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FAQs: Integrating Novel Therapies Into the Management of Gynecologic Cancers

David Scott Miller, MD, FACOG, FACS

Amy and Vernon E. Faulconer Distinguished Chair in Medical Science
Director and Dallas Foundation Chair in Gynecologic Oncology
Professor of Obstetrics & Gynecology
Fred F. Florence Bioinformation Center
University of Texas Southwestern Medical Center
Medical Director of Gynecologic Oncology
Cancer Committee
Parkland Health & Hospital System
Dallas, Texas

David Scott Miller, MD, FACOG, FACS, has disclosed that he has received consulting fees from AbbVie, AstraZeneca, Eisai, EMD Serono, GlaxoSmithKline, Incyte, iTeos Belgium SA, Myriad Genetics, Novocure, Seagen, Tarveda, and Tesaro and funds for research support from Advenchen, Agenus, Akeso Bio Australia PTY, Eisai Europe Limited, EMD Serono, Karyopharm, Merck Sharp & Dohme, Novocure, and Tesaro.

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Angeles Alvarez Secord, MD, MHSc

Division of Gynecologic Oncology
Department of OB/GYN
Duke Cancer Institute
Duke University Health System
Durham, North Carolina

Angeles Alvarez Secord, MD, MHSc, has disclosed that she has received consulting fees from Eisai and Myriad Genetics and funds for research support from AbbVie, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Eisai, Immutep, Merck, OncoQuest, PharmaMar, Roche/Genentech, Seagen, Tesaro/GlaxoSmithKline, and VBL Therapeutics.

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Released: May 23, 2022

In this commentary adapted from a discussion between Angeles Alvarez Secord, MD, MHSc, and David Scott Miller, MD, FACOG, FACS, the experts address important clinical questions about how to integrate novel therapies into treatment of patients with cervical, endometrial, and ovarian cancers.

When is the best time to use PARP inhibitors in patients with homologous recombination proficient (HRP) epithelial ovarian cancer?

David Scott Miller, MD, FACOG, FACS:
Our ability to identify markers of treatment response in ovarian cancer is still developing. Homologous recombination deficiency (HRD) may be the best marker for response to PARP inhibitors currently, but there probably are better markers yet to be defined. We know from case series that once patients have progressed on a PARP inhibitor, they are unlikely to respond to subsequent chemotherapy. So that’s why we need to talk to patients with HRP disease about the potential benefit of a PARP inhibitor, such as niraparib, for which we have the strongest evidence.

Angeles Alvarez Secord, MD, MHSc:
The PRIMA trial compared niraparib vs placebo in patients newly diagnosed with advanced ovarian cancer who had responded to first-line platinum-based chemotherapy. PRIMA recruited a patient population with a poor prognosis, and data were reported in patient subgroups who demonstrated the best response. Patients with tumors with HRD gained the best response from niraparib, but a benefit also was seen in those with HRP tumors. This is probably because HRD is not a perfect marker. Patients with tumors responsive to chemotherapy are likely to benefit from a PARP inhibitor.

The PRIME study supports the overall findings of PRIMA regarding the efficacy of niraparib in platinum-sensitive ovarian cancer. That said, PRIME was conducted in China, and I wonder how generalizable those results are to my patient population in the United States. We know there are pharmacogenomic differences and probably some differences in how patients are treated after receiving treatment with niraparib.

HRD is not a functional biomarker, and we really need to identify a functional biomarker to direct treatment. In lieu of that, HRD is the best marker we have to identify patients who are most likely to benefit from PARP inhibitors. My preference for patients with HRP disease is to put them on a clinical trial that can provide access to a novel therapy. There are some data that show little benefit from PARP inhibitors for HRP disease based on tumor biology and progressive disease; I think one of the ARIEL studies first showed that, and my clinical experience supports that.

What are your thoughts on weekly dosing of maintenance selinexor in endometrial cancer?

David Scott Miller, MD, FACOG, FACS:
The SIENDO/ENGOT-EN5/GOG-3055 phase III trial recently reported a significant increase in progression-free survival with weekly maintenance selinexor vs placebo in patients with advanced or recurrent endometrial cancer.

Patients with cancer will endure much, but one of the things we hope to improve with treatment is their quality of life, which I also refer to as “doctor-free time.” In that sense, weekly dosing is not as good as dosing every 3 weeks or every 6 weeks, but it is better than dosing every day.

Angeles Alvarez Secord, MD, MHSc:
We have seen some interesting data on the use of immuno-oncology therapy in advanced cervical cancer. KEYNOTE‑A18/GOG 3047, which is a phase III study of chemoradiotherapy with or without pembrolizumab in patients with locally advanced cervical cancer, is still recruiting participants. Another phase III trial, the CALLA study of chemoradiotherapy with durvalumab or placebo in women with locally advanced cervical cancer, recently reported that durvalumab had no significant effect on progression-free survival. That is a surprising result, in my view. We have only seen the headline results in a press release so far, so I look forward to seeing the full data analysis from that study.

David Scott Miller, MD, FACOG, FACS:
I think we have assumed that all PARP inhibitors are essentially the same and that pembrolizumab and dostarlimab may be very much the same, but CALLA reminds us that this is not necessarily the case. Many people think that radiation therapy and immuno-oncology agents ought to be synergistic, so I am looking forward to seeing data from KEYNOTE‑A18 to see if that is really true.

What do you use as second-line therapy in patients with cervical cancer who progress on chemotherapy and pembrolizumab with or without bevacizumab?

David Scott Miller, MD, FACOG, FACS: Tisotumab vedotin is our go-to therapy in second-line treatment for cervical cancer. Tisotumab vedotin is associated with ocular adverse events, and patients receiving this therapy require a visual examination prior to every dose and as clinically indicated. I work in a large county hospital, and having to involve other consultants to manage patients, particularly ophthalmologists, is a challenge given that these are not particularly complex examinations. As we learn more about these various ocular toxicities, I hope we will be able to make using these treatments a little less labor intensive. We have done that with immune-related toxicities; now, we have to step up our expertise in relation to ocular toxicities.

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