The approval by the US Food and Drug Administration (FDA) was based on results from the Phase III PROfound trial, which were published in the New England Journal of Medicine.
Prostate cancer is the second most common cancer in men and despite an increase in the number of available therapies for men with mCRPC, five-year survival remains low. HRR gene mutations occur in approximately 20%-30% of patients with mCRPC.
Maha Hussain, one of the Principal Investigators of the PROfound trial and deputy director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said: “Prostate cancer has lagged behind other solid tumors in the era of precision medicine. I am thrilled by the approval of LYNPARZA which now brings a molecularly targeted treatment to men with HRR gene-mutated metastatic castration-resistant prostate cancer 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.”
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “Today marks the first approval for LYNPARZA in prostate cancer. 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. 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.”
Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories, said, “LYNPARZA is the only PARP inhibitor approved with Phase III data for men with HRR gene-mutated metastatic castration-resistant prostate cancer. This approval highlights the importance of genomic testing to identify treatment options for men in this patient population. We are proud to work in collaboration with AstraZeneca toward our overall goal of improving outcomes for patients.”
The primary endpoint of the trial was radiographic progression-free survival (rPFS) in men with BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations. Results showed LYNPARZA reduced the risk of disease progression or death by 66% (equal to a hazard ratio of 0.34; p-value <0.0001) and improved rPFS to a median of 7.4 months versus 3.6 months with enzalutamide or abiraterone.
LYNPARZA also showed an rPFS benefit in the overall HRR gene-mutated trial population, a key secondary endpoint, and reduced the risk of disease progression or death by 51% (equal to a hazard ratio of 0.49; p-value <0.0001) and improved rPFS to a median of 5.8 months versus 3.5 months with enzalutamide or abiraterone.
Additional results announced on April 24, 2020 demonstrated a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival (OS) with LYNPARZA versus abiraterone or enzalutamide in men with mCRPC and BRCA1/2 or ATM gene mutations. Results showed LYNPARZA reduced the risk of death by 31% (equal to a hazard ratio of 0.69 and p-value 0.0175) and improved OS to a median of 19.1 months versus 14.7 months with enzalutamide or abiraterone.
Fatal adverse reactions occurred in 4% of patients treated with LYNPARZA. These included pneumonia (1.2%), cardiopulmonary failure (0.4%), aspiration pneumonia (0.4%), intestinal diverticulum (0.4%), septic shock (0.4%), Budd-Chiari Syndrome (0.4%), sudden death (0.4%), and acute cardiac failure (0.4%). Serious adverse reactions occurred in 36% of patients receiving LYNPARZA. Serious adverse reactions in ≥2% were anemia (9%), pneumonia (4%), pulmonary embolism (2%), fatigue/asthenia (2%), and urinary tract infection (2%).
The most common adverse reactions (Grade 1-4) occurring in ≥10% in the LYNPARZA arm (N=256) were anemia (46%), nausea (41%), fatigue including asthenia (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%) and dyspnea (10%).
In addition, venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone.
AstraZeneca and Merck are testing LYNPARZA in additional trials in prostate cancer including the ongoing Phase III PROpel trial as a 1st-line treatment in combination with abiraterone acetate for patients with mCRPC versus abiraterone acetate alone.
Following this approval for LYNPARZA in the US, AstraZeneca will receive a regulatory milestone payment from Merck of $35m, anticipated to be booked as Collaboration Revenue by the Company during the second quarter of 2020.
Source: Company Press Release