Recent Developments in Management of Gynecologic Cancers - Episode 5

Managing Platinum-Resistance and Recurrent Disease


Bradley Monk, MD, FACOG, FACS: Let’s continue our discussion today with recurrent ovarian cancer. Unfortunately, most patients diagnosed with advanced ovarian cancer recur and ultimately get many lines of therapy. I’m happy to say that although the number of ovarian cancer cases is actually decreasing, that the prevalence is increasing. So what that probably means is that patients are living longer, and I think the SEER [Surveillance, Epidemiology, and End Results Program] database has told us that. And it’s probably related to these targeted agents that we’re talking about and also just better clinical care. So, Jubilee, tell us though how the kind of the goals of therapy change from front-line to recurrent disease.

Jubilee Brown, MD: Sure. I think, Tom, you alluded to before, that it’s not just about overall survival [OS] anymore. And some of this is really about how patients tolerate therapy, in addition to getting as much as you can out of every single treatment in terms of additive PFS [progression-free survival] and in terms of quality of life. So, when we look at this, we have to look at strategies for quality of life as well as outcomes.

Bradley Monk, MD, FACOG, FACS: What I tell my patients: live longer and better.

Jubilee Brown, MD: Exactly.

Bradley Monk, MD, FACOG, FACS: It used to be we just had to help them live longer, but that’s not acceptable anymore.

Jubilee Brown, MD: Exactly. And now I think we’re seeing things, we’re seeing a lot of data where we can pick the singlet or doublet in chemotherapy, and we can add either PARP [poly ADP ribose polymerase] inhibitor or bev [bevacizumab] to that. And it’s the strategy of finding which of those therapies gives the patient the best outcome.

Bradley Monk, MD, FACOG, FACS: Right. So we used to talk about platinum-resistant and platinum-sensitive. We’ve actually tried to get away from those, and Tom, you’ve been a great teacher in messaging that. Tell me how we’re getting away from this platinum-sensitive, platinum-resistant definition, what the new terminology is.

Thomas Herzog, MD: Yeah. So the traditional paradigm has always been to look at basically a timeline. And those patients who recur between 0 and 6 months were classified as platinum-resistant, those beyond 6 months, platinum-sensitive. And we realized the patient that’s 5 months and a half is probably going to behave a little more like an intermediately platinum-sensitive patient, the 6- to 12-month group or someone at 6 months and a day is probably going to be very close to behaving like a platinum-resistant patient. So you get into these gradations.

And then we’ve really evolved, Brad. I mean, there’s been a lot of translational science and everything else, and we’re looking at molecular signatures that are unique to different histologies. And so we really moved on to now looking at a multivariate approach. And so we look at the histology, the molecular signature that’s there such as BRCA and so forth. We also look at treatment-free interval, and I think number of lines of therapy is still important. And so consensus conferences now, they’ve really, if you look at GCIG [Gynecologic Cancer Intergroup], most recent consensus conference, they defined it into patients that are appropriate for platinum and those that are not appropriate for platinum. And that can be due to an allergy, it could be too many lines of therapy.

Bradley Monk, MD, FACOG, FACS: Rare histology.

Thomas Herzog, MD: Exactly.

Bradley Monk, MD, FACOG, FACS: I love it.

Thomas Herzog, MD: Yeah.

Bradley Monk, MD, FACOG, FACS: I’m going to say that again because I wrote it down as you said it— number of lines of therapy, molecular signature, histologic type, and platinum-free interval.

Thomas Herzog, MD: Yup.

Bradley Monk, MD, FACOG, FACS: Thank you for that and I’m grateful for your passion on that. So let’s take a patient that would not be eligible for a platinum. What would be the standard single agents that would not be eligible for a platinum?

Jubilee Brown, MD: Well, so I think we certainly can look at things like liposomal doxorubicin, gemcitabine, topotecan, paclitaxel.

Bradley Monk, MD, FACOG, FACS: There you go. Weekly paclitaxel.

Jubilee Brown, MD: Exactly.

Bradley Monk, MD, FACOG, FACS: I like it.

Jubilee Brown, MD: We can potentially add bevacizumab to those agents for even better outcomes.

Bradley Monk, MD, FACOG, FACS: So that was the first FDA-approved usage of bevacizumab, adding to those agents, not gemcitabine but the other 3 in the AURELIA trial. And then, Michael, we had the GOG-0213 and OCEANS as the platinum-sensitive 2016 opportunity. Tell me about OCEANS and GOG-0213 at a high level.

Michael J. Birrer, MD, PhD: Yeah, so both were well-conducted large studies looking at the addition of bevacizumab to a platinum doublet, carboplatin and gemcitabine for OCEANS and carboplatin and Taxol for GOG-0213. And both showed a remarkable similar result, I think, with a prolongation of PFS of about somewhere around 4 to 6 months, again somewhat reminiscent to GOG-0218, actually. There is some discussion, I’m sure you’ll be invested in this, about whether there’s actually an OS difference on GOG-0213. I’m not a particular believer on that, but the bottom line is that bev is active in that patient population. And that led to the FDA approval.

Bradley Monk, MD, FACOG, FACS: Yeah, right? So, Krish, we have 3 PARP inhibitors now in platinum-sensitive maintenance. Just tell us what those agents are and what the label is for those.

Krishnansu S. Tewari, MD: So, for women that are in need of second-line platinum therapy, they’re platinum-sensitive by the original definition, not the new paradigm but more than 6 months, re-treat with platinum. And, if they respond and it could be a partial or a complete response, those patients are eligible for any 1 of the 3 approved PARP inhibitors—olaparib, niraparib, or rucaparib.

Bradley Monk, MD, FACOG, FACS: So rucaparib, ARIEL3; olaparib, Study 19, SOLO-2, and then ARIEL3, rucaparib.

Krishnansu S. Tewari, MD: Well, NOVA for niraparib.

Bradley Monk, MD, FACOG, FACS: Oh, NOVA and niraparib. Thank you. There are so many opportunities. I understand I had 3 patients.

Krishnansu S. Tewari, MD: It brings up a very interesting new paradigm because bevacizumab is also approved with chemotherapy in this recurrent population. So there’s an opportunity, depending on how things go, tolerability levels, etc, to switch maintenance therapy to a PARP inhibitor once the patient has a partial or complete response. And, in my practice, I don’t go for the complete response unless they’ve had a very long platinum-free interval. Because I may lose that opportunity to treat them with a PARP inhibitor.

Bradley Monk, MD, FACOG, FACS: So ARIEL3, rucaparib; Study 19, SOLO-2, olaparib. Niraparib, NOVA.

Krishnansu S. Tewari, MD: Right.

Bradley Monk, MD, FACOG, FACS: Study 213, GOG-0213 and OCEANS. I got 5 trials. How many patients do you think are not getting maintenance? This should be a paradigm shift. I’ve got 5 positive phase III trials that I can barely name. Do you think everyone is getting maintenance in platinum-sensitive relapsed ovarian cancer?

Michael J. Birrer, MD, PhD: We don’t really need to guess at that. I mean, there’s some substantial data from Flatiron Health databases and other sources that suggest that the amount of patients getting maintenance is somewhere around 30%. I find that astonishing.

Bradley Monk, MD, FACOG, FACS: Astonishing.

Thomas Herzog, MD: It’s a little bit higher in an abstract at ASCO [The American Society of Clinical Oncology] Annual Meeting in 2019, but it’s still well taken. It’s still under 50%.

Transcript Edited for Clarity