Our understanding of the genomic landscape of metastatic castration-resistant prostate cancer has been rapidly progressing, with new clinical data emerging to clarify and, in many cases, support the use of PARP inhibitors in the treatment of these patients.
Celestia S. Higano, MD
Our understanding of the genomic landscape of metastatic castration-resistant prostate cancer (CRPC) has been rapidly progressing, with new clinical data emerging to clarify and, in many cases, support the use of poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of these patients.
“PARP is an important mediator of DNA repair as the DNA strand breaks,” explained Celestia S. Higano, MD, during a presentation at the New York GUTM: 10th Annual Interdisciplinary Prostate Cancer Congress® and other Genitourinary Malignancies. “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.”
Study results published inCellin 2015 showed that genomic testing of bone or soft tissue biopsies from patients with metastatic CRPC proved that 23% of metastatic CRPC tumors harbor DNA repair alterations. Aberrations of the androgen receptor (AR), ETS fusions,TP53mutations, andPTENmutations were frequently observed (40%-60% of cases), with TP53 and AR alterations enriched in metastatic CRPC compared with primary prostate cancer.1
Additionally, aberrations of BRCA1/2 and ATM genes were observed at substantially higher frequencies (19.3% overall) compared with those in primary prostate cancers. The study found that 89% of affected individuals harbored a clinically actionable DNA aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with pathogenic germline alterations that are actionable. The study also determined that the frequency of DNA repair alterations increases with disease progression.
In a phase II study of olaparib (Lynparza), a PARP inhibitor, treating patients with metastatic CRPC and DNA repair defects, the drug was proven to lead to high response rates in this patient population. The study enrolled 50 patients who were no longer responding to standard treatments, including docetaxel (Taxotere), 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,” commented Higano, professor at the University of Washington School of Medicine and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center.
DNA repair alterations are present in approximately 25% to 30% of cases of metastatic CRPC. These include BRCA1/2, ATM, Fanconi’s anemia, CHEK2, and other gene alterations. Higano stressed that there are 2 ways a patient can have these alterations: either in tumor DNA, which is observed in about 25% of patients, or in the germline setting, which is observed in approximately 12% of patients.
If these DNA repair alterations are present after treatment with abiraterone, docetaxel, or enzalutamide, there is a higher response rate to olaparib. However, 1 challenge is the lack of data regarding the overall survival (OS) benefit for patients with CRPC, although olaparib has a breakthrough designation from the FDA based on a study published in the New England Journal of Medicine.2 “It’s not that difficult to get olaparib for your patients,” Higano commented.
Numerous other PARP inhibitors are also in development, including veliparib, niraparib (Zejula), rucaparib (Rubraca), and talazoparib. 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.
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 metastatic CRPC (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.
A phase II randomized, open-label, multicenter trial is also assessing the efficacy abiraterone and prednisone with or without added olaparib in comparison with olaparib monotherapy (NCT03012321). Patients with metastatic CRPC that have anATM,BRCA1, orBRCA2mutation will be randomized to 1 of 3 arms.
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, several 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 metastatic CRPC 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 of niraparib, investigators are assessing the efficacy, safety, and pharmacokinetics of niraparib in men with metastatic CRPC and DNA repair anomalies (NCT02854436). The trial is looking at overall response rate as its primary endpoint, with OS and time to prostate-specific antigen progression included as secondary endpoints.
“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.