Lynparza Receives FDA Approval for Prostate Cancer with 66% Reduction in Risk of Progression or Death

On May 20, AstraZeneca and MSD announced that Lynparza (olaparib) had been approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations. The U.S. FDA approval was based on results from the Phase III PROfound trial, in which Lynparza demonstrated a radiographic progression-free survival (rPFS) of 7.4 months in mCRPC patients with BRCA1 and ATM mutations, compared to 3.6 months in the control group receiving abiraterone or enzalutamide. Lynparza reduced the risk of disease progression or death by 66% (HR=0.34; p<0.0001).

PROfound is a prospective, multicenter, randomized, open-label Phase III clinical 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 these two agents and harbor mutations in BRCA1/2, ATM, or 12 other genes involved in the homologous recombination repair (HRR) pathway. The primary endpoint was radiographic progression-free survival (rPFS) in male patients carrying BRCA1/2 or ATM gene mutations (a subgroup of HRR gene-mutated patients). Lynparza also demonstrated an rPFS benefit in the overall HRR gene-mutated study population, a key secondary endpoint, reducing the risk of disease progression or death by 51% (HR=0.49; p<0.0001) and improving median rPFS to 5.8 months compared with 3.5 months for enzalutamide or abiraterone. The full approved indication is for the treatment of adult patients with mCRPC harboring deleterious or suspected deleterious germline or somatic HRR gene mutations who have progressed following prior treatment with enzalutamide or abiraterone.

Additional results from the PROfound trial, announced on April 24, 2020, demonstrated that Lynparza provided a statistically and clinically significant improvement in overall survival (OS), a key secondary endpoint, compared with enzalutamide or abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 or ATM gene mutations. The results showed that Lynparza reduced the risk of death by 31% (HR=0.69; p=0.0175) and improved median OS to 19.0 months, compared with 14.6 months for enzalutamide or abiraterone.

“Prostate cancer has lagged behind other solid tumors in the era of precision medicine,” said Maha Hussain, Deputy Director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University and one of the principal investigators of the PROfound trial. “I am excited about the approval of Lynparza, which now brings molecularly targeted therapy to men with metastatic castration-resistant prostate cancer (mCRPC) harboring HRR gene mutations in the United States. This landmark trial was an international effort, and I would like to thank the patients, their families, investigators, and their teams for making it possible.”

Dave Fredrickson, Executive Vice President of AstraZeneca’s Oncology Business Unit, stated: “Today marks the first approval of Lynparza for prostate cancer. In the PROfound trial, Lynparza more than doubled median radiographic progression-free survival compared with enzalutamide or abiraterone in men harboring BRCA or ATM mutations, and it is the only PARP inhibitor to demonstrate an overall survival benefit. These findings further establish that genomic testing for HRR mutations should be a critical step in diagnosing and determining treatment strategies for men with advanced prostate cancer.”

Roy Baynes, Senior Vice President of Research Laboratories at Merck & Co., Inc., Global Head of Clinical Development, and Chief Medical Officer, stated, “Lynparza is the only PARP inhibitor approved for the treatment of male patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations. This approval underscores the importance of genomic testing in helping to determine treatment options for this patient population. We are proud to collaborate with AstraZeneca to achieve our shared goal of improving patient outcomes.”

Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is the second most common cancer in men, with an estimated 1.3 million new cases diagnosed globally in 2018, accompanied by a high mortality rate. The onset and progression of prostate cancer are often driven by male sex hormones known as androgens, including testosterone. Metastatic castration-resistant prostate cancer (mCRPC) is a severe form of prostate cancer in which the disease has spread to other parts of the body, and tumors continue to proliferate even when androgen levels are reduced to very low levels. Despite the use of androgen deprivation therapy to block the effects of male sex hormones, mCRPC continues to grow and spread to other parts of the body. Approximately 10–20% of men with advanced prostate cancer develop castration-resistant prostate cancer (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% may develop metastases within two years. Although treatment options for men with mCRPC have increased, the five-year survival rate remains low.

HRR Gene Mutations

Approximately 20–30% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination repair (HRR) genes. HRR genes precisely repair damaged DNA in normal cells. Homologous recombination deficiency (HRD) disrupts the DNA repair mechanism in normal cells, potentially leading to cell death. However, this mechanism manifests differently in cancer cells: a mutation in the HRR pathway leads to aberrant cell growth and carcinogenesis; the inability to properly repair DNA damage results in genomic instability, which further fuels cancer progression. HRD is a well-established target for PARP inhibitors (such as Lynparza). PARP inhibitors trap PARP bound to single-strand DNA breaks, thereby blocking the DNA damage repair mechanism, causing replication fork stalling, inducing double-strand DNA breaks, and ultimately leading to cancer cell death.

Lynparza

Lynparza is the first PARP inhibitor and the first targeted therapy to block the DNA damage response (DDR) in cells/tumors with homologous recombination repair deficiencies (such as BRCA1 and/or BRCA2 mutations). Inhibition of PARP by Lynparza leads to the trapping of PARP at DNA single-strand breaks, causing replication fork stalling, their collapse, and the generation of DNA double-strand breaks, ultimately resulting in cancer cell death. Lynparza is being evaluated in a range of PARP-dependent tumor types characterized by defects and dependencies in DDR pathways.

Lynparza is currently approved in multiple countries for the maintenance treatment of platinum-sensitive recurrent ovarian cancer. It is approved in the United States, the European Union, Japan, China, and several other countries as first-line maintenance treatment for advanced ovarian cancer with BRCA mutations following a response to platinum-based chemotherapy. It is also approved in the United States, Japan, and several other countries for the treatment of germline BRCA-mutated, HER2-negative metastatic breast cancer in patients who have previously received chemotherapy. Lynparza is approved in the United States and several other countries for the treatment of metastatic pancreatic cancer with germline BRCA mutations. Regulatory reviews for ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer are ongoing. Lynparza is currently under regulatory review in the European Union and other jurisdictions for the treatment of male patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations.

AstraZeneca and MSD are evaluating the therapeutic efficacy of Lynparza in other trials for metastatic castration-resistant prostate cancer (mCRPC), including the ongoing Phase III PROpel trial, which compares first-line combination therapy with abiraterone acetate versus abiraterone acetate monotherapy.

(Original Title: Synthetic Lethality Gains Further Recognition! PARP Inhibitor Olaparib Approved by FDA for Prostate Cancer Treatment)