Daniel J. George, MD, discusses recent clinical trial data on the PARP inhibitors rucaparib and talazoparib for treatment of prostate cancer.
Case: A 65-Year-Old Man With Prostate Cancer
Daniel J. George, MD: It’s important to recognize that PROpel was a confirmation phase 3 study from an earlier proof of concept phase 2 study. They’re not the only 2 studies of PARP inhibitors in metastatic castrate-resistant prostate cancer. There is a study with enzalutamide and talazoparib called TALAPRO-2, which had a very similar design to the PROpel study. It also took an all-comers population, but it did prespecify patients who had homologous recombination repair [HRR] defects and BRCA defects from those who had non-HRR mutated tumors and separated those populations. They were stratified by that and, again, randomized to either enzalutamide and placebo or enzalutamide plus talazoparib. They were able to demonstrate a significant radiographic progression-free survival benefit for the intention-to-treat population, but a greater benefit associated with patients who had BRCA mutations and even those who had homologous recombination repair defects. That has led to its approval by the FDA for a similar indication in metastatic castrate-resistant prostate cancer of patients with BRCA or homologous recombination repair defect to receive enzalutamide in combination with talazoparib.
Then there was another full approval based on the TRITON3 study, which was a phase 3 study of rucaparib, a third PARP inhibitor. This was studied in patients with metastatic castrate-resistant prostate cancer who had received a prior novel hormonal agent and docetaxel chemotherapy. In this study, patients were randomized to best supportive care, whether that was another novel hormonal agent, chemotherapy, or rucaparib, and they were able to demonstrate a benefit associated with rucaparib in patients who had BRCA or a homologous recombination repair defects. It was specifically BRCA1/2 and ATM that their population focused on. So specifically looking at those patients, they were able to demonstrate a benefit both in radiographic progression-free survival and overall survival.
These are important trends we’re seeing now of the benefits in this selected population of patients from the addition of PARP inhibitors, whether it be after a novel hormonal agent as a single agent, or in the case of talazoparib and olaparib, in combination with a novel hormonal agent in this first-line castrate-resistant prostate cancer setting. It opens the door for our patients to benefit from these drugs earlier and potentially take advantage of some synergy between the novel hormonal agent, androgen receptor [AR] pathway inhibition and the role the androgen receptor plays on DNA repair as well as PARP inhibition, which the androgen receptor works through for DNA repair and which can trap PARP and prevent any additional AR signaling from repairing DNA in these patients. It’s a great opportunity to maximize the benefit associated with PARP inhibition in these selected patients.
Transcript edited for clarity.