New Developments in Gynecological Cancer Research

Substantial unmet needs exist in the diagnosis and treatment of gynecologic cancers. Often, these tumors are detected in later stages when treatment options are limited, and prognosis is poor. However, the gynecologic cancer space is on the cusp of change. The recent introduction of novel medicines, namely targeted therapies, has improved patient care and outcome. This progress—along with increased focus on women’s health, clinical trial diversity, and health equity—has renewed interest in developing gynecologic cancer treatments.

Brief Background on Gynecologic Cancers

Gynecologic cancers comprise five major types: ovarian, uterine and endometrial, cervical, vaginal, and vulvar. All biological females are at risk for gynecologic cancers, and this risk increases with age. Other risk factors include:

  • Family history
  • History of human papillomavirus (HPV) infection, for cervical cancer
  • Genetic mutations such as BRCA1 and BRCA2, for ovarian cancer
  • Hormone replacement therapy

Awareness, education, and screening, if available, play important roles in prevention, but gynecologic cancers continue to be a major cause of morbidity and mortality worldwide.

Emergence and Growth of Targeted Therapeutics and Immunotherapies

Ovarian cancer is associated with high mortality rates as it often goes undiagnosed until it has reached an advanced stage.1 According to American Cancer Society estimates, there were more than 21,000 new diagnoses of ovarian cancer and more than 13,000 deaths from this disease in 2021.2 Currently, no screening tests for early detection of ovarian cancer are commercially available. First-line treatments include debulking surgery and perioperative platinum-based chemotherapy, followed by adjunctive radiation.3 Response rate for first-line treatment is high, but most patients eventually relapse.

Recent molecular and technological advances have enhanced our understanding of ovarian cancer and accelerated the development of novel targeted therapies. Recent approvals include anti-angiogenic drugs, poly (ADP-ribose) polymerase (PARP) inhibitors, and immunotherapeutic agents, leading to meaningful outcomes and stimulating new research, particularly combination therapy trials.

Progress in Ovarian Cancer

In recent years, research and development activity in ovarian cancer has been robust, with approved maintenance therapies, promising treatments in development, and new tumor detection methods.

Approved Maintenance Therapy

Due to the high risk of recurrence, maintenance therapy is often necessary in gynecologic cancers. Substantial progress has been made in developing maintenance therapies for ovarian cancers, driven in part by identifying relevant biomarkers such as BRCA1, BRCA2, and related gene mutations. To date, the FDA has approved three PARP inhibitors—olaparib, niraparib, and rucaparib—for ovarian epithelial cancer. In registration trials, 90% of patients were able to stay on PARP inhibitor therapy for the study duration. About 25% of patients with ovarian cancer have either a loss of heterozygosity or homologous recombination deficiency (HRD), and these phenotypes predict a high likelihood of response to PARP inhibitors. In contrast, homologous recombination proficient (HRP) patients typically demonstrate minimal response to maintenance therapies.

The agency has also approved bevacizumab, a vascular endothelial growth factor (VEGF)-A inhibitor, either alone or in combination with a PARP inhibitor, for maintenance therapy in ovarian epithelial cancer. Following initial treatment with bevacizumab plus chemotherapy, patients with advanced ovarian cancer can continue with bevacizumab maintenance therapy and experience up to 18 months of progression-free survival.4

Treatments in Development

Antibody-drug conjugates such as mirvetuximab soravtansine are showing promise for treatment of platinum-resistant ovarian cancer. Progress is also being made with different immunotherapy approaches. Preliminary study data for oregovomab, an anti-CA125 antibody, indicate it may elicit an immune response to ovarian cancers.5 In addition, gemogenovatucel-T (Vigil), an autologous tumor cell vaccine transfected with a DNA plasmid for transforming growth factor (TGF)-β, has been studied in patients with advanced high-grade ovarian cancer.6 In a Phase 2b trial, Vigil showed significant clinical benefit with improvements in relapse free (RFS) and overall survival (OS) when used as frontline maintenance in patients with newly diagnosed stage III/IV ovarian cancer and BRCA wild type or HRP molecular profiles.5,7

Genomic sequencing is now enabling the repurpose or reuse of known or approved compounds in new indications, which can help accelerate development. For example, trastuzumab (Herceptin), a monoclonal antibody approved for HER2+ breast and gastrointestinal cancers, may benefit women with a rare form of uterine cancer that overexpresses the HER2 gene. Multicenter randomized Phase 2 trials have evaluated trastuzumab as single agent maintenance or in combination with chemotherapy.8,9

Tumor Detection Methods

On November 29, 2021, the FDA approved pafolacianine (Cytalux), an optical imaging agent, as an adjunct for intraoperative identification of malignant lesions, improving the ability of surgeons to locate difficult-to-detect cancerous tissue. Pafolacianine is a fluorescent drug that targets folate receptors, which may be overexpressed in ovarian cancer.2

When ovarian cancer is diagnosed at stage I, the five-year survival rate is 92%.10 Given that the overall five-year survival rate is just 46%, there is a need for tools or technologies that facilitate accessibility and early diagnosis. Currently, researchers at Sloan Kettering Institute are exploring the use of nanotechnology for early cancer detection. These scientists are developing several different nanosensors for detecting ovarian cancer-associated biomarkers in people at higher-than-average risk, such as those with inherited BRCA mutations or family history of the disease.9

Considerations for Clinical Research in Gynecologic Cancers

Sponsors involved in or considering research for treatments of gynecologic cancers, should keep in mind four important factors:

1. Need for Novel Study Designs

Traditional study designs used for cytotoxic chemotherapies may not be suitable for immunotherapies, which have fundamentally distinct mechanisms of action and dose response curves. Rather than using the classic 3+3 design for dosing, therapeutic developers may want to consider Bayesian and other model-based designs that offer greater flexibility.

Another factor to consider is the shift toward decentralized clinical trials (DCTs) that bring the study to the patient, rather than the other way around. Pandemic-related site closures and travel restrictions required sponsors, sites, and study participants to adapt to performing many protocol activities remotely, from consent and assessments to data collection and monitoring. To keep pace with this accelerated transition to DCTs, the FDA has issued a new clinical trial guidance on alternate approaches to study execution.

Targeted drugs and immunotherapies may also require co-development of companion and complementary diagnostics that confirm the tumor’s molecular profile and identify those patients most likely to benefit from treatment. For sponsors, developing a diagnostic in parallel with a drug may help support both regulatory approval and commercial success.

2. Regulatory Emphasis on Diversity

The FDA has been pressing for increased subject diversity in clinical trials to improve delivery of the right drug to the right patient, including historically underserved racial and ethnic minorities. In addition, sponsors should consider population analyzes to better understand the epidemiology of the disease under investigation and the percentage of racial and ethnic minorities affected. In doing so, sponsors can ensure that they properly enroll reflects diversity.

3. Focus on Quality of Life

Increasingly, therapeutic selection is focusing on quality-of-life assessments. Clinical benefit must be balanced with maintenance of quality of life. One challenge, however, is that while there are methodologies for assessing quality of life in gynecologic cancers, there are currently no validated models that can be utilized as primary endpoints for approval or even included in the labeling for an approved product.

4. Eligibility for Orphan Designation or Accelerated Pathways

The past few years have demonstrated a growing trend toward greater specialization in clinical trials. One area reflecting this trend is orphan drug designation, especially as molecular profiling has shed light on disease subtypes that can now be characterized as rare diseases. For instance, ovarian, fallopian tube, and primary peritoneal cancers all arise from the same basic cell type and are treated the same ways.

However, orphan drug designations are granted for specific drugs, so these three cancers are classified as separate diseases. Sponsors can apply for orphan drug designation for each indication separately, even if all three cancers are represented in the same basket trial. Of note, pafolacianine was granted orphan drug, priority, and fast track designations during its pathway to approval.2

Key Takeaway

Gynecologic cancer researchers are advancing new therapeutics that improve clinical outcomes and quality of life for patients. As a result, significant progress has been made in ovarian cancer, creating better solutions for diagnosing and treating patients suffering from this insidious disease.


1. Dilley J, et al. “Ovarian cancer symptoms, routes to diagnosis and survival – Population cohort study in the ‘no screen’ arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).” Gynecol Oncol. 2020;158(2);316-322.

2. US Food and Drug Administration. “FDA Approves New Imaging Drug to Help Identify Ovarian Cancer Lesions,” November 29, 2021. Available at -identify-ovarian-cancer-lesions.

3. Reid BM, et al. “Epidemiology of ovarian cancer: a review.” Cancer Biol Med. 2017. PMID: 28443200.

4. US Food and Drug Administration. “FDA approves bevacizumab in combination with chemotherapy for ovarian cancer,” June 13, 2018. Available at ovarian-cancer.

5. “A Controlled Study of the Effectiveness of Oregovomab (Antibody) Plus Chemotherapy in Advanced Ovarian Cancer,” 2020.

6. Rocconi RP, et al. “Maintenance vigil immunotherapy in newly diagnosed advanced ovarian cancer: Efficacy assessment of homologous recombination proficient (HRP) patients in the phase IIb VITAL trial.” J Clin Oncol. 2021;39(15_suppl):5502.

7. Rocconi RP, et al. “Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer.” Gynecol Oncol. 2021;161(3):676-680.

8. Tymon-Rosario J, et al. “Trastuzumab tolerability in the treatment of advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress HER2/neu.” Gynecol Oncol. 2021;163(1):93-99.

9. Fader AN, et al. “Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis. Clin Cancer Res. 2020;26(15):3928-3935.

10. Memorial Sloan Kettering Cancer Center. “To Detect Ovarian Cancer Early, Researchers Look to Nanotechnology,” September 21, 2021. Available at

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