Inhibitors of PARP show promise in mCRPC gene and biallelic DNA repair gene defects

Evan Ya-Wen Yu, MD

Recent data suggest that PARP inhibitors may be a beneficial therapeutic option in patients with metastatic castration-resistant prostate cancer who express a homologous recombination deficiency or who exhibit repair gene abnormalities. of biallelic DNA, said Evan Y. Yu, MD.

The GALAHAD study, a Phase II study presented at the Symposium on Genitourinary Cancers in 2019, evaluated the use of niraparib as monotherapy in patients with mCRPC gene defects and repair of the disease. 39, biallelic DNA. At a median follow-up of 5.7 months, the composite response rate was 65% in biallelic patients. BRCA1 / 2 mutations. The composite response rate is an evaluation criterion taking into account factors such as RECIST badessment and the decline of the prostate specific antigen (PSA). Among the 20 respondents, the duration of the response exceeded 4 months in 13 patients and 6 months in 8 patients; 14 patients remain on treatment.¹

In the KEYNOTE-365 Phase I study, another early clinical trial evaluating the use of PARP inhibitors in this space, response rates were modest. Study cohort A examined the combination of pembrolizumab (Keytruda) and olaparib (Lynparza), a PD-1 inhibitor, in patients pretreated with docetaxel. After 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 at the Seattle Cancer Care Alliance, said the benefits of PARP inhibitors could extend beyond these subsets of patients selected at the same time. molecular level. These are preliminary data, but they suggest that treatment in the field of prostate cancer is moving towards a precision medicine approach.

In an interview with OncLive, Yu highlighted two key studies on PARP inhibitors in the mCRPC and discussed the challenges in this space to keep moving forward.

OncLive: What were KEYNOTE-365's main takeaways?

Yu: This is a study evaluating mCRPC combinations with pembrolizumab as well as several treatment options. What I presented at the symposium on genitourinary cancers of 2019 was: [data from] Cohort A, [in which, investigators evaluated the combination of] pembrolizumab with olaparib in patients who have previously received docetaxel. These patients had received up to 1 other line of chemotherapy and thus could have received docetaxel and cabazitaxel. They also could have received up to 2 hormonal treatments such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi). This was a fairly advanced patient population, as evidenced by the fact that 41% of patients had measurable visceral disease. Patients were then given 200 mg pembrolizumab every 3 weeks with olaparib 400 mg.

What we saw was that the combination was tolerated fairly well – only about 15% of patients had immune-mediated side effects, and these events only affected grades 1 and 2. No Grade 3 or 4 event has not been observed. With respect to efficacy, we observed that about half of the patients had a decrease in prostate specific antigen (PSA), but the confirmed response rate of PSA was 12 %. With respect to soft tissue diseases, we found that about 29% of patients had shrinkage greater than 30% of soft tissue diseases. I think it is impressive. The confirmed [overall] The response rate was however 7%. We need to determine the gap between the narrowing and the potential ability to confirm it with a second imaging study.