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Molecular Features in Gynecologic Cancers and the Optimal Use of PARP Inhibitors

David Scott Miller, MD, FACOG, FACS
Program Director

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: researcher: EMD Serono; consultant: AbbVie, Agenus, Alexion Pharmaceuticals, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical Research Institute, Clovis Oncology, Eisai, Eisai Europe, EMD Serono, Genentech, GlaxoSmithKline, Guardant Health, Immunogen, Incyte, iTeso Belgium, Janssen Oncology, Karyopharm Therapeutics, Merck Sharp & Dohme, Myriad Genetic Laboratories, Novocure, Seagen, Tarveda Therapeutics, Tesaro; researcher (funds paid to his institution): Advaxis, Advenchen, Aeterna Zentaris, Agenus, Akesobio, Aprea AB, AstraZeneca, Immunogen, Incyte, Janssen, Karyopharm Therapeutics, Leap Therapeutics, Mateon Therapeutics, Merck Sharp & Dohme, Millennium Pharmaceuticals, Novartis, NVision, Regeneron, Syros Pharmaceuticals, Tesaro, TRACON Pharma, US Biotest, Xenetic Biosciences.

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Nicoletta Colombo, MD

Professor of Obstetrics and Gynecology
University of Milan-Bicocca
European Institute of Oncology
Milan, Italy

Nicoletta Colombo, MD: consultant: AstraZeneca, Clovis, Eisai, GlaxoSmithKline, ImmunoGen, Mersana, MSD, Pfizer, Roche.

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Shannon N. Westin, MD, MPH

Associate Professor
Division of Surgery
Department of Gynecologic Oncology and Reproductive Medicine
University of Texas MD Anderson Cancer Center
Houston, Texas

Shannon N. Westin, MD, MPH: researcher: AstraZeneca, Bayer, Clovis Oncology, Cotinga, GlaxoSmithKline, Mereo, Novartis, OncXerna, Roche/Genentech, Zentalis; consultant: Agenus, AstraZeneca, Caris, Clovis Oncology, Eisai, EQRX, GlaxoSmithKline, ImmunoGen, Karyopharm, Lilly, Merck, Mereo, Mersana, Roche/Genentech, Vincerx, Zentalis.

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Released: July 14, 2022

In this commentary, David Scott Miller, MD, FACOG, FACS; Nicoletta Colombo, MD; and Shannon N. Westin, MD, MPH, answer questions about the molecular characteristics of various gynecologic malignancies and the optimal application of PARP inhibitors. The questions were submitted by an audience of healthcare professionals during a recent live Clinical Care Options satellite symposium held during the 2022 American Society of Clinical Oncology Annual Meeting.

What percentage of patients with endometrial cancer harbor p53 wild‑type disease?

David Scott Miller, MD, FACOG, FACS:
It varies based on the histologic subtype. In the SIENDO trial evaluating patients with advanced or recurrent endometrial cancer, approximately 73% of patients had p53 wild-type disease. Wild-type tumors are more sensitive to platinum and/or taxane-based chemotherapy, making complete responses more likely in this disease subset.

Nicoletta Colombo, MD:
The rate of PD-L1 positivity among patients with persistent, recurrent, or metastatic cervical cancer and no previous systemic chemotherapy in the phase III KEYNOTE-826 trial was approximately 89%. PD-L1 positivity was similar to that of patients with advanced cervical cancer who progressed on or were intolerant to standard therapy enrolled on the phase II KEYNOTE-158 basket trial at 84%. It is important to remember that testing for PD-L1 expression is not perfect because several factors can potentially influence the results, including the choice of antibody, the platform being used, and the “freshness” of the tissue.

Shannon N. Westin, MD, MPH:
I would add that the rate of PD-L1 expression in cervical cancer also is skewed based on tumor histology, with PD-L1 positivity much more common in squamous tumors than in adenocarcinomas.

Does the progression-free survival benefit (PFS) seen with olaparib in patients with BRCA wild-type ovarian cancer in the OReO trial correlate with prior responses to therapy?

Nicoletta Colombo, MD:
OReO was a placebo-controlled phase IIIb trial evaluating olaparib vs placebo in 220 patients with relapsed, nonmucinous epithelial ovarian cancer. Is important to note that the patients in the study were highly selected and are not representative of patients with relapsed ovarian cancer. In patients with BRCA wild-type disease, PARP inhibitor exposure was required to be at least 12 months after first chemotherapy or at least 6 months after the second or later line of chemotherapy. This means that those patients were responding to the PARP inhibitor. In addition, there was a requirement for a complete or partial response to the most recent platinum-based chemotherapy or no evidence of disease following surgery.

Among patients with BRCA wild-type disease, the median PFS was 5.3 months with olaparib and 2.8 months with placebo (HR: 0.43). The PFS benefit was significant regardless of the duration of prior PARP inhibitor exposure, complete vs partial response with the most recent chemotherapy, number of previous chemotherapy regimens, and previous use of bevacizumab.

However, due to the requirements for patients to be platinum sensitive at relapse and previously responsive to therapy with a PARP inhibitor, OReO could not answer our questions about rechallenging with PARP inhibitors in other patient populations. It is likely that outcomes in this trial were better than what we would see in other groups of patients because platinum sensitivity alone is a strong predictive factor for response to PARP inhibitors.

When would you choose PARP inhibitor monotherapy over combination therapy with bevacizumab for fully-resected ovarian cancer?

Nicoletta Colombo, MD:
This is a very good question. The SOLO-1 and PAOLA-1 trial data inform my perspective. In SOLO-1, which evaluated olaparib alone vs placebo, the median PFS was 56.0 months vs 13.8 months with placebo in patients with BRCA-mutated disease (HR: 0.33). These data are so good that you can consider using olaparib alone, but I prefer to use bevacizumab in combination with olaparib in all patients unless contraindicated, and that is based on data from the PAOLA-1 trial, which evaluated olaparib in combination with bevacizumab vs placebo plus bevacizumab. In this study, the median PFS was 37.2 months with the combination and 21.7 months with bevacizumab alone (HR: 0.31).

An indirect comparison between the SOLO-1 and PAOLA-1 trials suggest a benefit in the 12- and 24-month rates of PFS with the addition of bevacizumab to olaparib vs olaparib alone, with a 12-month rate of PFS of 96% vs 88% and 24-month rate of 82% vs 73% (HR: 0.71). Because the first‑line setting is the only setting where we can hope to cure patients, I prefer to use the best regimen up front rather than wait until later lines, when cure is not possible.

How do you select which PARP inhibitor to use?

Shannon N. Westin, MD, MPH:
The efficacy data are consistent between the PARP inhibitors, so I start by considering the FDA-approved indications, to which my institution closely adheres. Then I think it comes down to what you are most comfortable using based on the toxicities patients have already experienced from other drugs and their preexisting conditions. Hypertension, for example, would contraindicate niraparib, as it can worsen hypertension. Niraparib might be ideal for other patients, however, because it has few drug–drug interactions. So, if a patient is taking many prescription drugs for comorbidities, niraparib may be safest.

Nicoletta Colombo, MD:
I agree. The efficacy is very similar, but there are differences in toxicity. Niraparib is convenient because it is once daily and the others are twice daily. You have to judge what is best for your patients and feel confident that you can manage the adverse events.

David Scott Miller, MD, FACOG, FACS:
I mainly choose a PARP inhibitor based on the adverse events I anticipate the patient experiencing because there is no evidence that one PARP inhibitor is more effective than the others.

Your Thoughts?

What are your thoughts and questions about the management of gynecologic malignancies based on molecular characteristics and with PARP inhibitors? Please answer the polling question and join the conversation by posting a comment in the discussion section below.

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