Novel Therapies Propel the Paradigms of Breast and Gynecologic Cancers Forward

Elena Ratner, MD

Advances with antibody-drug conjugates, targeted therapy, PARP inhibitors, and other novel strategies in the treatment of patients with HER2-positive breast cancer, triple-negative breast cancer (TNBC), ovarian cancer, and endometrial and cervical cancers have pushed the paradigms forward to improve outcomes compared with historical standard therapies, according to a panel of expert from the Yale Cancer Center that presented during an OncLive® Institutional Perspectives in Cancer webinar on women’s health.

Notably, the chair of the event, Elena Ratner, MD, professor of Obstetrics, Gynecology & Reproductive Sciences at Yale University School of Medicine, co-chief of the Section of Gynecologic Oncology, co-director of Discovery to Cure, director of Discovery to Cure Early Ovarian Cancer Detection program, founder and director of Sexuality, Intimacy, and Menopause cancer survivorship program at Yale Medicine, discussed the role of PARP inhibitors as maintenance therapy in ovarian cancer.

Ratner was joined by fellow faculty from the Yale Cancer Center:

• Lajos Pusztai, MD, DPhil, professor of medicine, Yale University, director, Breast Cancer Translational Research, co-director, Cancer Center Genomics, Genetics, and Epigenetics Program, Yale Cancer Center
• Maryam Lustberg, MD, MPH, associate professor of internal medicine (medical oncology), Yale University, director, Breast Center, Smilow Cancer Hospital, chief, Breast Medical Oncology, Yale Cancer Center
• Gary Altwerger, MD, assistant professor of obstetrics and gynecology, member, Wellness committee, Obstetrics, Gynecology & Reproductive Sciences, Yale Medicine

During the meeting, the panelists spoke to the latest advances in targeting HER2-positive breast cancer, the rapidly evolving landscape of TNBC, the role of maintenance therapy in ovarian cancer, and recent updates in the treatment of patients with endometrial and cervical cancers.

HER2-Positive Breast Cancer

Lustberg: The integration of targeted therapy for patients with HER2-positive breast cancer serves as a testimony to the success of precision medicine. Therapies such as tucatinib [Tukysa], fam-trastuzumab deruxtecan-nxki [Enhertu], ado-trastuzumab emtansine [T-DM1; Kadcyla], have been significant advances in this space.

Regarding sequencing, we will likely end up using all available agents at some point, so although sequencing matters, patient preference, scheduling, and toxicity need to be considered.

Ultimately, more can be achieved in the coming years to continue improving the outcomes and tolerability of HER2-directed agents for patients with early-stage and metastatic HER2-positive breast cancer.

TNBC

Pusztai: TNBC is no longer an orphan disease associated with poor prognosis and limited chemotherapeutic treatment options.

Neoadjuvant chemotherapy is now the preferred sequence for patients with TNBC, even in patients with clinically T1 disease. The extent of residual cancer can guide postoperative systemic adjuvant treatment decisions with capecitabine or olaparib [Lynparza] if the patient harbors a germline BRCA mutation. Currently, the National Comprehensive Cancer Network [NCCN] guidelines recommend BRCA testing at diagnosis in patients aged younger than 60 years. Moreover, it is likely that all patients with TNBC who are potential candidates for PARP inhibitors should undergo germline BRCA testing.

Neoadjuvant pembrolizumab [Keytruda] followed by 1 year of adjuvant pembrolizumab is the standard of care for patients with clinically T2 or lymph node–positive TNBC, irrespective of PD-L1 status. Moreover, regarding pembrolizumab, tumor size and nodal status are not predictive markers of benefit, but rather define higher-risk populations with higher absolute population-level benefit from therapy.

Ovarian Cancer

Ratner: Despite several novel approaches to manage ovarian cancer, the high rates of death from epithelial disease have remained largely unchanged for several years.

However, based on data from the SOLO-1 [NCT01844986], PRIMA [NCT02655016], and PAOLA-1 [NCT02477644] trials, the NCCN updated their guidelines to include PARP inhibitors as first-line maintenance therapy options for patients with ovarian cancer. I’m optimistic and certain that this is practice changing for these women.

Cervical and Endometrial Cancers

Clinical trials being done for patients with recurrent or metastatic cervical cancer, carcinosarcoma, or endometrial cancer have begun to evolve the paradigms of these historically difficult-to-treat diseases.

The innovaTV 204 trial [NCT03438396] evaluated tisotumab vedotin-tftv [Tivdak] in patients with previously treated metastatic or recurrent cervical cancer, the majority of whom had received prior platinum-based chemotherapy and bevacizumab [Avastin]. Additionally, most of the patients enrolled in the study were resistant to chemotherapy. Tisotumab vedotin elicited an objective response rate [ORR] of 24% compared with other available treatment options, such as pembrolizumab, gemcitabine, bevacizumab, and pemetrexed [Alimta], which are associated with ORRs of 14%, 5%, 11%, and 15%, respectively.

The ongoing ROCSAN trial [NCT03651206] is evaluating niraparib [Zejula] in combination with dostarlimab-gxly [Jemperli] or niraparib alone vs chemotherapy in patients with metastatic or recurrent endometrial or ovarian carcinosarcoma who received at least 1 prior line of chemotherapy. Historically, there wasn’t a consensus in the field of how to best treat patients with this aggressive cancer. Although the trial is far from being completed, the data help to identify targeted approaches with biomarkers for this patient population.

Finally, the KEYNOTE-775 trial [NCT03517449] evaluated the combination of lenvatinib [Lenvima] and pembrolizumab vs physician’s choice of treatment in patients with advanced endometrial cancer. The results of the study suggested that lenvatinib/pembrolizumab is an option for patients with mismatch repair–proficient recurrent endometrial cancer, providing an ORR of 30% vs 15% with standard chemotherapy. The toxicities associated with lenvatinib may be mitigated by adjusting the dose to individual patients.