Advanced Ovarian Cancer: Optimizing Therapy Based on Current Data - Episode 5

The Evolution of Single-Agent PARP Inhibitors


Bradley J. Monk, MD, FACS, FACOG: The other thing is, in the olden days I worked on—I don’t know if you remember this—GG 178 maintenance paclitaxel. Maintenance makes so much sense to me. And as you mentioned, I’ve been involved in the maintenance bevacizumab [Avastin], and certainly now all of us are involved in maintenance PARP inhibitors. The reason maintenance paclitaxel was a bad idea, was because it didn’t work very well; it was toxic, and it was inconvenient.

Now we have medications that are less toxic, more efficacious, and it’s a pill. So, it’s no surprise in SOLO-1 [trial] that the patient reported outcomes did not show a decrement, which you could never do with paclitaxel causing neuropathy and alopecia, and so on.

Ursula A. Matulonis, MD: Exactly, that’s correct.

Michael J. Birrer, MD, PhD: You know the biggest challenge with that particular drug was the capsule forms, which has now been solved.

Ursula A. Matulonis, MD: With the tablet formulation.

Michael J. Birrer, MD, PhD: This is all in tablet, which is easy to take.

Bradley J. Monk, MD, FACS, FACOG: Let’s talk about the historical revolution. On December 19, 2014, you received olaparib [Lynparza] approved in the capsule for treatment. Three prior regimens, germline mutation treatment; 137 patients, 34% response rate. And then on August 17, 2017, almost 3 years later, it became this maintenance indication, second-line, SOLO-2, Study 19. Now we have frontline and, undoubtedly, it’ll be FDA approved probably early in 2019. So, we had treatment in second-line maintenance, frontline maintenance, what’s next?

Ursula A. Matulonis, MD: I think what’s next is really determining better biomarkers for responsiveness to single-agent PARP inhibitors.

Bradley J. Monk, MD, FACS, FACOG: Beyond BRCA you mean?

Ursula A. Matulonis, MD: Well, not just [BRCA]. Certainly, not all patients who have germline or somatic BRCA mutations are going to respond. We always think that way and we hope that, but it doesn’t always work out that way, unfortunately. So better biomarkers, and then combination strategies. And I know we’ve talked about olaparib, but obviously there’s rucaparib [Rubraca], and niraparib [Zejula], both of which also have a maintenance [indication] and are also doing trials in earlier settings as well.

Bradley J. Monk, MD, FACS, FACOG: Let’s talk about that. So niraparib is a very different medication. I used to think that these medications were more similar than different. Niraparib is more lipophilic, given at a lower dose. It’s given once daily, and has some thrombocytopenia challenges, but now we’re learning that if you’re underweight, and if you have a low baseline platelet count, we start at a reduced dose. So, there’s this study PRIMA, frontline niraparib. Tell us about that.

Michael J. Birrer, MD, PhD: Well, I think that that’s an equally interesting study compared to SOLO-1. It’s very similar to that, with the exception being that the company evolved, as you know because you’re PI [principal investigator] of that trial, and [had] the foresight to think about, are the only patients for PARP inhibitors, BRCA patients?

Bradley J. Monk, MD, FACS, FACOG: Beyond BRCA. HRD [homologous recombination deficiency].

Michael J. Birrer, MD, PhD: That’s right. And of course, NOVA [trial] demonstrated [that] not only did germline mutation patients benefit—this is in the recurrent setting—but that HRD patients benefit. And then even non-HRD wild-type BRCA. So, everyone seems to be benefiting to a certain extent. And PRIMA incorporates that, so it will be very important.

Bradley J. Monk, MD, FACS, FACOG: PRIMA is associated; a first-line trial of niraparib for all comers, but with the primary endpoint being HRD. Tell our audience what HRD is.

Michael J. Birrer, MD, PhD: HRD stands for homologous recombination deficiency. It’s the functional outcome from the loss of BRCA1 or BRCA2, meaning that the cancer cells themselves cannot repair double-strand breaks, and that’s a lethal event. So, measuring HRD is important. You can do it by sequencing individual genes as a sort of surrogate to it. But 2 companies, both Myriad and Foundation Medicine, have developed what’s known as genomic scarring assays, or HRD assays. And I think there was a lot of excitement and hope that those would functionally identify patients whose tumors would respond to PARP inhibition. And the answer is sort of yes and no. I think it does show you an enriched group of patients whose tumors are sensitive to PARP. But it also clearly misses patients. So, I personally don’t do them very often.

Bradley J. Monk, MD, FACS, FACOG: So, not yet, because there’s not an indication, but if PRIMA shows that there is, maybe you will. What’s the difference between DDR [DNA damage response], HRD, and LOH [loss of heterozygosity]?

Michael J. Birrer, MD, PhD: Well, LOH, it’s sort of a measure that is used for HRD. Most of the HRD assays look at the loss of heterozygosity, meaning the DNA loss in the tumor, and they put a cutoff on it. And if you’re LOH high, you’re HRD; if you’re LOH low, your tumor is well-behaved and you’re not losing DNA; you’re not likely to respond to a PARP Inhibitor.

Now there are twists in this in that the one assay for Myriad adds an American balance and a few other things which I don’t think is worth going into, but there are a couple of different flavors for how one defines HRD. This is why, in my view, we don’t understand it well enough.

Bradley J. Monk, MD, FACS, FACOG: So figure it out, you’re the translational scientist.

Ursula A. Matulonis, MD: And the other issue, just to build upon Mike’s point, is that the HRD assays are typically done on initial tumors—so initial biopsies at a time of surgery or initial biopsy.

Bradley J. Monk, MD, FACS, FACOG: But the concept is sort of the same—LOH high, HRD, or DDR—to try to go beyond BRCA to assess the inability to repair double stranded DNA breaks.

Ursula A. Matulonis, MD: Right. And I think that’s going to be important when you’re thinking PRIMA for another trial when you’re using a PARP inhibitor upfront. But when you’re using it out back—and I think our practices will change to use PARP inhibitors more upfront—we do have a lot of women who haven’t had BRCA testing, and are still going to get a PARP inhibitor. So that’s where the HRD assays really don’t do a good job.

Michael J. Birrer, MD, PhD: So basically, what you’re saying is that the genomic scar remains.

Ursula A. Matulonis, MD: That’s correct. The biology and the clinical pieces all do change.

Bradley J. Monk, MD, FACS, FACOG: Well as you know, all 3 PARP inhibitors, they’re FDA approved in second-line maintenance, if you respond to platinum-based chemotherapy. And the idea is that in the distinction from a biomarker, if a tumor can’t repair a platinum-induced double stranded break, they can’t repair a PARP-induced double stranded break. So it’s kind of an opportunity to have a clinical biomarker rather than a molecular biomarker.

Transcript Edited for Clarity