PARP Inhibitor Tested in mCRPC

Charles J. Ryan, MD

Rucaparib (Rubraca), a drug approved for the treatment of ovarian cancer, might also be used to treat patients with metastatic castration-resistant prostate cancer (mCRPC), pending the results of a phase III study.

Rucaparib targets PARP, poly (ADP-ribose) polymerase, which inhibits some tumor cells from repairing their own DNA. In December 2016, the FDA approved the drug for women with recurrent ovarian cancer that expresses BRCA mutations. Now, the drug is being tested in men with mCRPC and homologous recombination deficiency (HRD) whose disease has progressed despite treatment with prior therapy. The multicenter, randomized TRITON3 clinical trial (NCT02975934) is evaluating rucaparib as a single agent, comparing its effectiveness with physician’s choice of abiraterone acetate (Zytiga), enzalutamide (Xtandi), or docetaxel (Taxotere). The trial, now enrolling, seeks to address an unmet clinical need: No standard of care has been established for men with mCRPC and mutations to BRCA and other HRD genes associated with hereditary cancers.

Rucaparib selectively targets tumors with these deficiencies, which preventing cancer cells from repairing their DNA. To compensate, the cancer cells rely on the protein PARP to facilitate DNA repair. “In the world of prostate cancer, we have preliminary data that PARP inhibitor therapies have activity in this group of patients with BRCA1, BRCA2, and ATM mutations, but PARP inhibition has not been tested definitively and validated as a standard-of-care therapy,” said Charles Ryan, MD, professor of clinical medicine and urology and associate director for clinical sciences at UCSF Helen Diller Family Comprehensive Cancer Center. Ryan is the principal investigator of the North American branch of the TRITON3 study.

Trial Details

“There are conflicting data now on the efficacy of abiraterone in a BRCA-mutated population, and this will potentially highlight some of the overlap between hormone sensitivity and DNA repair alterations.”The trial is designed to test the efficacy of rucaparib in patients who have received either abiraterone or enzalutamide as initial treatment for mCRPC, but have not received chemotherapy. Eligible patients will also have a deleterious mutation in the BRCA1, BRCA2, or ATM genes.

An estimated 400 patients will be randomized 2:1 to receive rucaparib monotherapy or physician’s choice of therapy based mainly on prior treatment (Figure). The trial will record the genetic alterations in patients’ tumors and their therapeutic outcomes, focusing on time until disease progression, to better understand who within this patient population is most likely to benefit from PARP inhibitors. Patients whose disease progresses on the control arm will be allowed to cross over to receive rucaparib.

Figure. Rucaparib in Patients With mCRPC and DNA Repair Mutations

According to Ryan, the main adverse events (AEs) the investigators expect to see with rucaparib are common to PARP inhibitors, and are primarily hematologic, including anemia. Other AEs observed in past trials of PARP inhibitors include fatigue, leukopenia, thrombocytopenia, and neutropenia.

In the concurrently running phase II TRITON2 trial (NCT02952534), led by principal investigator Wassim Abida, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, investigators are determining how patients with mutated mCRPC respond to rucaparib as a monotherapy.

Encouraging Data From Previous Trials

The trial differs from TRITON3 in a few key areas: It is a single-arm study for patients with mCRPC who previously received abiraterone and/or enzalutamide, as well as docetaxel, and patients are being screened for mutations not only in BRCA1, BRCA2 and ATM, but in 12 additional genes. An estimated 160 patients will receive rucaparib daily, with the primary endpoints being objective response rate and prostate-specific antigen (PSA) response. Higher levels of PSA in blood can be an indicator of the presence or growth of prostate cancer.Prior studies have shown efficacy of PARP inhibitors in mCRPC. In the phase II TOPARP-A trial, investigators assessed Lynparza (olaparib) in patients with mCRPC who had received prior treatment with docetaxel, the majority of whom (98%) had also received abiraterone or enzalutamide. Of 49 evaluable patients, 16 (33%) had a response, and 12 received treatment for more than 6 months. Among men with BRCA1, BRCA2, or ATM mutations, the overall response rate to olaparib was 87.5% The study concluded that this PARP inhibitor sparked a high response rate in patients with mCRPC and DNA repair mutations whose disease was no longer responsive to standard treatments.

Another phase II study, presented at the 2017 American Society of Clinical Oncology Annual Meting, tested the experimental PARP inhibitor veliparib combined with abiraterone and prednisone versus abiraterone and prednisone alone in patients with mCRPC. There was no statistically significant difference between the 2 arms in overall survival, progression-free survival or PSA response rate.

However, in a secondary analysis of patients with DNA repair mutations versus those without them, the PSA response rate in the veliparib arm was statistically significant compared with abiraterone and prednisone alone. Those with DNA repair mutations had a PSA response rate of 90% across both trials versus 56.5% for those without mutations. Rucaparib is being developed by Clovis Oncology, which is sponsoring the TRITON trials. TRITON3 “is a registrational trial, as well, so, pending positive results, it would be reasonable to expect that the FDA would review rucaparib as a standard-of-care treatment in patients with mCRPC (with DNA repair deficiency) who have progressed after prior abiraterone- or enzalutamide-based therapy,” Ryan said.