Rubraca Granted Breakthrough Designation for Prostate Cancer

The FDA has granted the PARP inhibitor Rubraca (rucaparib) a breakthrough therapy designation for single-agent use in adult patients with BRCA1/2-positive metastatic castration-resistant prostate cancer (mCRPC) following at least one androgen receptor—directed therapy and taxane-based chemotherapy.

The designation, which will expedite the development and review of rucaparib in this setting, is based on initial data from the ongoing TRITON2 phase 2 study in advanced prostate cancer (NCT02952534). Clovis Oncology, the manufacturer of the PARP inhibitor, reported in press release that the study data will be presented at the 2018 ESMO Congress.

“We hope the decision by the FDA to grant this breakthrough therapy designation for Rubraca offers encouragement to the prostate cancer community, and we will do our best to make Rubraca available to eligible prostate cancer patients as quickly as possible,” Patrick J. Mahaffy, President and CEO of Clovis Oncology, said in the press release.

The single-arm phase 2 TRITON2 study is enrolling men with mCRPC with germline or somatic BRCA1/2 mutations and evidence of a homologous recombination gene deficiency. Patients are unable to enroll if they previously received a PARP inhibitor, mitoxantrone, cyclophosphamide or any platinum-based chemotherapy. Individuals with symptomatic and/or untreated CNS metastases are also not eligible. The study is being conducted at 106 locations and the targeted enrollment is 160 patients.

The primary endpoints are objective response rate, and prostate-specific antigen (PSA) response. Secondary outcome measures include duration of response, radiologic progression-free survival, overall survival, clinical benefit rate, time to PSA progression and safety/tolerability. The estimated primary completion date is October 2019.

“We are pleased the FDA has granted breakthrough therapy designation to Rubraca in mCRPC,” Howard R. Soule, Ph.D., executive vice president and chief scientific officer of the Prostate Cancer Foundation, said in a statement. “There is tremendous need for new therapeutic options in advanced prostate cancer. In particular, we are enthusiastic about the potential for targeted therapies that may provide more meaningful benefit to patients with specific genetic mutations.”

Beyond TRITON2, the multicenter, randomized phase 2 TRITON3 clinical trial (NCT02975934) is comparing single-agent rucaparib with physician’s choice of Zytiga (abiraterone acetate), Xtandi (enzalutamide) or Taxotere (docetaxel) in men with mCRPC and homologous recombination deficiency whose disease has progressed despite treatment with prior therapy.

Rucaparib has approved indications in ovarian cancer. Success with PARP inhibitors has spread to the field of breast cancer, and now, there is growing evidence of the efficacy of these agents in prostate cancer.

Celestia S. Higano, M.D., discussed emerging strategies to target PARP in prostate cancer during a presentation at the New York GUTM: 10th AnnualInterdisciplinary Prostate Cancer Congress® and other Genitourinary Malignancies conference, held by Physicians’ Education Resource^® (PER^®).

“PARP is an important mediator of DNA repair as the DNA strand breaks,” said Higano, a professor at the University of Washington School of Medicine and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center in Seattle. “And so, when we have a patient who has an underlying DNA repair problem and we inhibit PARP, we can end up with a situation where there is no DNA repair, leading to cell death.”

PARPs, a family of multifunctional enzymes, play a critical role in base excision repair, a process through which single-strand DNA breaks are mended. In her presentation, Higano identified other key repair pathways for different types of DNA damage: homologous recombination repair and nonhomologous end joining for double-strand breaks; nucleotide excision repair and translesion synthesis for bulky adducts; and mismatch repair for nucleotide mutations, substitutions, deletions and insertions.

In study results published in Cell in 2015, genomic testing of bone or soft tissue biopsies demonstrated that aberrations of BRCA1/2 and ATM were observed at substantially higher frequencies (19.3 percent overall) in advanced prostate cancer compared with those in primary prostate cancers. The study also determined that the frequency of DNA repair alterations increases with disease progression.

Overall, the study found that 89 percent of affected individuals harbored a clinically actionable DNA aberration, including 62.7 percent with aberrations in the androgen receptor, 65 percent in other cancer-related genes and 8 percent with germline alterations.

Lynparza (olaparib), the first PARP inhibitor to gain the FDA’s approval in 2014 with an indication in recurrent ovarian cancer, is being investigated in prostate cancer under a breakthrough therapy designation based on phase 2 study data. In the trial, Lynparza demonstrated high response rates in patients with mCRPC and DNA repair defects.

The study enrolled 50 patients who were no longer responding to standard treatments, including docetaxel, Zytiga, Xtandi or Jevtana (cabazitaxel). Genomic sequencing was performed on tumor biopsies as a requirement of the study. Of the 49 evaluable patients, 16 (33 percent) had a response to the treatment with Lynparza, with 12 receiving the treatment for more than six months.

The study concluded that the presence of defects in DNA repair genes found in biopsies of metastatic tumors was associated with a high response rate to Lynparza in 14 of 16 patients, including all seven with loss of BRCA2.

“They didn’t really know this until after the study, but 14 out of the 16 responders had DNA repair alterations. This was a pretty small study, but it has prompted a lot of interest in researching PARP inhibitors in prostate cancers,” said Higano.