Can an Ovarian Cancer Drug Work in Prostate Cancer?

RUBRACA (RUCAPARIB), 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 3 study.

Rubraca (rucaparib) is a targeted drug known as a PARP, or poly (ADP-ribose) polymerase, inhibitor. The pill inhibits the ability of certain tumor cells to repair their own DNA. In December 2016, the Food and Drug Administration approved it for women with recurrent ovarian cancer that expresses BRCA gene mutations.

Now, the drug is being tested in men whose prostate cancer expresses similar mutations, is metastatic and has progressed despite treatment with an initial therapy. The multicenter, randomized TRITON3 clinical trial (NCT02975934) is evaluating Rubraca as a single agent, comparing its effectiveness with that of doctor’s choice of one of three standard drugs: hormonal treatments Zytiga (abiraterone acetate) or Xtandi (enzalutamide), or the chemotherapy drug docetaxel. 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 genes such as BRCA that are associated with hereditary cancers, known as homologous recombination gene deficiencies.

Rubraca selectively targets tumors with these deficiencies, which prevent cancer cells from repairing their DNA. To compensate, the cancer cells rely on the protein PARP to facilitate DNA repair. Rubraca inhibits PARP, so that, when the cell attempts to divide, it cannot repair its DNA, and dies.

“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, M.D., professor of clinical medicine and urology and associate director for clinical sciences at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and principal investigator of the North American branch of the TRITON3 study.

“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.”

TRIAL DETAILS

The trial is designed to test the efficacy of Rubraca in patients who have received either Zytiga or Xtandi 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 Rubraca monotherapy or physician’s choice of therapy based mainly on prior treatment. 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 arm receiving physician’s choice of therapy will be allowed to cross over to receive Rubraca.

According to Ryan, the main side effects the investigators expect to see with Rubraca are common to PARP inhibitors, and are primarily hematologic, including anemia. Other side effects observed in past trials of PARP inhibitors include fatigue, leukopenia (a reduction in white blood cells), thrombocytopenia (a drop in the number of blood platelets) and neutropenia (a dip in the number of neutrophils, a type of protective white blood cell).

In the concurrently running phase 2 TRITON2 trial (NCT02952534), led by principal investigator Wassim Abida, M.D., Ph.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, investigators are determining how patients with the same disease and gene mutations respond to Rubraca as a monotherapy.

The trial differs from TRITON3 in a few key areas: It is a single-arm (not randomized) study for patients with mCRPC who previously received Zytiga and/or Xtandi, 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 Rubraca 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.

ENCOURAGING DATA FROM PREVIOUS TRIALS

Prior studies have shown efficacy of PARP inhibitors in mCRPC. In the phase 2 TOPARP-A trial, investigators assessed Lynparza (olaparib) in patients with mCRPC who had received prior treatment with docetaxel, the majority of whom (98 percent) had also received Zytiga or Xtandi. Out of 49 evaluable patients, 16 (33 percent) had a response, and 12 received treatment for more than six months. Among men with BRCA1, BRCA2 or ATM mutations, the overall response rate to Lynparza was 87.5 percent. 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 2 study, presented at the 2017 Annual Meeting of the American Society of Clinical Oncology, tested the experimental PARP inhibitor veliparib combined with Zytiga and prednisone versus Zytiga and prednisone alone in patients with mCRPC. There was no statistically significant difference between the two arms of the trial in terms of 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 Zytiga and prednisone alone. Those with DNA repair mutations had a PSA response rate of 90 percent across both trial arms, while those without mutations logged a 56.5 percent PSA response rate.

Rucaparib is being developed by Clovis Oncology, which is sponsoring the TRITON2 and TRITON3 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 standardof- care treatment in patients with mCRPC (with DNA repair deficiency) who have progressed after prior abiraterone- or enzalutamide-based therapy,” Ryan said.