Daniel J. George, MD, provides insights on how to treat patients with prostate cancer who have pathogenic non-BRCA HRD mutations, and his approach when patients progress on a PARP inhibitor.
Case: A 65-Year-Old Man With Prostate Cancer
Daniel J. George, MD: If I have a patient who has an HRD [homologous recombination deficiency mutation that’s not BRCA, maybe it’s a CDK12, FANCD2, or a PALB2, these are alterations that are still associated with defects and recombinant DNA repair in the same machinery associated with BRCA. Mechanistically, they’re related to [patients with BRCA mutations], and if we look at our PROpel [study; NCT03732820] data, and at the TALAPRO-2 [study; NCT03395197] data, there’s still evidence, even though it’s more modest, of a benefit associated with the addition of a PARP inhibitor with a novel hormonal agent.
In my mind, this is still a population of patients that have a genetically aggressive disease course and biology associated with their [castration]-resistant prostate cancer [CRPC] and one that I’m going to want to try to maximize our benefits for. These are situations where I would still consider using my combination of a PARP inhibitor and novel hormonal agent, particularly in populations where we want to be more aggressive—younger patients, patients who have more symptomatic disease, and patients who have maybe prior chemotherapy in the hormone-sensitive disease setting. In the PROpel data, these were subgroups where we saw greater benefit associated with those disease settings, those subgroups of patients. To me, this is where I think we take our labels and our uses, we look at the data, and we try to do what we think is best for the patient. When possible, I think layering our concomitant use of these agents makes sense. Of course, we are limited sometimes by our guidelines and our labels, so I will consider maybe talazoparib in a situation like that because it’s got a slightly broader label than olaparib, but it’s the same concept; it’s very similar data. It’s the population of patients we want to be aggressive with.
These are the situations where we can absolutely maximize these benefits. Even if for that individual patient, the benefit isn’t as great as what we see with a BRCA mutation. That patient doesn’t get to choose, [and] I don’t get to choose, what mutation they have. We must deal with whatever biology and circumstances they’re dealing with, and for each patient, we want to maximize that benefit. Whether it’s a modest or a dramatic benefit, it’s still a benefit. On these individual patients, improvements of even just a few months in the radiographic progression-free survival is meaningful. To me, this is still something that on an individual basis, we’ll discuss and consider for treatment—again, on a case-by-case basis.
One of the challenges going forward for us in this disease is what to do for patients who have had a PARP inhibitor with a BRCA or HRR mutation and now have disease progression because that’s still a relevant biology. It’s much like our engine-deprivation therapy. The question is, is there any role for re-challenging with PARP inhibitors in patients previously treated with a PARP inhibitor? And I think my first answer to that is to change mechanism.
The reason I like to change mechanism is because when I have a patient who has progressed on a PARP inhibitor, there are 2 things that come with that. One is the toxicity associated with that prior PARP inhibitor, and if they’ve had significant anemia, they’ve had other complications associated with that, I’d like to give those cells a chance to recover and that patient a chance to recover from that toxicity. Secondly, the biology of resistance is fluid; this isn’t necessarily always associated with a genetic selection. There can be RNA expression and protein expressions and other epigenetic effects that are driving that heterogeneity and disease resistance that will change over time. Having some separation from that PARP inhibitor changing to a different mechanism, maybe going back to chemotherapy if they haven’t had chemotherapy, trying that, or maybe a radiotherapeutic targeted ligand therapy and what have you. Recognizing that following that therapy the patient still is likely to have biology driven through that BRCA mutation, [so] a rechallenge with a PARP inhibitor is not unusual, not unreasonable because, especially if we think that the patient can tolerate this therapy and one PARP inhibitor might be better tolerated than another. We don’t know that yet, we don’t have head-to-head data, but [adverse] effect profiles do look different, so there’s a rationale there.
These aren’t "me-too” drugs; they have different ways of inhibiting PARP. So rechallenging that in that context, and maybe again in the context with a novel hormonal agent, if the patient’s had some separation from their last prior novel hormonal agent, is something we do in a number of cancers, and prostate cancer is no exception. These are strategies that we follow on a case-by-case basis when we have patients who have demonstrated responsiveness in the past, resistance, subsequent other therapies, and there are limited standard treatment options. These are some of the things that we can try in these patients that can be beneficial. We’ll have the individual patient response to judge that clinical benefit, for we’ll know if their symptoms are improving, if their PSA [prostate-specific antigen level] is dropping, if their radiographic scans are stable. These are ways of being able to assess whether or not there’s clinical benefit associated on an individual basis with that intervention.
Transcript edited for clarity.