MULTIPLE POLY (ADP-ribose) polymerase (PARP) inhibitors are under study in metastatic prostate cancer and no clear winner has emerged yet. Some studies suggest that the best use of PARP inhibitors may be in patients whose cancers harbor DNA-repair defects and BRCA1/2 mutations, but other data suggest these drugs may have a broader application.
Two separate preliminary studies presented at the 2019 Genitourinary Cancers Symposium showed promise for the use of PARP inhibitors in previously treated metastatic castration-resistant prostate cancer. The open-label phase II GALAHAD study evaluated single-agent niraparib in patients with metastatic castration-resistant prostate cancer and DNA-repair defects, mainly BRCA1/2 defects.1 The phase Ib/II KEYNOTE-365 study evaluated a cohort of patients with metastatic castration-resistant prostate cancer (unselected for DNA-repair defects) treated with the combination of the checkpoint inhibitor pembrolizumab plus the PARP inhibitor olaparib.2
The GALAHAD Study
THE ONGOING, open-label phase II GALAHAD trial evaluated single-agent niraparib in patients with metastatic castration-resistant prostate cancer and biallelic DNA-repair defects whose disease progressed after docetaxel and enzalutamide and/or abiraterone acetate. Currently, it has enrolled 120 patients.
The analysis presented at the symposium was based on 39 patients with metastatic castration-resistant prostate cancer who had biallelic loss or defect in both copies of a DNA-repair pathway gene (23 with BRCA1/2 mutations and 16 with a different alteration). Patients were treated with niraparib at 300 mg/d.
At a median follow-up of 5.7 months, in the 23 patients with BRCA1/2 mutations, niraparib achieved an objective response rate of 38% and a composite response rate of 65%. In the 16 patients who had another DNA-repair alteration, the objective response rate was 11% and the composite response rate was 31%.
The composite response rate encompasses Response Evaluation Criteria in Solid Tumors for response, at least a 50% decline in prostate-specific antigen (PSA), and/or conversion of circulating tumor cells to < 5 per 7.5 mL of blood.
“These preliminary results suggest that PARP inhibition with niraparib may play an important role in the treatment of men with metastatic castration-resistant prostate cancer who have mutations in DNA-repair genes.”— Matthew R. Smith, MD
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“These preliminary results suggest that PARP inhibition with niraparib may play an important role in the treatment of men with metastatic castration-resistant prostate cancer who have mutations in DNA-repair genes. Additional therapies are needed to address the unmet medical needs in metastatic castration-resistant prostate cancer, and we look forward to accumulating more evidence about the role of niraparib in this important setting,” said lead author Matthew R. Smith, MD, Director of Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center.
The most common grades 3 and 4 adverse events were mainly hematologic: anemia (26%), thrombocytopenia (15%); neutropenia (8%), and leukopenia (6%). The most common grades 3 and 4 nonhematologic adverse events were asthenia (6%) and back pain (5%).
A phase III trial called MAGNITUDE has been initiated to evaluate niraparib in combination with abiraterone acetate and prednisone as front-line treatment of castration-resistant prostate cancer.
PARP INHIBITORS IN PROSTATE CANCER
- Early studies with PARP inhibitors (eg, olaparib, rucaparib, niraparib) in advanced prostate cancer are encouraging, although it is not yet clear which subsets of patients will have the greatest benefit.
- Studies to date have focused on the metastatic castration-resistant prostate cancer setting, and some experts wonder whether this approach may also work in earlier stages of the disease (perhaps even in the absence of hormonal therapy).
- Further study is needed to determine the optimal biomarker panel to predict greatest sensitivity to PARP inhibitors in prostate cancer.
KEYNOTE-365
THE PHASE IB /II KEYNOTE-365 trial was designed to evaluate pembrolizumab in combination with several different treatment options, including a PARP inhibitor in cohort A. Patients entered in cohort A of KEYNOTE-365 had disease progression within 6 months after 1 to 2 previous lines of chemotherapy (docetaxel or cabazitaxel) for metastatic castration-resistant prostate cancer and up to 2 second-generation hormonal therapies (enzalutamide and/ or abiraterone acetate).
At the symposium, Evan Y. Yu, MD, reported the results of cohort A, which included 41 men treated with the combination of pembrolizumab plus olaparib. Dr. Yu is Professor of Medicine at the University of Washington and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center.
Patients in cohort A were treated with pembrolizumab at 200 mg every 3 weeks plus olaparib at 400 mg twice daily. The median age of patients was 69 years. The majority of patients had an Eastern Cooperative Oncology Group Performance Status of 1. A total of 11 patients (27%) had programmed cell death ligand 1–positive disease; 28 (68%) had measurable disease (41% of those had visceral disease); and the median prostate-specific antigen (PSA) level was 129 ng/mL. The patient population was unselected for molecular abnormalities. “This was a population with pretty advanced disease,” Dr. Yu said.
Toxicity and Response
IMMUNE-MEDIATED adverse events occurred in about 15% of patients; the most common of these was hypothyroidism, occurring in 2 patients. No grade 3 or 4 immune-mediated adverse events were reported.
About 50% of patients experienced some decline in PSA level; 39% had tumor reduction, and 29% had tumor reduction of more than 30%. “I think this is impressive,” Dr. Yu added. “However, response rates were modest.” At a median follow-up of 11 months, the composite response rate in these patients was 12%. The confirmed overall response rate was 7%.
The median radiographic progression-free survival was 4.7 months. The median overall survival was 13.5 months.
“Pembrolizumab/olaparib had promising activity in molecularly unselected patients who received previous treatment with chemotherapy and second-generation hormonal therapy. These results support further evaluation,” Dr. Yu told listeners. The phase II cohort will be expanded to 100 patients.
Evan Y. Yu, MD
Phase III Trial Planned
A PHASE III trial of the pembrolizumab/olaparib combination is planned to enroll unselected patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and either enzalutamide or abiraterone acetate, but not both. Patients will be randomly assigned to receive pembrolizumab/ olaparib vs either enzalutamide or abiraterone acetate, depending on which of the two hormonal agents the patient previously did not receive. The study will be sponsored by Merck and will be conducted at 42 sites in 8 countries. “A randomized phase III trial will tell us more about the role of this combination,” Dr. Yu said. ■
DISCLOSURE: Dr. Smith is a consultant/advisor for Bayer, Janssen, Amgen, and Pfizer; and has received institutional research funding from Janssen, Gilead Sciences, and Bayer. Dr. Yu is a consultant/advisor for Janssen, Bayer, Merck, AstraZeneca, EMD Serono, Churchill Pharmaceuticals, Incyte, Amgen, Tolmar, and QED Therapeutics; has received institutional research funding from Agensys, Astellas Pharma, Dendreon, Genentech/Roche, Bayer, Merck, and Seattle Genetics.
REFERENCES
1. Smith MR, Sandhu SK, Kelly WK, et al: Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer and biallelic DNA-repair defects: Preliminary results of GALAHAD. 2019 Genitourinary Cancers Symposium. Abstract 202. Presented February 14, 2019.
2. Yu EY, Massard C, Retz M, et al: KEYNOTE-365 cohort A: Pembrolizumab plus olaparib in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer. 2019 Genitourinary Cancers Symposium. Abstract 145. Presented February 14, 2019.
