Only PARP Inhibitor to Improve Overall Survival vs. New Hormonal Agent Treatments for Advanced Prostate Cancer, A Key Secondary Endpoint
AstraZeneca and Merck & Company have announced further positive results from the Phase 3 PROfound trial evaluating LYNPARZA in men with metastatic castration-resistant prostate cancer (mCRPC) who have a homologous recombination repair gene mutation (HRRm) and whose disease had progressed on prior treatment with new hormonal agent (NHA) treatments (e.g. enzalutamide or abiraterone).
Results from the trial showed a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival (OS) with LYNPARZA vs. enzalutamide or abiraterone in men with mCRPC selected for BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations.
The Phase 3 PROfound trial had met its primary endpoint in August 2019, showing treatment with LYNPARZA 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.
The safety and tolerability profile of LYNPARZA was generally consistent with previous trials. The most common adverse events (AEs) ≥20% for LYNPARZA compared to abiraterone or enzalutamide were anemia (47% vs. 15%), nausea (41% vs. 19%), fatigue and asthenia (41% vs. 32%), decreased appetite (30% vs. 18%), and diarrhea (21% vs. 7%). Grade 3 or above AEs were anemia (22% vs. 5%), fatigue and asthenia (3% vs. 5%), vomiting (2% vs. 1%), dyspnea (2% vs. 0%), urinary tract infection (2% vs. 4%), nausea (1% vs. 0%), decreased appetite (1% each) and diarrhea (1% vs. 0%).
Dose interruptions due to an AE of any grade occurred in 45% of patients receiving LYNPARZA and 19% of those receiving an NHA; dose reductions due to an AE occurred in 22% of LYNPARZA patients and 4% of patients who received an NHA. Discontinuation due to AEs occurred in 16% of LYNPARZA patients and 9% in patients who received an NHA.
Dr. José Baselga, executive vice president, oncology R&D, AstraZeneca, said, “Overall survival in metastatic castration-resistant prostate cancer has remained extremely challenging to achieve. We are thrilled by these results for LYNPARZA and we are working with regulatory authorities to bring this medicine to patients as soon as possible.”
Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, “LYNPARZA has demonstrated significant clinical benefit across key endpoints in PROfound, including overall survival for patients with BRCA or ATM mutations, and this reinforces its potential to change the treatment standard for patients with metastatic castration-resistant prostate cancer. These data further support Merck and AstraZeneca’s commitment to uncovering the ways in which LYNPARZA can help patients impacted by cancer.”
This data will be presented at a forthcoming medical meeting.
LYNPARZA was granted Priority Review by the U.S. Food and Drug Administration for patients with HRRm mCRPC in January 2020, with regulatory reviews ongoing in the European Union and other jurisdictions. AstraZeneca and Merck are exploring additional trials in prostate cancer, including the ongoing Phase 3 PROpel trial, with first data expected in 2021, evaluating LYNPARZA as a first-line therapy for patients with mCRPC in combination with abiraterone acetate.
PROfound is a prospective, multi-center, randomized, open-label, Phase 3 trial evaluating the efficacy and safety of LYNPARZA vs. NHA (e.g. abiraterone or enzalutamide) in patients with mCRPC who have progressed on prior treatment with a new hormonal anticancer treatment and have a qualifying tumor mutation in one of 15 genes involved in the HRR pathway, among them BRCA1/2, ATM and CDK12.
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 HRRm genes; key secondary endpoint).
Other secondary endpoints included OS, objective response rate, time to pain progression, rPFS in patients with HRRm genes, and safety.