Lynparza (olaparib) has been recommended for approval in the European Union to treat men with metastatic castration-resistant prostate cancer (mCRPC) who carry mutations in BRCA1 and BRCA2, two DNA repair genes.
The marketing authorization application is specific for men whose disease progressed after treatment that included a newer hormone therapy, such as Xtandi (enzalutamide) or Zytiga (abiraterone acetate).
The positive opinion by the Committee for Medicinal Products for Human Use (CHMP) was based on a subgroup analysis of mCRPC patients with BRCA mutations from the Phase 3 PROfound trial (NCT02987543), showing that Lynparza was more effective than those two hormone therapies at delaying disease progression or death, and extending overall survival.
“In the PROfound trial, Lynparza provided a significant clinical benefit to men with BRCA1/2-mutated metastatic castration-resistant prostate cancer,” Roy Baynes, MD, senior vice president and head of global clinical development, and chief medical officer at Merck Research Laboratories, said in a press release. Merck is known as MSD outside North America.
“If approved, Lynparza could be transformative in the treatment paradigm, bringing an additional option to certain prostate cancer patients in the EU,” Baynes added.
The recommendation follows Lynparza’s approval in the U.S. for a similar but expanded indication, including patients with mutations in the BRCA and ATM genes, also involved in DNA repair processes known as homologous recombination repair (HRR).
Lynparza, an oral PARP inhibitor developed by AstraZeneca and Merck, works by blocking the activity of the PARP enzyme — a DNA damage sensor — leading to the accumulation of DNA damage and ultimately the death of cancer cells.
This therapy is particularly effective in cancer cells that rely on PARP to survive and grow due to defects in other DNA repair pathways — such as those with mutations in HRR genes like BRCA1, BRCA2, and ATM.
About 20–30% of men with mCRPC have tumors positive for HRR mutations, and 10% have a BRCA mutation.
The PROfound trial compared the safety and effectiveness of Lynparza to Xtandi and Zytiga in 387 men diagnosed with mCRPC whose disease progressed while on these newer hormone treatments, and whose tumors carried mutations in one of 15 HRR genes.
The study included 245 patients with mutations in the BRCA1, BRCA2, or ATM genes — the most common HRR mutated genes — and 142 men with mutations in the other 12 HRR genes.
Patients in each group were randomly assigned to either Lynparza (300 mg twice daily) or investigators’ choice of either Xtandi (160 mg daily) or Zytiga (1,000 mg daily, plus prednisone).
All treatments were taken by mouth until patients experienced disease worsening or toxicity. Crossover from hormone therapy to Lynparza was allowed in eligible patients after imaging-based disease progression.
Top-line data showed that the trial met its main goal, as Lynparza more than doubled the time men carrying BRCA or ATM mutations lived without signs of disease progression on imaging scans (7.4 months), compared with hormone therapies (3.6 months).
This represented a 66% decrease in the risk of disease worsening or death, which was more pronounced than the 51% lower risk found for the overall patient population.
Among patients with BRCA or ATM mutations, Lynparza also resulted in significantly better response rates (33% vs. 2%), delayed pain worsening, and significantly lowered prostate-specific antigen levels — a biomarker of prostate cancer — in a greater proportion of patients, compared with hormone therapy.
Final results, recently presented at the 2020 European Society of Medical Oncology (ESMO) virtual congress and simultaneously published in the New England Journal of Medicine in the study “Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer,” also demonstrated Lynparza’s superiority in overall survival, a key secondary goal.
At a median follow-up of nearly two years, men with BRCA or ATM mutations receiving Lynparza lived significantly longer (19.1 months) than those on hormone therapy (14.7 months), with the treatment cutting the risk of death by 31%.
This was observed despite 66% of men in the hormone therapy group crossing over to Lynparza following disease progression.
Lynparza also dropped the risk of death by 21% in the overall population, but this reduction was not statistically significant.
Exploratory analyses also showed that, compared with hormone therapy, Lynparza lowered the risk of death by 58% in men with mutations only in BRCA1, by 41% in those with BRCA2 mutations only, and by 7% in those with mutations only in ATM.
These findings highlighted that mCRPC patients with tumors positive for BRCA mutations will benefit more from Lynparza than those carrying ATM mutations, supporting the CHMP’s recommendation for men with BRCA mutations.
Lynparza’s safety and tolerability profiles were consistent with those observed in prior clinical trials, with the most common adverse events being anemia (50%), nausea (43%), fatigue and generalized weakness (42%), decreased appetite (31%), diarrhea (21%), and vomiting (20%).
José Baselga, MD, the executive vice president of AstraZeneca’s oncology research and development, said that “this recommendation for Lynparza brings us closer to making it the only PARP inhibitor to improve overall survival in this setting available to men in the EU.”
Testing for BRCA mutations “should now become a critical step for the diagnosis and determination of treatment options for men with advanced prostate cancer in the EU,” he added.
AstraZeneca and Merck are exploring Lynparza in additional trials in metastatic prostate cancer, including the ongoing, international PROpel Phase 3 study (NCT03732820). PROpel is testing the addition of Lynparza to Zytiga as a first-line treatment in mCRPC patients who have not been given chemotherapy or newer hormonal agents, and regardless of mutations in DNA repair genes.