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
, 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.
“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
, or ATM
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.