The European Commission has approved Lynparza (olaparib) to treat people with metastatic castration-resistant prostate cancer (mCRPC) who carry mutations in the DNA repair genes BRCA1 and BRCA2.
The approval follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), an arm of the European Medicines Agency.
“This approval in the EU is a landmark moment that begins a new era of precision medicine in prostate cancer,” Johann de Bono, PhD, a professor at The Institute of Cancer Research, London, said in a press release.
Damage to a cell’s DNA can be fatal, which is why cells have several molecular pathways they can use to detect and repair DNA damage. The BRCA genes are involved in one such pathway; but in some cancers, including about 12% of mCRPC cases, these genes are mutated. Having BRCA mutations compromises the DNA repair mechanism, which makes the cancer cell more heavily dependent on other DNA repair enzymes for survival.
Lynparza, an oral therapy developed by AstraZeneca and MSD (known as Merck in North America), works by blocking the activity of the PARP enzyme, a DNA damage sensor on which cells with BRCA mutations tend to rely. By blocking PARP, the therapy makes cancer cells more vulnerable to DNA damage, which limits the cells’ ability to grow and survive.
Lynparza is the first and only PARP inhibitor to be approved in the European Union (EU) as a treatment for advanced prostate cancer with mutations in specific DNA repair genes. In the U.S., the therapy has been approved to treat people with mCRPC who have mutations in BRCA genes or in ATM, another gene that is involved in DNA repair.
In both the EU and the U.S., the therapy is specifically indicated for patients who have progressed following treatment with newer forms of hormone therapy, such as Xtandi (enzalutamide) or Zytiga (abiraterone acetate).
The approvals were based on data from the PROfound Phase 3 trial (NCT02987543), which included 245 participants with mutations in the BRCA1, BRCA2, or ATM genes — the most commonly mutated DNA repair genes — as well as 142 participants with mutations in 12 other DNA repair-related genes.
Participants in each group were assigned randomly to either Lynparza (300 mg twice daily) or to an investigators’ choice of hormone therapies: Xtandi at 160 mg daily, or Zytiga at 1,000 mg daily, plus the corticosteroid prednisone.
The main goal of the trial was to determine whether Lynparza outperformed the hormone therapies at delaying disease progression — assessed via regular imaging scans — or death from any cause.
Top-line data showed that participants treated with Lynparza carrying BRCA mutations lived significantly longer without signs of disease progression on imaging scans, compared with those given hormone therapies (median 9.8 months vs. three months). This represented a 22% reduction in the risk of disease worsening or death.
Lynparza also outperformed hormone therapies in response rates, delaying pain worsening, and lowering levels of prostate-specific antigen, a prostate cancer biomarker, in the blood.
Final results, published in the New England Journal of Medicine, demonstrated Lynparza’s superiority in overall survival, a key secondary measurement.
After a median follow-up of nearly two years, participants with BRCA mutations receiving Lynparza lived significantly longer than those on hormone therapy (median 20.1 months vs. 14.4 months). The overall risk of death was reduced significantly (by 37%) in these participants.
In the whole study population, Lynparza also was associated with a lower risk of death, but the difference was not statistically significant (meaning it could be attributed to random chance, rather than an effect of treatment). Further analyses showed that the risk of death was reduced much more in participants with mutations in BRCA1 or BRCA2, compared to those with ATM mutations.
“Lynparza more than tripled radiographic progression-free survival and is the only PARP inhibitor to show an overall survival benefit versus certain new hormonal agents for men with BRCA-mutated metastatic castration-resistant prostate cancer,” said Dave Fredrickson, executive vice president, oncology business unit, AstraZeneca. “This approval means BRCA testing should now become a critical step in the diagnosis and determination of treatment for men with advanced prostate cancer in the EU.”
“Lynparza now provides a targeted treatment option at a molecular level to patients with advanced prostate cancer who have historically poor prognosis and few treatment options,” added de Bono, one of the principal investigators of the PROfound trial.
Regulatory reviews of Lynparza are ongoing in other countries around the world. AstraZeneca and MSD are conducting other clinical trials of Lynparza, such as the Phase 3 trial PROpel (NCT03732820), which is investigating this treatment, in combination with Zytiga, for treating mCRPC. Results are expected in late 2021.