The U.S. Food and Drug Administration has approved the oral therapy Lynparza (olaparib) for treating men with metastatic castration-resistant prostate cancer (mCRPC) who carry mutations in homologous recombination repair (HRR) genes, including BRCA or ATM.
Approval is specific for men who failed prior treatment with Xtandi (enzalutamide) or Zytiga (abiraterone acetate), two hormone therapies. The decision was based on findings from the Phase 3 PROfound trial (NCT02987543), in which Lynparza significantly extended survival and the time without disease worsening or death, compared with these hormone therapies.
“Today marks the first approval for Lynparza in prostate cancer,” Dave Fredrickson, executive vice president of the Oncology Business Unit at AstraZeneca, said in a press release. “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.”
Lynparza, developed by AstraZeneca and Merck (known as MSD outside the U.S. and Canada), is a type of treatment called a PARP inhibitor and has also been approved to treat advanced cancers of the ovary, breast, and pancreas.
It works by inhibiting the PARP enzyme — a DNA damage sensor — leading to the accumulation of DNA damage and ultimately the death of cancer cells.
PROfound is comparing the safety and efficacy of Lynparza with that of Xtandi or Zytiga across 387 mCRPC patients whose disease progressed while on these hormone therapies.
PARP inhibitors are particularly effective in cancer cells carrying defects in other DNA repair pathways — because they need PARP to survive and grow. In the PROfound trial, researchers examined Lynparza in men carrying mutations in one of 15 genes involved in HRR.
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 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.
PROfound’s primary goal was to determine if Lynparza extended the time patients lived without signs of disease progression on imaging scans — a measure called radiographic progression-free survival (rPFS) — in the subgroup of patients with BRCA or ATM mutations.
Secondary measures included the proportion of men responding to treatment, time to pain progression, and overall survival.
Merck and AstraZeneca announced in August 2019 that PROfound had achieved its primary goal: Lynparza more than doubled rPFS in men with BRCA or ATM mutations, from 3.6 months on hormone therapies to 7.4 months, corresponding to a 66% decrease in the risk of disease worsening or death.
A clinical benefit was also seen in the overall population, with patients receiving Lynparza living a median of 5.8 months without disease progression, compared with 3.5 months for those on newer hormone therapies — a 51% reduction in risk of disease worsening or death.
More recently, the team found that patients with BRCA or ATM mutations on 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%.
Results, recently published in the New England Journal of Medicine in the study “Olaparib for Metastatic Castration-Resistant Prostate Cancer,” also demonstrated Lynparza’s benefits across a range of other secondary measures.
Among patients with mutations in BRCA or ATM genes, the targeted therapy significantly increased the proportion of responders (33% vs. 2%), delayed worsening in pain scores, and increased the proportion of patients with significantly lower prostate specific antigen (PSA) levels — a biomarker of prostate cancer.
Results were similar in the overall population included in PROfound, although the extent of benefits was not as great as in the subgroup with BRCA or ATM mutations. Lynparza also cut the risk of death in the global population by 33%, extending patients’ lives from 14.3 months to 17.5 months.
The safety and tolerability profile of Lynparza was similar to that observed in prior clinical trials. About 36% of patients on Lynparza experienced serious adverse reactions, such as anemia, pneumonia, and pulmonary embolism. Adverse reactions were the cause of death in 4% of patients receiving the targeted treatment, and included pneumonia, heart failure, and problems in the intestinal tract.
“Prostate cancer has lagged behind other solid tumors in the era of precision medicine,” said Maha Hussain, MD, one of the principal investigators of PROfound.
“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,” she added. “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.”