Note: This story was updated May 21, 2020, to note that Merck is known as MSD outside the U.S. and Canada, not as EMD Serono.
The U.S. Food and Drug Administration (FDA) has granted priority review status to an application to extend the use of the oral therapy Lynparza (olaparib) to men with metastatic castration-resistant prostate cancer (mCRPC) who carry mutations in DNA repair genes, including BRCA or ATM, and who have failed prior treatment with a new hormone therapy.
Priority review status cuts the time to six months for the FDA to make its decision, from the typical 10 months under standard review. A final resolution on the supplemental new drug application is expected for the second quarter of this year, according to a press release.
The application from AstraZeneca and Merck (known as MSD outside the U.S. and Canada) was based on positive results from the Phase 3 PROfound trial (NCT02987543).
The study compared the efficacy and safety of Lynparza to that of Xtandi (enzalutamide; by Astellas and Pfizer Oncology) or Zytiga (abiraterone; by Janssen) in mCRPC patients whose disease progressed while on these newer hormone treatments, and whose tumors carried mutations in one of 15 genes involved in the homologous recombination (HR) pathway of DNA repair.
Tumors with this kind of mutation are more likely to respond to a class of anti-cancer medicines known as PARP inhibitors, which includes Lynparza.
In the study, patients were treated with 300 mg twice daily of Lynparza, or the investigators’ choice of either Xtandi (160 mg daily) or Zytiga (1,000 mg daily, plus prednisone).
Results presented last year at the ESMO Congress 2019, held in Barcelona, Spain, showed that Lynparza reduced the risk of death or cancer progression in a clinically meaningful way.
The largest benefit was seen in patients with cancer mutations in the BRCA1, BRCA2, and ATM genes, the most common HR repair gene mutations.
Among these patients, those taking Lynparza lived significantly longer without seeing their cancer worsen — a median of 7.4 months versus 3.6 months in men receiving Xtandi or Zytiga. This corresponded to a 66% reduction in the risk of disease progression or death.
A clinical benefit also was seen in the overall population of men with HR repair-mutated tumors (including mutations in BRCA1/2, ATM, CDK12 or 11 other genes) where Lynparza reduced the likelihood of disease progression or death by 51% and improved progression-free survival to a median of 5.8 months versus 3.5 months in men treated with Xtandi or Zytiga.
The safety and tolerability profile of Lynparza was similar to that observed in prior clinical trials. The side effects more commonly associated with the treatment, compared with Xtandi or Zytiga, were anemia (47% vs. 15%), nausea (41% vs. 19%), fatigue and generalized weakness (41% vs. 32%), decreased appetite (30% vs. 18%), and diarrhea (21% vs. 7%).
Lynparza is an oral targeted therapy approved as a first-line maintenance treatment for some advanced ovarian and breast cancers. In December, the medicine’s label was extended in the U.S. to include initial maintenance treatment for BRCA-mutated metastatic pancreatic cancer.
Lynparza acts by blocking the activity of the PARP enzyme which works as a sensor of DNA damage. PARP normally binds to the sites of DNA damage to promote repair but when blocked by Lynparza in cancer cells, those injuries in DNA cannot be corrected and begin to accumulate, eventually leading to the death of cancer cells.
That is why the therapy can be particularly effective in cancers with genetic defects in DNA repair which are more dependent on PARP to survive.
Lynparza is being tested in other prostate cancer trials, including the PROpel Phase 3 study (NCT03732820) testing the addition of Lynparza to Zytiga as a first-line treatment in certain mCRPC patients, and the TOPARP Phase 2 trial (NCT01682772), which was designed to evaluate Lynparza in mCRPC patients and identify predictive biomarkers of response to the therapy.