Robert Wenham, MD, MS, FACOG, FACS, gynecologic oncologist, chair, the Gynecologic Oncology Program, Moffitt Cancer Center, discusses the importance of clinical trials in ovarian cancer.

The benchmark for treatment in ovarian cancer keeps moving forward because of clinical trials. As such, it is important for physicians to refer patients early for clinical trials and encourage their participation, Wenham explains. It is crucial not to wait too long in the treatment process or to wait until every other option has been exhausted to refer patients, Wenham adds. This then excludes patients from the opportunity to be involved in the novel trials that are pushing the space forward, Wenham adds.

Institutions, such as Moffitt Cancer Center, are investigating options such as antibody-drug conjugates, as well as anti-PARP resistance mechanisms and CAR T-cell therapies, Wenham continues. Overall, these research options are great opportunities for patients to be involved in because they may represent the future standard of care, Wenham concludes.

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Robert Wenham, MD, MS, FACOG, FACS, discusses the importance of clinical trials in ovarian cancer.


Dr. Wenham on the Importance of Clinical Trials in Ovarian Cancer

Robert Wenham, MD, MS, FACOG, FACS, gynecologic oncologist, chair, the Gynecologic Oncology Program, Moffitt Cancer Center, discusses the role of antibody-drug conjugates (ADCs) in ovarian cancer.

The underlying thought behind ADCs is compelling, since the agents can target biomarkers expressed only on cancer cells before delivering a payload to attack the cancer and preserve health cells, Wenham says. As the technology behind ADCs has improved, they have become more realistic options for use in ovarian and other cancers, Wenham adds.

In ovarian cancer, the ADC mirvetuximab soravtansine has been evaluated for patients with folate receptor alpha–high, platinum-resistant ovarian cancer. FRα is an ideal target since it is overexpressed in many patients with ovarian cancer, Wenham explains.

Ongoing clinical trials in ovarian cancer are exploring a variety of combination therapies, including platinum-based chemotherapy combinations, Wenham continues. Combinations examining platinum with anti-VEGF and immunotherapy are being evaluated to see if they can become viable options in ovarian cancer, Wenham adds. Moreover, additional ADCs are being explored as single agents and in various combinations, Wenham explains. Although it is unknown which ADC target will be the most successful for ovarian cancer, it is hoped that several will be found through future trials, Wenham says.

Regarding PARP inhibitors in ovarian cancer, there have been an abundance of data favoring patients harboring 

 mutations, Wenham emphasizes. The phase 3 SOLO2 trial (NCT01874353) investigated olaparib (Lynparza) vs placebo as maintenance therapy for patients who had a complete or partial response to platinum-based chemotherapy, and it demonstrated an overall survival benefit with olaparib, Wenham says. Various therapies are being explored to attempt to overcome PARP resistance and make more patients respond, Wenham continues.

Considering the emergence of ADCs and PARP inhibitors, the importance of biomarker testing has been amplified for patients with ovarian cancer, Wenham explains. By identifying 

 mutations or homologous recombination repair deficiency, more targeted therapies can be selected, and more than half patients with ovarian cancer will test positive for these biomarkers, Wenham concludes.

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Robert Wenham, MD, MS, FACOG, FACS, discusses the role of antibody-drug conjugates in ovarian cancer.


Dr. Wenham on the Role of ADCs in Ovarian Cancer

Robert Wenham, MD, MS, FACOG, FACS, gynecologic oncologist, chair, Gynecologic Oncology Program, Moffitt Cancer Center, discusses the potential for immunotherapy in ovarian cancer.

Although many promising ongoing randomized phase 3 trials are examining immunotherapy as a treatment for patients with ovarian cancer, no standard approach utilizing checkpoint inhibitors exists for this patient population, Wenham says. New insights on efficacious combinations and comparators may emerge as data from these trials read out, Wenham adds.

In the recurrent space, combining checkpoint inhibitions with other drugs may resulted in improved outcomes, although determining which patients stand to derive the most benefit from these combinations will be challenging, Wenham adds. Additionally, antibody-drug conjugates, such as mirvetuximab soravtansine (IMGN853), have shown potential, according to Wenham. Overall, although immunotherapy may have a role in the ovarian cancer paradigm, deriving benefit from this approach will be more difficult than in other cancer types, Wenham concludes.

Robert Wenham, MD, MS, FACOG, FACS, discusses the potential for immunotherapy in ovarian cancer.


Dr. Wenham on the Potential for Immunotherapy in Ovarian Cancer

Robert Wenham, MD, MS, FACOG, FACS, a gynecologic oncologist and chair of the Gynecologic Oncology Program at Moffitt Cancer Center, discusses future directions with antibody-drug conjugates (ADCs) in the treatment of patients with ovarian cancer.

ADCs are a key focus for research in ovarian cancer, Wenham says. If a selective target can be identified on a cancer cell, a very toxic payload can be delivered in a way that had not been previously possible, leading to greater efficacy, which makes the use of ADCs attractive, Wenham explains. This has been examined in early studies, specifically folate receptor α (FRα), Wenham notes.

Currently, several studies are examining ADCs are ongoing, most of which are utilizing microtubule-disrupting agents, as their payload can target a host of different targets like MUC, mesothelin, tissue factor, FRα, and TIM-1, Wenham says. However, none of these targets are standard and still need to be properly examined, Wenham concludes.

Robert Wenham, MD, MS, FACOG, FACS, discusses future directions with antibody-drug conjugates in the treatment of patients with ovarian cancer.


Dr. Wenham on Future Directions with Antibody-Drug Conjugates in Ovarian Cancer

Robert Wenham, MD, MS, FACOG, FACS, a gynecologic oncologist and chair of the Gynecologic Oncology Program at Moffitt Cancer Center, discusses novel immunotherapy combinations for the treatment of patients with ovarian cancer.

The rationale behind combining immune checkpoint inhibitors with chemotherapy is to not only kill cells through cytotoxic activity that increases the amount of antigen exposure, but also chemically debulking tumors, Wenham says. With less tumor, it is possible that cell anergy will also be decreased, Wenham notes.

With PARP inhibitors, while repairing DNA, it is possible to inhibit the PARP enzyme and increase the number of DNA replication errors, which will then increase the number of antigens. Cytotoxicity would then be increased, due to increased antigen exposure, which makes the combination of PARP inhibitors and checkpoint inhibitors attractive, Wenham concludes.

Robert Wenham, MD, MS, FACOG, FACS, discusses novel immunotherapy combinations for the treatment of patients with ovarian cancer.


Dr. Wenham on Rationale for Novel Immunotherapy Combos in Ovarian Cancer

Robert M. Wenham, MD, gynecologic oncologist and chair of the Gynecologic Oncology Program at Moffitt Cancer Center, discusses data with intraperitoneal (IP) chemotherapy, dose-dense chemotherapy, and intravenous (IV) chemotherapy in patients with advanced ovarian cancer.

The decision between giving IP, IV, or dose-dense chemotherapy has been confounded by clinical trial data, explains Wenham. Three randomized trials—SWOG-8501/GOG-104, SWOG-9227/GOG-114, and GOG-172&mdash;showed about a 20% to 25% improvement in overall survival with IP chemotherapy. However, the approach wasn’t widely adopted because many women aren’t treated at centers that are equipped to deliver IP chemotherapy, says Wenham. Additionally, toxicity concerns were associated with the approach. However, while IP chemotherapy can be more cumbersome to give, it shouldn’t be more toxic than standard approaches, says Wenham.

Although the GOG-252 trial was designed to evaluate IP chemotherapy, it examined dose-dense chemotherapy versus IP chemotherapy in addition to bevacizumab (Avastin). The trial design was similar to that of GOG-262, in which bevacizumab was given in combination with dose-dense and weekly chemotherapy. In the GOG-262 trial, dose-dense chemotherapy was superior to every-3-week administration. However, in the 15% of patients who received every-3-week administration and bevacizumab, patients experienced similar outcomes as those who received dose-dense chemotherapy.

Dr. Wenham on Trials Evaluating IP, IV, and Dose-Dense Chemotherapy in Ovarian Cancer

Robert M. Wenham, MD, gynecologic oncologist and chair of the Department of Gynecologic Oncology at Moffitt Cancer Center, sheds light on the debate between neoadjuvant chemotherapy and primary debulking surgery in patients with newly diagnosed, advanced ovarian cancer. 

Surgery is recommended for patients who present with advanced disease, says Wenham. Historically, up-front primary debulking surgery was the standard of care. However, 4 randomized trials have shown that neoadjuvant chemotherapy followed by interval debulking surgery is a reasonable alternative to primary debulking surgery.

These data may be biased in that the patients who are the best candidates for neoadjuvant chemotherapy are similar to the ones who enrolled on the trials, says Wenham. Approximately one-quarter of those patients had bulky stage IV disease and poor performance status. In terms of patient selection for primary debulking surgery, data have shown that patients with less disease and a better performance status might have better outcomes, adds Wenham.

In the ongoing TRUST trial, patients were randomized to primary debulking surgery followed by chemotherapy or neoadjuvant chemotherapy followed by interval debulking surgery. Notably, bevacizumab (Avastin) was incorporated into both arms of the trial. The trial is expected to complete in 2023 and may shed light on the optimal timing of debulking surgery in ovarian cancer, concludes Wenham.

Robert M. Wenham, MD

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