The genomic landscape of metastatic castration-resistant prostate cancer is becoming increasingly well defined, with new clinical data emerging to clarify and, in many cases, support the use of PARP inhibitors.
Celestia Higano, MD
The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) is becoming increasingly well defined, with new clinical data emerging to clarify and, in many cases, support the use of poly (ADP-ribose) polymerase (PARP) inhibitors.
“PARP is an important mediator of DNA repair as the DNA strand breaks,” said Celestia S. Higano, MD. “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.”
Higano discussed emerging strategies to target PARP in prostate cancer during a presentation at the New York GUTM: 10th Annual Interdisciplinary Prostate Cancer Congress® and other Genitourinary Malignancies conference that Physicians’ Education Resource® (PER®) hosted March 18 in New York City. She is 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.
PARPs, a family of multifunctional enzymes, play a critical role in base excision repair, a process through which single-strand DNA breaks are mended (Figure). 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.
DNA repair alterations are present in approximately 25% to 30% of cases of mCRPC, Higano said. These include BRCA1/2, ATM, Fanconi’s anemia, CHEK2, and other gene alterations. Higano stressed that there are 2 ways a patient can develop these alterations: either in tumor DNA, which is observed in about 25% of patients, or in the germ- line setting, which is observed in approximately 12% of patients.
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% overall) in advanced prostate cancer compared with those in primary prostate cancers.1 The study also determined that the frequency of DNA repair alterations increases with disease progression.
Targeting PARPs in Cancer
Overall, the study found that 89% of affected individuals harbored a clinically actionable DNA aberration, including 62.7% with aberrations in the androgen receptor, 65% in other cancer-related genes, and 8% with germline alterations.Olaparib (Lynparza), 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 II study data. In the trial, olaparib demonstrated high response rates in patients with mCRPC and DNA repair defects.2
The study enrolled 50 patients who were no longer responding to standard treatments, including docetaxel, abiraterone acetate (Zytiga), enzalutamide (Xtandi), or cabazitaxel (Jevtana). Genomic sequencing was performed on tumor biopsies as a requirement of the study. Of the 49 evaluable patients, 16 (33%) had a response to the treatment with olaparib, with 12 receiving the treatment for more than 6 months.2
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 olaparib in 14 of 16 patients, including all 7 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.
If these DNA repair alterations are present after treatment with abiraterone, docetaxel, or enzalutamide, there is a higher response rate to olaparib, although 1 challenge is the lack of data regarding the overall survival (OS) benefit for patients with CRPC. However, given the breakthrough designation, “it’s not that difficult to get olaparib for your patients,” Higano commented.
Other PARP inhibitors are also in development for patients with prostate cancer, including niraparib (Zejula), rucaparib (Rubraca), and talazoparib (Table). Additionally, there are many combinations studies with PARP inhibitors, and so patients who do not have a DNA repair alteration are not necessarily excluded from the potential benefits of PARP inhibitors, Higano said.
HR indicates homologous recombination; mCRPC, metastatic castration-resistant prostate cancer.
One such combination study is the phase I KEYNOTE-365 trial, which is investigating the safety and efficacy of combination therapies with pembrolizumab (Keytruda) in patients with mCRPC (NCT02861573). There will be 3 cohorts in this study, each with approximately 70 participants: cohort A will receive pembrolizumab combined with olaparib, cohort B will receive pembrolizumab combined with docetaxel and prednisone, and cohort C will receive pembrolizumab combined with enzalutamide.
There are some challenges facing the development of PARP inhibitors. One of the problems is that it takes a long time, often 2 to 6 weeks, for the results of tumor biopsies and germline tests to be processed for eligibility for biomarker-driven trials. Despite these challenges, a number of studies of PARP inhibitors driven by DNA repair biomarkers are ongoing. In the phase III, randomized TRITON3 study, investigators will be assessing how patients with mCRPC and evidence of a homologous recombination gene deficiency respond to treatment with rucaparib verses treatment with a physician’s choice of abiraterone, enzalutamide, or docetaxel (NCT02975934). This study is currently enrolling participants who have a deleterious mutation in the BRCA1/2 or ATM gene.
“The thing that makes this trial stand out from all the others is that most of the other trials require patients to have failed docetaxel, whereas this rucaparib trial allows patients to be treated with rucaparib or a choice of abiraterone, enzalutamide, or docetaxel. In terms of patient accrual, patients are allowed to cross over to the rucaparib arm once they fail in the control arm,” Higano said.
In the phase II Galahad study, investigators are assessing the efficacy, safety, and pharmacokinetics of niraparib in men with metastatic CRPC and DNA repair anomalies (NCT02854436).
“I think it’s become increasingly apparent that we need a thorough family history of cancer that might point to patients with DNA repair defects,” said Higano. As genomic testing for directing targeted therapies becomes more integrated into the standard of care for patients with CRPC and PARP inhibitors show more durable responses in clinical trials, these agents will become increasingly available.