFS, the primary endpoint, with both statistical and clinical significance. The median time to disease progression was extended to 7.4 months in patients with BRCA1/2 or ATM mutations treated with Lynparza, compared to 3.6 months in those treated with abiraterone or enzalutamide, representing a 66% reduction in the risk of disease progression or death (HR 0.34 [95% CI, 0.25–0.47]; p<0.0001). The trial also met the key secondary endpoint of rPFS in the overall HRRm population, where Lynparza reduced the risk of disease progression or death by 51%, with a median rPFS improvement of 5.8 months compared to 3.5 months for patients receiving abiraterone or enzalutamide (HR 0.49 [95% CI, 0.38–0.63]; p<0.0001).

Prostate cancer is the second most common cancer in men, with an estimated 1.3 million new cases diagnosed globally in 2018, and it is associated with a high mortality rate. The development of prostate cancer is often driven by male sex hormones known as androgens, including testosterone. Despite the use of androgen deprivation therapy to block the effects of male sex hormones, metastatic castration-resistant prostate cancer (mCRPC) can still occur when prostate cancer grows and spreads to other parts of the body. Approximately 10–20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these patients have metastases at the time of CRPC diagnosis. Among men without metastases at the time of CRPC diagnosis, 33% are likely to develop metastases within two years. Although the number of available treatments for men with mCRPC has increased, the five-year survival rate remains low. In metastatic prostate cancer, approximately 20–25% of patients exhibit defects in DNA repair genes, most commonly mutations in BRCA1 and BRCA2, with other implicated genes including PALB2, ATM, and CDK12. Homologous recombination repair (HRR) is a DNA repair process that allows for high-fidelity, error-free repair of damaged DNA, such as double-strand breaks and interstrand crosslinks. Failure to properly repair DNA damage leads to genomic instability and contributes to carcinogenesis. Deficiency in HRR impairs the ability to repair damaged DNA and is a characteristic of cancer cells, making it a target for PARP inhibitors (such as Lynparza). PARP inhibitors block DNA damage repair by trapping PARP bound to single-strand DNA breaks (leading to replication fork stalling and collapse) and causing double-strand DNA breaks, ultimately resulting in cancer cell death.

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted therapy directed at defects in the DNA damage repair (DDR) pathway, such as BRCA1 and/or BRCA2 mutations. Inhibition of PARP by Lynparza results in the trapping of PARP bound to DNA single-strand breaks, leading to replication fork stalling and collapse, the formation of DNA double-strand breaks, and ultimately cancer cell death. Lynparza was first approved by the FDA in December 2014 for the treatment of patients with advanced ovarian cancer harboring germline BRCA mutations, becoming the first approved PARP inhibitor globally. It has since received FDA approval for the treatment of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, and pancreatic cancer. In August 2018, Lynparza (brand name: Liparzhuo) was approved for marketing in China, marking the first new targeted drug for ovarian cancer to become available in the country. One week ago, the olaparib combination regimen for first-line maintenance treatment in specific patients with advanced ovarian cancer was granted Priority Review, with the PDUFA date set for the second quarter of 2020.

References:

[1] Lynparza regulatory submission granted Priority Review in the US for HRR-mutated metastatic castration-resistant prostate cancer. Retrieved 2020-01-20, from https://www.astrazeneca.com/media-centre/press-releases/2020/lynparza-regulatory-submission-granted-priority-review-in-the-us-for-hrr-mutated-metastatic-castration-resistant-prostate-cancer-20012020.html

Original Title: FDA Grants Priority Review to Marketing Application for Olaparib in the Treatment of HRR-Mutated Prostate Cancer

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