Combining Immunotherapy and PARP Inhibition in Advanced Uterine Cancer

MedPage Today brought together three expert leaders in the field — moderator Susana Campos, MD, from the Dana-Farber Cancer Institute in Boston, is joined by Richard Penson, MBBS, of Mass General Cancer Center at Massachusetts General Hospital in Boston, and Elizabeth K. Lee, MD, also from the Dana-Farber Cancer Institute — for a virtual roundtable discussion on gynecologic cancers.

This second of four exclusive episodes focuses on the clinical implications of the DUO-E and SIENDO trials in advanced or recurrent endometrial cancer. Results from DUO-E showed the benefit of adding durvalumab (Imfinzi) plus olaparib (Lynparza) to standard chemotherapy, while SIENDO suggested that maintenance selinexor (Xpovio) may benefit patients with wild-type p53 disease. You can watch other videos in this series here.

Following is a transcript of their remarks:

Campos: More currently at ESMO [European Society for Medical Oncology] was the DUO-E, which was a study of durvalumab plus or minus olaparib. And Dr. Lee, can you review that for us just for a second?

Lee: Yes, absolutely. So the DUO-E study was a study of looking at carboplatin-Taxol [paclitaxel] in endometrial cancer plus or minus durvalumab given concurrently and continued subsequently with maintenance therapy or given … durvalumab, followed by durvalumab plus olaparib maintenance therapy. And this was in advanced and recurrent endometrial cancer as well. I thought it was really interesting to see the subgroup analysis for both the PFS with durvalumab as well as durvalumab plus olaparib. I think as we expected for the mismatch repair-deficient [dMMR] group, they did benefit from both durvalumab as well as durvalumab plus olaparib. I don’t think that’s unexpected given the results that we’ve just mentioned for NRG-GY018 as well as RUBY.

I think what was a little bit more interesting was seeing the breakdown within the mismatch repair-proficient [pMMR] group. I think this is the group where most of our discussion and active debates with each other about the new standard of care is really arising. And so with the mismatch repair-proficient group, it seemed that the durvalumab plus olaparib combination did seem to bring about a PFS benefit. They also looked at whether PD-L1 expression was a differential prognostic factor for this combination. And it did seem to be that the PD-L1-positive endometrial cancer patients also seemed to derive more benefit from the [durvalumab] plus olaparib combination compared to chemotherapy alone.

And so I would say overall, this is bringing about many more, I would say, questions than true answers because I think it’s really important to try to drill down. And then we haven’t seen this yet in terms of other molecular subtypes and maybe benefiting more p53, histologic subtypes, et cetera. But I think certainly adding more food for thought.

Campos: And would you foresee that, for example, patients that are proficient in MMR but PD-L1 positive, are you more apt to give these individuals durvalumab and olaparib? I’ll ask you both the same question, but Dr. Lee first.

Lee: I’d certainly consider it. I think I would like to see a little bit more mature data. I would like to see more subgroup analysis as to really what is separating out those PD-L1-positive patients who are benefiting from the [durvalumab] plus olaparib, versus those on just [durvalumab]. But I would certainly consider that.

Campos: And Dr. Penson your take, I mean proficient MMR PD-L1-positive — is PD-L1 positive a new biomarker for uterine cancer. It’s not something that we normally measure.

Penson: No. So it is really fascinating. So PD-L1 being an eloquent biomarker in DUO-E is really hypothesis-generating because what we said about the subgroups. So the sort of intention to treat take-home message was that in the deficient mismatch repair, olaparib was irrelevant. That’s the sort of high level…you didn’t need that. You need immunotherapy for that group. But for the pMMR group, in the old world when drugs weren’t so expensive, this would be an instant success. Hazard ratio of 0.71, I think it was. That’s really impressive, a statistically significant delay in time to recurrence. So that’s like a positive study.

The other negative study with a PARP inhibitor, the UTOLA study was really sort of an unfair interpretation. So the positive DUO-E, UTOLA looked at very similar, but just olaparib maintenance, and it was touted as being negative statistically. But in 140 participants, it really looked like the curves were separating. And so I think that you sort of have to wait, exactly as Betsy [Elizabeth] says, for mature data. And what we don’t know from the regulatory authorities is whether they’re going to want to wait for overall survival in these groups of patients with immunotherapy agents. I hope not. I hope this is sufficient data for them to get this option approved.

Campos: Now in the DUO-E, they measure…they did not measure CPS [combined positive score], they measured TAP [tumor area positivity], which is slightly different. And TAP can be greater than equal to 1%, greater than 10%, greater than or equal to 10 to five in different studies. Does it bother you at all in terms of how they actually measured the PD-L1? Do you think? I’ll ask you both of these questions. In our organization, we measure CPS in cervical cancer. We don’t measure PD-L1 in uterine cancer. But those two different ways of measuring PD-L1 expression, does that at all bother you or challenge your interpretation of this data?

Penson: I was one of the advisors for the development of atezolizumab [Tecentriq]. We went back and forth through every assay, every option. It gets really murky. And my bias is that they’re all pretty similar. And so it’s helpful to have a couple of different assays that really strengthen your analysis of biologically what’s happening. But it’s a bit more…there’s going to be differences between assays. For example, HER2 gastric versus breast. There’s a lot of fuss about that at the moment. So unfortunately, the companion diagnostics do matter and the FDA will be pretty clear about what they’re approving.

Campos: And last but not least, in terms of the IGCS [International Gynecologic Cancer Society], the role of selinexor in patients with uterine cancer, specifically in p53 wild-type. Betsy, do you want to talk a little bit about that? Now we have an oral drug that’s maintenance therapy for a specific subtype of uterine cancer, specifically wild-type. Can you share some of that data?

Lee: Yeah, absolutely. I think it’s a very interesting new mechanism of action for this type of drug. It’s an XPO1 inhibitor, and so it’s essentially trying to retain…it’s a nuclear retention of specific proteins. And I don’t think it is too far stretched to really see why it is the p53 wild-type patients who are deriving greater benefit compared to those that are p53-mutated. Since p53 is a tumor suppressor, really if you are retaining that more of the nucleus and you are essentially allowing reactivation of that function of tumor suppressor control, then that can lead to improved progression-to-survival and significant benefit. Whereas if you’re retaining essentially nuclear expression of the mutated p53, this is non-functional p53. And so from a mechanistic level, I think that is pretty much in line.

Campos: Can you see yourself getting p53 this particular agent and p53 mutant-type, perhaps IO [immunotherapy] therapy starting to differentiate which maintenance therapy? I don’t know.

But that’s a great summation of uterine cancer in terms of, just to recap, NRG, RUBY01, the DUO-E, and some of the oral maintenance drugs for uterine cancer. So clearly more to come and the data does indeed have to mature. But that’s a really quite nice synopsis.

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