An expert on prostate cancer provides insights on patients best suited for PARP inhibitor treatment and how to select and sequence therapy.
Case: A 65-Year-Old Man With Prostate Cancer
Daniel J. George, MD: In my practice today, most of my patients are being diagnosed with prostate cancer either in the metastatic hormone-sensitive setting or relapse after local therapy, and we’re considering novel hormonal agents. More and more data are supporting the use of novel hormonal agents alone or in combination with chemotherapy in this metastatic hormone-sensitive disease setting. Even in patients with recurrent prostate cancer that’s nonmetastatic, there are data to support novel hormonal agents there as well. In more of my practice, I’m using novel hormonal agents early in the disease course. When patients get to the metastatic castrate-resistant prostate cancer setting, they carry that prior exposure with them. If they are BRCA-mutated positive, then I’m going to think about a PARP inhibitor. The question is going to be whether I’m going to use a novel hormonal agent in combination with that. My thinking is like this, the answer is unknown whether a novel hormonal agent in somebody who’s had prior exposure is beneficial with a second trial of that agent or a different agent, or whether I should just use the PARP inhibitor alone.
My thinking is this, if a patient had evidence of response to that novel hormonal agent, particularly if it was a long response, if that progression is relatively subtle, if the progression is associated with a relatively limited new metastatic site of disease or minimal symptoms, and if the patient tolerated that novel hormonal agent well, I’m going to consider keeping that going and adding my PARP inhibitor, similar to what we do with ADT [androgen deprivation therapy]. My rationale is that this progression may not be completely homogeneous. There may be parts of that tumor, maybe significant areas of that tumor, that are still responsive to novel hormonal agents. I don’t want to give that up in the setting of my PARP inhibition. We may get further benefit in those sites of disease and prevent further sites of progressing and keep that progression to a limited number of sites.
The other approach is in patients who have had an interruption in their novel hormonal agent. Take the case that we just presented, where a patient had abiraterone and ADT, developed castrate-resistant disease, then was treated with docetaxel, got a response, a break from hormonal therapy, and then progression off that novel hormonal agent. The idea would be to rechallenge with that novel hormonal agent, particularly if they were tolerating it OK, and to add my PARP inhibitor olaparib in that setting. The idea is if I’m able to get even a modest response to the androgen deprivation therapy, even stable disease, that may add to the clinical benefit associated with PARP inhibition. Because when I look at the radiographic progression-free survival from the PROfound study of 7.4 months median, it’s much shorter than what we’re seeing in the PROpel study.
To me, it makes sense to say, if there’s any hope of that synergy, I’d like to see it. Certainly, if the patients have difficulty tolerating the combination, I’m going to rethink that. But if I can see evidence that they’re able to tolerate that combination OK and they’re getting a clinical benefit, I’m going to want to maximize this because this is an accelerated natural history, an aggressive disease course. Patients are more likely to have symptomatic progression in the past or the future. These are patients we may not necessarily have an option to treat with 3 or 4 or 5 lines of therapy. We want to use our best treatments in that first-line metastatic castrate-resistant setting.
Transcript edited for clarity.