The activity of PARP inhibitors (PARPi) in patients with homologous recombination repair (HRR) mutations and metastatic castration-resistant prostate cancer has been established. We hypothesized that the benefit of PARPi can be maintained in the absence of androgen deprivation therapy (ADT) in an HRR-mutated population. We report the results of a phase II clinical trial of rucaparib monotherapy in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
This was a multi-center, single-arm phase II trial (NCT03413995) for patients with asymptomatic, mHSPC. Patients were required to have a pathogenic germline mutation in an HRR gene for eligibility. All patients received rucaparib 600 mg by mouth twice daily, without androgen deprivation. The primary endpoint was a confirmed PSA50 response rate.
Twelve patients were enrolled, 7 with a BRCA1/2 mutation and 5 with a CHEK2 mutation. The confirmed PSA50 response rate to rucaparib was 41.7% (N = 5/12, 95% CI: 15.2-72.3%, one-sided P = .81 against the 50% null), which did not meet the pre-specified efficacy boundary to enroll additional patients. In patients with measurable disease, the objective response rate was 60% (N = 3/5), all with a BRCA2 mutation. The median radiographic progression-free survival on rucaparib was estimated at 12.0 months (95% CI: 8.0-NR months). The majority of adverse events were grade ≤2, and expected.
Rucaparib can induce clinical responses in a biomarker-selected metastatic prostate cancer population without concurrent ADT. However, the pre-specified efficacy threshold was not met, and enrolment was truncated. Although durable responses were observed in a subset of patients, further study of PARPi treatment without ADT in mHSPC is unlikely to change clinical practice.
The oncologist. 2024 Jun 17 [Epub ahead of print]
Mark C Markowski, Cora N Sternberg, Hao Wang, Tingchang Wang, Laura Linville, Catherine H Marshall, Rana Sullivan, Serina King, Tamara L Lotan, Emmanuel S Antonarakis
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, United States., Division of Hematology/Oncology, Englander Institute for Precision Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell, New York, NY, United States., Division of Quantitative Sciences, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, United States., Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, United States., Department of Medicine, Masonic Cancer Center, University of Minnesota Medical Center, Minneapolis, MN, United States.