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PARP Inhibitors Hold Promise in mCRPC and Biallelic DNA Repair Gene Defects

Brandon Scalea
Published: Sunday, Feb 17, 2019

Evan Ya-Wen Yu, MD

Evan Ya-Wen Yu, MD

Recent data suggest that PARP inhibitors could be a beneficial treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC) who express homologous recombination deficiency (HRD) or who have biallelic DNA repair gene defects, said Evan Y. Yu, MD.

The GALAHAD trial, a phase II study presented at the 2019 Genitourinary Cancers Symposium, evaluated the use of single-agent niraparib (Zejula) in patients with mCRPC and biallelic DNA repair gene defects. At a median follow-up of 5.7 months, the composite response rate was 65% in patients with biallelic BRCA1/2 mutations. Composite response rate is an endpoint taking into consideration factors like RECIST evaluation and prostate-specific antigen (PSA) decline. Among the 20 responders, duration of response exceeded 4 months in 13 patients and 6 months in 8 patients; 14 patients remain on treatment.1

In the phase I KEYNOTE-365 study, another early clinical trial assessing the use of PARP inhibitors in this space, response rates were modest. Cohort A of the study looked at the combination of the PD-1 inhibitor pembrolizumab (Keytruda) plus olaparib (Lynparza) in docetaxel-pretreated patients. At a median follow-up of 11 months, the composite response rate in these patients was 15%.2

Yu, a professor of medicine at the University of Washington in the Seattle Cancer Care Alliance, said that the benefit of PARP inhibitors may extend beyond these specific molecularly selected subsets of patients. These are early data, but they suggest that treatment in the field of prostate cancer is moving toward a precision medicine approach.

In an interview with OncLive, Yu highlighted 2 key studies with PARP inhibitors in mCRPC and discussed challenges that need to be addressed in this space in order to further progress.

OncLive: What were the biggest takeaways from KEYNOTE-365?

Yu: This is a study evaluating combinations in mCRPC with pembrolizumab plus several different treatment options. What I presented at the 2019 Genitourinary Cancers Symposium was [data from] Cohort A, [in which, investigators evaluated the combination of] pembrolizumab with olaparib in patients who previously received docetaxel. These patients had received up to 1 other line of chemotherapy, so they could have had docetaxel and cabazitaxel. They could have also received up to 2 hormonal therapies such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi). It was a pretty advanced patient population, as evidenced by the fact that 41% of patients had measurable visceral disease. The patients then received pembrolizumab at 200 mg every 3 weeks with olaparib at 400 mg.

What we saw was that the combination was pretty well tolerated—only about 15% of patients had immune-mediated adverse events, and these events were only grade 1 and 2. There were no grade 3 or 4 events observed. In regard to efficacy, we saw about half of the patients had some prostate-specific antigen (PSA) decline, but the confirmed PSA response rate was 12%. In regard to soft tissue disease, we saw that about 29% of patients had >30% shrinkage in soft tissue disease—I think this is impressive. The confirmed [overall] response rate, however, was 7%. We need to figure out what the discrepancy was between those who had shrinkage and the eventual ability to confirm it with a second imaging study.

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