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PARP Inhibitor Active in BRCA1/2-Mutated Metastatic Castration-Resistant Prostate Cancer


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THE SEARCH for biomarkers in prostate cancer has proved frustrating, partly due to the complexity of the disease and its heterogeneity. A preliminary analysis of a phase II (TRITON2) study suggests that rucaparib (Rubraca), a poly (ADP-ribose) polymerase (PARP) inhibitor, may be active in men with BRCA1/2-positive metastatic castration-resistant prostate cancer.1 In the TRITON2 trial, the confirmed objective response rate was 44% (95% confidence interval, 24%–65%) in 25 patients evaluable by RECIST (Response Evaluation Criteria in Solid Tumors), according to results presented at the European Society for Medical Oncology (ESMO) 2018 Congress.

Wassim Abida, MD

Wassim Abida, MD

“Among men with BRCA1/2 alterations, 51% had a confirmed prostate-specific antigen [PSA] response,” said lead author Wassim Abida, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York.

This is one of the first genetically targeted therapies to show a benefit in prostate cancer. Better treatments are needed for men with metastatic castration-resistant prostate cancer once their disease progresses on androgen-deprivation therapy and taxane chemotherapy.

Up to 25% of patients with metastatic castration-resistant prostate cancer have a germline and/or somatic mutation in BRCA1, BRCA2, ATM, or other homologous recombination repair (HRR) genes. PARP inhibitors have been approved by the U.S. Food and Drug Administration (FDA) in the treatment of BRCA1/2-mutant ovarian and breast tumors, and the investigators hypothesized that prostate cancers harboring BRCA1/2-gene alterations would respond to PARP inhibition as well. Both rucaparib and the PARP inhibitor olaparib (Lynparza) now have FDA Breakthrough Therapy designation status for single-agent use in adults with BRCA1/2-positive metastatic castration-resistant prostate cancer following at least one androgen receptor–directed therapy and taxane-based chemotherapy.

Study Description

THE INTERNATIONAL, multicenter, open-label TRITON2 trial is currently recruiting patients at approximately 120 locations, with a planned enrollment of up to 100 men with metastatic castration-resistant prostate cancer with a deleterious BRCA1/2 alteration who have measurable visceral and/or nodal disease; patients without measurable disease and/or with a deleterious alteration in 1 of 12 other HRR genes are also being enrolled. All men must have experienced disease progression after prior androgen receptor–directed therapy and a prior taxane therapy.

Dr. Abida reported the results for 85 men enrolled in the study, from a June 29, 2018, visit cutoff date, with a median follow-up of 5.7 months. Some patients had been followed for as long as 16 months.

INTERIM ANALYSIS OF TRITON2 TRIAL

  • Thus far, the TRITON2 trial showed encouraging responses with the PARP inhibitor rucaparib in heavily pretreated men with BRCA1/2 alterations and metastatic castration-resistant prostate cancer.
  • These findings are preliminary, and a phase III confirmatory trial (TRITON3) is active and recruiting patients.

Patients were treated with rucaparib at 600 mg twice daily until radiographic disease progression, unacceptable toxicity, or other reason for treatment discontinuation. Radiographic assessment was performed every 8 weeks for 24 weeks, then every 12 weeks. PSA levels were measured every 4 weeks. A total of 25 patients with BRCA1/2 mutations were evaluable for radiographic response, and 45 patients with BRCA1/2 mutations were evaluable for PSA response. One-third had a germline BRCA1/2 mutation, and two-thirds had a somatic BRCA1/2 mutation.

Patients were pretreated with a variety of drugs. Prior therapies included abiraterone (Yonsa, Zytiga; 55.6%), enzalutamide (Xtandi; 73.3%), both abiraterone and enzalutamide (31.1%), docetaxel (95.6%), cabazitaxel (Jevtana; 8.9%), sipuleucel-T (Provenge; 13.3%), and radium-223 (Xofigo; 11.1%). About 89% had bone metastases, two-thirds had positive nodes, and about 42% had visceral metastases. The median treatment duration for the BRCA1/2 cohort was 4.4 months.

Response and Toxicity

AMONG EVALUABLE BRCA1/2-positive patients, all 11 radiographic responses (44%) were partial responses. Nine patients (36%) had a best response of stable disease. Partial radiographic responses were observed in two of eight patients with alterations in other HRR genes, namely in one patient a BRIP1 alteration and one patient with a FANCA alteration. Although no radiographic response was observed in five ATM-mutated cancers, there were reductions in target lesion measurements and PSA measures observed in some patients. Stable disease was the best response in four patients in the ATM-mutated  group (80.0%) and five patients in the CDK12-mutated group (62.5%). Based on the protocol-specified stopping rules, the study will no longer continue to enroll patients with CDK12 alterations; patients with ATM alterations will continue to be enrolled.

In this early report of the phase II trial, the safety profile of rucaparib is similar to that reported in ovarian and other cancers. In the total evaluable study population, the most common treatment-emergent adverse events of any grade were asthenia/fatigue (44.7%), nausea (42.4%), anemia/decreased hemoglobin (28.2%), and decreased appetite (28.2%).

DISCLOSURE: Dr. Abida has received honoraria from Caret; is a consultant/advisor to Clovis Oncology, Janssen, and MORE Health; has received research funding from AstraZeneca, Zenith Epigenetics, Clovis Oncology, and GlaxoSmithKline; and has received reimbursement for travel expenses from GlaxoSmithKline and Clovis Oncology.

REFERENCE

1. Abida W, Bryce AH, Vogelzang NJ, et al: Preliminary results from TRITON2: A phase 2 study of rucaparib in patients with metastatic castration-resistant prostate cancer associated with homologous recombinant repair gene alterations. ESMO 2018 Congress. Abstract 793PD. Presented October 21, 2018.


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