Survival Benefits of PARP Inhibitors in Metastatic CRPC Favor BRCA1/2 Over ATM Mutations

Catherine Handy Marshall, MD, MPH, Assistant Professor, Johns Hopkins Hospital, talks about the different responses to PARP inhibitor therapy seen in patients with metastatic CRPC and BRCA1/2 versus ATM mutations.

Transcript

My name is Cathy Marshall. I'm an Assistant Professor at Johns Hopkins Hospital.

PARP inhibitors are increasingly being used in clinical trials, but then also off of clinical trials, and they're not FDA approved yet in prostate cancer.

There were 2 recent announcements—one that 1 PARP inhibitor was granted breakthrough designation status by the FDA looking at patients with BRCA1/2 and ATM mutations, and then a different PARP inhibitor, which just focused on BRCA1/2 mutations.

Now, the ATM protein and the BRCA1 and 2 proteins do act differently, which led us to hypothesize that patients may not be deriving the same benefit, meaning patients with BRCA1/2 mutations may not have the same benefit as patients with ATM mutations, and vice versa.

That was really what prompted us to look at our own experience and collaboration with the group at Mayo Clinic in Arizona to see if there were any differences between the way that those 2 populations were responding to off-label treatment.

So in our study we had 40 men who had been given olaparib off-label for metastatic castration-resistant prostate cancer. Only 17 of those patients had pathogenic mutations in either BRCA1/2 or ATM, so those were the patients that we focused on.

Most of those patients had germline mutations; 11 of 17 patients had germline mutations, 6 had somatic alterations only. They had a range of Gleason scores; 5 of them had Gleasons sums that were <7, 24% (or 4 patients) had Gleason sums of 8. Then the rest, or 8 patients, had Gleason sums of 9 or 10.

The mean age of start of therapy for olaparib was 65 years, which is not unexpected. Most patients had received prior chemotherapy, and most of them had received prior novel hormonal therapy.

What we found was that we were looking primarily at progression-free survival (PFS), and then also PSA responses. We did see PSA responses in 10 of the 12 men who had BRCA1/2 mutations, but we did not see any PSA responses in those with ATM mutations.

Then thinking about how long these responses lasted, or if people were gaining benefit, comparing the 2 groups, those with BRCA1/2 mutations did have a much longer PFS of 12 months, compared to 3 months for those with ATM mutation.

We were looking at this to see if there was a difference, and based on PSA responses and PFS, there really was a difference. Where patients who were treated with olaparib and had BRCA1/2 mutations did seem to derive clinical benefit. Those patients who had ATM mutations did not appear to have the same benefit as those with the BRCA1/2 mutations.

Our study was a retrospective study. Meaning that we were looking back after people had been treated. Really the next step is to look in a prospective fashion, so to look ahead of time and see, like, from the beginning design a trial where we can really compare these 2 groups of populations, or in the trials that are already ongoing, see if we can power them such that we can be able to detect real differences.

Because the question then becomes, “Should patients with ATM mutations be treated with PARP inhibitors or do we need to be thinking about novel therapies or other therapies that would be targeted specifically to those patients?”

Right now, these drugs are all off-label, so all of this should be done within the context of a clinical trial, but I think it's important when we're designing our trials to think about which patients we're targeting for those trials, and, you know, potential differences between those patient populations.

We did look with additional patients from another institution as well that we collaborated with for the complete paper, which will be coming up. And then also in thinking about designs of clinical trials, we are not leading any of those clinical trials, but I know that there is some interest in pulling out ATM patients for trials with different therapies.