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LYNPARZA is the Only PARP Inhibitor to Demonstrate Improved Overall Survival in Metastatic Castration-Resistant Prostate Cancer
KENILWORTH, N.J.--(BUSINESS WIRE)-- AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced final results from the Phase 3 PROfound trial which showed LYNPARZA demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus enzalutamide or abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC) who have BRCA1/2 or ATM gene mutations. Patients had progressed on prior treatment with enzalutamide and/or abiraterone.
Prostate cancer is the second most common type of cancer in men, with an estimated 1.3 million new patients diagnosed worldwide in 2018. Approximately 20-30% of men with mCRPC have an homologous recombination repair (HRR) gene mutation, of which BRCA1/2 and ATM mutations are a subpopulation. Approximately 10-20% of early stage hormone-sensitive prostate cancer cases will develop into CRPC within approximately five years.
In the key secondary endpoint of OS in men with BRCA1/2 or ATM gene mutations, LYNPARZA reduced the risk of death by 31% vs. retreatment with enzalutamide or abiraterone (HR 0.69 [95% CI, 0.50, 0.97], p=0.0175). Median OS was 19.1 months for LYNPARZA vs. 14.7 months for enzalutamide or abiraterone, despite 66% of men on these treatments having crossed over to receive treatment with LYNPARZA following disease progression.
An exploratory analysis also showed a non-statistically significant improvement in OS in the overall trial population of men with HRR gene mutations (BRCA1/2, ATM, CDK12 and 11 other HRR-mutated [HRRm] genes), reducing the risk of death by 21% with LYNPARZA vs. enzalutamide or abiraterone (HR 0.79 [95% CI, 0.61, 1.03]. Median OS was 17.3 months vs. 14 months for enzalutamide or abiraterone.
The most common adverse reactions (ARs) ≥15% were anemia (50%), nausea (43%), fatigue/asthenia (42%), decreased appetite (31%), diarrhea (21%), vomiting (20%) and constipation (19%). Grade 3 or above ARs were anemia (23%), nausea (2%), fatigue or asthenia (3%), decreased appetite (2%) and diarrhea (1%). Twenty percent of patients on LYNPARZA discontinued treatment due to ARs and 23% had their dose reduced due to an AR.
Dr. Johann de Bono, one of the principal investigators of the PROfound trial and head of drug development at the Institute for Cancer Research and the Royal Marsden Hospital, said, “LYNPARZA has demonstrated significant clinical benefit across key endpoints in PROfound and the final overall survival results for men with BRCA1/2 or ATM mutations reinforce its potential to change the standard of care for men with metastatic castration-resistant prostate cancer. The PROfound trial shows that LYNPARZA can play an important role in this new era of precision medicine in prostate cancer, bringing targeted therapy at a molecular level to patients with a historically poor prognosis and few treatment options.”
Dr. José Baselga, executive vice president, Oncology R&D, AstraZeneca said, “These results help to transform the treatment landscape in certain men with metastatic castration-resistant prostate cancer, where overall survival has been very difficult to achieve. LYNPARZA is the only PARP inhibitor to demonstrate overall survival versus enzalutamide or abiraterone for men with BRCA or ATM mutations. We look forward to continuing to bring LYNPARZA to these patients around the world.”
Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, “The PROfound trial is the first positive Phase 3 trial using molecular biomarker testing to help identify treatment options for certain men with metastatic castration resistant prostate cancer. These results further underpin the importance of genomic testing for HRR gene mutations to help identify this at-risk patient population and help physicians make treatment decisions. These results demonstrate the potential of LYNPARZA for mCRPC patients with certain HRR mutations.”
Final OS results from the PROfound trial were presented on Sunday, Sept. 20, 2020, during the Presidential Symposium at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 and published simultaneously in The New England Journal of Medicine.
Summary of OS results
OS data cut-off date was March 20, 2020.
| Men with BRCA1/2 and ATM mutations (Cohort A) Secondary Endpoint | Overall population of men with HRR mutations (Cohorts A+B) Exploratory Endpoint | ||
LYNPARZA n=162 | Control n=83 | LYNPARZA n=256 | Control n=131 | |
Median, months | 19.1 | 14.7
| 17.3 | 14.0
|
Hazard ratio (95% CI)
| 0.69 (0.50, 0.97)
| 0.79 (0.61, 1.03)
| ||
P-value | 0.0175 | N/A | ||
The Phase 3 PROfound trial had met its primary endpoint in August 2019, showing significantly improved radiographic progression-free survival (rPFS) in men with mutations in BRCA1/2 or ATM genes, and had met a key secondary endpoint of rPFS in the overall HRRm population, which formed the basis of the U.S. Food and Drug Administration approval in May 2020. Regulatory reviews are ongoing in the EU and other regions.
AstraZeneca and Merck are exploring additional trials in metastatic prostate cancer including the ongoing Phase 3 PROpel trial, with first data expected in 2021, evaluating LYNPARZA as a first-line medicine for patients with mCRPC in combination with abiraterone acetate versus abiraterone acetate alone.
About PROfound
PROfound is a prospective, multi-center, randomized, open-label, Phase 3 trial evaluating the efficacy and safety of LYNPARZA versus enzalutamide or abiraterone in patients with mCRPC who have progressed on prior treatment with abiraterone or enzalutamide and have a qualifying HRR tumor mutation (BRCA1/2, ATM, CDK12, BARD1, BRIP2, CHEK1, CHEK2, PALB2, PPP2R2A, RAD51B, RAD51D, RAD54L).
The trial was designed to analyze patients with HRRm genes in two cohorts: the primary endpoint was rPFS in those with mutations in BRCA1/2 or ATM genes and then, if LYNPARZA showed clinical benefit, a formal analysis was performed of the overall trial population of patients with HRRm genes (BRCA1/2, ATM, CDK12 and 11 other HRR mutated genes; a key secondary endpoint).
In the U.S., patients are selected for treatment with LYNPARZA based on the following FDA-approved companion diagnostics:
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
There are no contraindications for LYNPARZA.
WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in
