FDA's Lynparza Approval Offers Certain Pretreated Patients with Metastatic Prostate Cancer Another Treatment Option

The Food and Drug Administration (FDA) recently approved Lynparza (olaparib) for the treatment of men with metastatic castration-resistant prostate cancer that is driven by a homologous recombination repair (HRR) gene defect and has progressed after treatment with the novel hormonal drugs Xtandi (enzalutamide) or Zytiga (abiraterone acetate), adding a new targeted treatment option for this specific patient group.

“Patients with homologous repair defects in the tumors, especially the alterations included in the trial, are able to receive treatment with olaparib (Lynparza) and that’s great news for our patients,” Dr. Neeraj Agarwal, director the Genitourinary Oncology Program at Huntsman Cancer Institute, said in an interview with OncLive®, a sister brand to CURE®.

The approval of Lynparza was based off findings from the phase 3 PROfound trial that showed Lynparza reduced the risk of disease progression or death in patients by 66% compared to Xtandi or Zytiga in patients with altered BRCA1, BRCA2 or ATM genes that are a part of DNA repair. Moreover, the median overall survival of patients on the study who took Lynparza was 17.5 months compared to 14.2 months with either Xtandi or Zytiga.

The FDA approved Lynparza for the use of patients with HRR defects whether that defect was inherited or acquired, meaning anyone with the HRR gene defect who progressed after treatment with hormonal drugs can use it. HRR defects are in cancer cells that make them vulnerable to a PARP inhibitor like Lynparza as the defect makes it difficult for the cancer cells to repair its DNA.

“I would like to highlight the fact that these are small subgroups,” Agarwal said in regard to individual patients with gene alterations like ATM. “Regarding ATM we know that PARP inhibitors are not so active in ATM alterations like it is in say BRCA1 or BRCA2 or maybe PALB1. But it is tricky to subgroup analysis of individual gene alterations because if you look at the numbers, they keep getting small and I would be hesitant to comment on the efficacy of individual gene alterations, just because the sample sizes are so small.”

In the phase 3 trial, 245 patients with alterations to their BRCA1, BRCA2 or ATM genes studied in one group of patients known as cohort A. BRCA1, BRCA2 and ATM genes are all known markers for HRR defects. In a second group of 142 patients, known as cohort B, patients were identified with either BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, or RAD54L genes, which are not as associated with DNA repair deficiencies in the cancer cells.

“My take on this (is) that patients who are harboring tumors with these genetic alterations I would exclude ATM mutations,” Agarwal explained. “But otherwise, I would not hesitate in using Lynparza for those patients.”

Looking at cohort A, the overall response rate was 33.3% for patients on Lynparza compared to 2.3% for patients on either Xtandi or Zytiga. Time until disease progression was also higher in Lynparza at 3.5 months compared to 3.6 months with the hormonal therapies. Moreover, researchers found a 56% reduction in the risk of pain progression for patients on Lynparza compared to 9.92 months with Xtandi or Zytiga as the median pain progression had not been reached at the time of the study.

The most common side effects were anemia, nausea, fatigue/weakness, decreased appetite and diarrhea in 20% of patients who took Lynparza. The most common serious side effects in 1% of patients who took Lynparza was anemia, fatigue/weakness, vomiting, difficulty breathing, urinary tract infection, pulmonary embolism, decreased appetite, diarrhea, back pain and nausea.

Read CURE’s original coverage of the approval here.