Recent Advances in the Treatment of Prostate Cancer - Episode 12

DNA Alterations and Selection of PARP Inhibitors in mCRPC

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Expert perspectives on how DNA alterations may inform the selection and use of PARP inhibitors in metastatic CRPC.


Alicia Morgans, MD, MPH: I want to pick up on one of the threads that you dropped related to differential responsiveness of particular alterations in patients to specific PARP inhibitors. I think this is a question that remains one of interest. Matthew, I’m curious, from your perspective, how do you view the different DNA repair defect alterations that have been included in trials like PROfound? Do you view all of these alterations as equal when you’re thinking about making treatment decisions, or are there some considerations that you have related to the gene of interest?

Matthew R. Smith, MD, PhD: Alicia, that’s a great question, and it’s critical to clinical decision-making. I think within trials and across trials, the clear conclusion is there are important differences for mutations in different genes. The clear benefit across trials in monotherapy, in particular, is in patients who are biomarker positive, and the majority of benefit is in patients with BRCA2 and BRCA1 mutations. I think the field should basically agree on that point. That’s what we see when we look within and across trials, and so that’s important in decision-making. If you give me a patient with a germline BRCA2 mutation, that’s easy because I’m going to prioritize getting that patient a PARP inhibitor, and I’ll most certainly give it prior to chemotherapy in mCRPC [metastatic castration-resistant prostate cancer]. It gets more nuanced if you have a mutation in a gene that’s less predictive of response. If you have a somatic ATM mutation, maybe I’ll give a PARP inhibitor, but I wouldn’t prioritize that before an AR [androgen receptor] pathway inhibitor or before docetaxel chemotherapy. I might act on that, but I’d be acting on it late.

Evan provided a great summary of the MAGNITUDE and PROpel trials, but the really interesting data are in the biomarker-negative group. One study reported no benefit, and the other reported positive, but it’s kind of positive. The size of the hazard ratio is, I think, 0.74 for rPFS [radiographic progression-free survival]. It corresponds to I believe a less than 6-month improvement in rPFS, so looking at it, between 1 and 2 imaging intervals. I look forward to seeing longer follow-up and seeing whether that would translate into improvements in other more important clinical outcomes like overall survival [OS]. But historically, that size of a difference in rPFS does not translate into an OS benefit. We really don’t know whether there’s going to be a role for treating biomarker-negative patients with a PARP inhibitor.

Alicia Morgans, MD, MPH: I think that’s fair. It’s a really important point to bring up. Even the point about PFS [progression-free survival] being the end point here. That does not tell us necessarily that the combination is better than the sequence of these agents. I think there’s definitely room for us to learn more, and we will learn more in follow-up. It is so interesting to think that biomarker-negative patients may be getting some benefit from a treatment that, as a single agent, they would be expected to receive no benefit from. That, I think, is at least intriguing to the field. As we think about that, Sandy, I’m curious: are there other combinations that you might be looking forward to hearing about with PARP inhibitors that perhaps promise this possible effectiveness even in settings where we wouldn’t necessarily see a PARP being effective as a single agent?

Sandy Srinivas, MD: I think there are so many trials, some of which are designed in selecting patients for biomarker selection and others that are for all-comers. I think we are just seeing the beginning. The first combination that PARP inhibitors have been studied with are these AR drugs. We have one with niraparib, and we await the other large trial, which is with talazoparib, the third PARP inhibitor, with enzalutamide. But that is just the beginning. There are a variety of trials, and I might not even cover all of the deletia, but there are PARP inhibitors in combination with AKT inhibitors with ipatasertib. There are trials in combination with antiangiogenic drugs. I think some of the interesting ones are also looking at DNA-damaging drugs, like combining PARP with agent such as temozolomide. I’ve seen a variety of trials combining PARPs with IOs [immunotherapy agents], with durvalumab, pembrolizumab, and with other IOs. I’m also looking forward to seeing some of the PARP trials with lutetium. I think those should all be interesting trials.

It’s nice that the field is so rich that now that we have PARP inhibitors approved in prostate cancer, and just finding the right partner to combine it with may increase patients who may be eligible, not just those who are biomarker-positive, is what I think is really interesting. Patients with ovarian cancer clearly have a heads-up. They use PARP inhibitors both in biomarker positive but also in all-comers. I’m really looking forward to having PARP inhibitors not just in monotherapy but also probably benefitting a larger group of patients with prostate cancer.

Transcript edited for clarity.