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European Union: Lynparza approved for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer

Lynparza ( Olaparib ) has been approved in the European Union ( EU ) for patients with metastatic castration-resistant prostate cancer ( mCRPC ) with breast cancer susceptibility gene 1/2 ( BRCA1/2 ) mutations, a subpopulation of homologous recombination repair ( HRR ) gene mutations.

Prostate cancer is the second-most common type of cancer in men, with an estimated 1.3 million patients diagnosed worldwide in 2018. Approximately 12% of men with mCRPC have a BRCA mutation.

The approval by the European Commission was based on a subgroup analysis of the PROfound phase III trial which showed Olaparib demonstrated a substantial improvement in radiographic progression-free survival ( rPFS ) and overall survival ( OS ) versus Enzalutamide or Abiraterone in men with BRCA1/2 mutations.

Lynparza is the first and only PARP inhibitor approved in the EU in biomarker-selected advanced prostate cancer.

The subgroup analysis from the PROfound trial showed Lynparza reduced the risk of disease progression or death by 78% ( based on a hazard ratio [HR ] of 0.22, 95% confidence interval [ CI ], 0.15-0.32; nominal p less than 0.0001 ) and improved rPFS to a median of 9.8 months versus 3.0 with Enzalutamide or Abiraterone in men with mCRPC with BRCA1/2 mutations. Olaparib reduced the risk of death by 37% ( based on a HR of 0.63, 95% CI 0.42-0.95 ) with median overall survival of 20.1 months versus 14.4 with Enzalutamide or Abiraterone.

The primary results and overall survival results from the PROfound trial were published in The New England Journal of Medicine ( NEJM ) earlier this year.

The full EU approved indication for Lynparza is for the treatment of adult patients with mCRPC and BRCA1/2 mutations ( germline and/or somatic ) who have progressed following prior therapy that included a new hormonal agent.

Prostate cancer is often driven by male sex hormones called androgens, including testosterone. In patients with mCRPC, prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.
Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis. Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.
Despite advances in treatment for men with mCRPC, five-year survival is low and extending survival remains a key treatment goal.

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role in maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer and confer sensitivity to PARP inhibitors including Olaparib.

PROfound is a prospective, multicentre, randomised, open-label trial testing the efficacy and safety of Olaparib versus Enzalutamide or Abiraterone in patients with mCRPC who have progressed on prior treatment with NHA treatments ( Abiraterone or Enzalutamide ) and have a qualifying tumour mutation in BRCA1/2, ATM or one of 12 other genes involved in the HRR pathway.
The trial was designed to analyse patients with HRR gene mutations in two cohorts: the primary endpoint was rPFS in those with mutations in BRCA1/2 or ATM genes and then, if Olaparib showed clinical benefit, a formal analysis was performed of the overall trial population of patients with HRR gene mutations ( BRCA1/2, ATM, CDK12 and 11 other HRR gene mutations ).

Olaparib is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response ( DDR ) in cells / tumours harbouring a deficiency in HRR, such as mutations in BRCA1 and/or BRCA2.
Inhibition of PARP with Olaparib leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. ( Xagena )

Source: AstraZeneca, 2020