Clinical Research: Phase 1 - Phase 4

Challenges and Opportunities in Gynecologic Cancer Research: Excerpts from a Round Table Discussion

Gynecologic cancers are comprised of five major types: ovarian, uterine, cervical, vaginal, and vulvar. All women are at risk for these, and risk increases with age. Specific risk factors include a family history, human papillomavirus (HPV) infections (cervical cancer), genetic mutations such as BRCA1 and BRCA2 (ovarian cancer or OC), and hormone replacement therapy. Early screening, lifestyle choices, and knowledge of family cancer history can help play a role in the prevention of gynecologic cancers.

Globally, gynecologic cancers continue to be a major cause of morbidities and mortality. Significant unmet needs exist in the diagnosis and treatment of these cancers. Often, these tumors are detected in later stages when treatment options are limited, and advanced or recurrent disease is associated with a poor prognosis.

Of all gynecologic cancers, screening tests have only been developed for cervical cancers, which remain a health concern in developing regions globally. Along with a significant number of vaginal and vulvar cancers, cervical cancers are linked to persistent HPV infections. Primary prevention aims at reducing  infections by HPV vaccine administration. Additionally, with routine screening and management of precancerous lesions, the prognosis for cervical cancer can be quite good.

Ovarian cancer continues to have high mortality rates as it is typically diagnosed at an advanced stage.[1] Unfortunately, to date, no screening tests are commercially available to improve early detection and outcomes of people with ovarian cancer. The standard-of-care first-line treatments for OC are debulking surgery and perioperative platinum-based chemotherapy.[2] Although the response rate for first-line treatment is high, most patients eventually relapse. Similarly, the incidence of endometrial cancers has been increasing in recent years and, like other cancers, patients with progression have a poor prognosis using conventional treatment. 

Recent molecular advances in endometrial and ovarian cancer have improved our understanding of these diseases and the development of novel targeted therapies. Recent approvals of targeted therapies including anti-angiogenic drugs, poly (ADP-ribose) polymerase (PARP) inhibitors, and immunologic agents have led to meaningful improvements in patient care and outcomes and have also stimulated research, particularly in combination trials.

Gynecologic cancers – the evolving landscape

Clinical research considerations

With the advent of immunotherapies and novel mechanisms of action, the classic methodologies of study design, traditional endpoints, and interpretations have been challenged. Bayesian and other model-based designs offer flexibility and efficiency over the classic 3+3 design and are being increasingly explored. Additionally, the co-development of companion and complementary diagnostics has been an area of increasing focus requiring a robust regulatory and commercial strategy.

Impact of COVID-19

Over the past two years, the pandemic had a negative impact on trial conduct and execution due to hospitals being overwhelmed and patients being unwilling or unable to travel to sites. It has been reported that patient access to sites was reduced by 80 percent.[3]  In response, clinical trials have evolved toward decentralization. Instead of requiring patients to travel to the trial site, the trial was taken to patients, and this was true across therapeutic areas. Patient consent was obtained remotely, and trial-related assessments were conducted by video conference. Sites also adapted by allowing virtual access to electronic medical recores and thereby remote monitoring. Although many aspects of decentralized trials have been around for a while, the pandemic provided an impetus for acceleration and adaptation. Additionally, regulators have supported the transition to more virtual elements by issuing new clinical trial guidance related to alternate approaches.

Increasing need for patient diversity

As new therapies are developed, the FDA is pressing for increased subject diversity in clinical trials to improve the ability to deliver the right drug to the right patient for the greatest benefit, including those in minority communities who are often underserved. Diversity linked to biomarkers is a research area in the spotlight along with diversity in racial and ethnic minority subgroups. Sponsors should conduct a population analysis for the epidemiology of the disease under investigation to determine which racial or ethnic minorities are affected and what percentage of total patients they represent. Then, commit to enrolling the trial to account for those subgroups.

Consideration for requesting orphan drug designation

In addition to regulatory shifts and innovative approaches to executing trial elements, the past two years have seen a growing trend toward greater specialization in clinical trials. One area reflecting this trend is orphan drug designation. Ovarian, fallopian tube, and primary peritoneal cancers are all the same basic cell type and are treated the same way. However, FDA orphan designation is granted for a drug and a disease, so they are classified as three separate diseases. Sponsors must apply for orphan designation for each indication separately, even if all three cancers are represented in the same trial.

Progress in therapeutic developments

A number of significant gynecologic oncology advancements have reached the market or are promising works-in-progress. In particular, ovarian cancer patients are benefiting from new treatments, maintenance therapies, and immunotherapies:    

  • PARP inhibitors for maintenance therapy in ovarian cancer, which can delay recurrence for up to three years, depending on a patient’s genomic profile.
  • In late 2021, the FDA approved Cytalux (pafolacianine), an imaging drug that identifies difficult-to-detect ovarian cancer lesions during surgery.[4]
  • Immunotherapies: Preliminary study data for oregovomab, an anti-CA125 antibody, indicates it may elicit an immune response to ovarian cancers.[5] The immunotherapy agent Vigil has shown particular efficacy in homologous recombination repair proficient (HR-proficient) patients for whom PARP inhibitors don’t work well.[6]
  • Genomic sequencing is enabling repurpose or reuse of compounds in new ways. For example,  Herceptin® (trastuzumab), an important treatment for breast cancer, can benefit women with a rare form of uterine cancer that overexpresses the HER2 gene.
  • Drug-antibody conjugates such as mirvetuximab soravtansine (MIRV) are showing promise for treatment of platinum-resistant ovarian cancer.
  • Nanotechnology is being developed to detect cancer-associated biomarkers in early-stage ovarian cancer.[7]

Gynecologic cancers affect fewer women than lung, breast, or colon cancers but can be much more deadly. However, the recent development of effective new therapeutics and technologies has given patients and their physicians reason to hope for better outcomes. Pharmaceutical and biotech sponsors, regulators, and other industry professionals have a golden opportunity to join efforts in creating better solutions for patients suffering from these insidious diseases.

Assistance with your gynecological oncology program

As a CRO committed to improving healthcare outcomes for women, Premier Research is dedicated to advancing and accelerating clinical development of more effective treatments for gynecological cancer. Our clinical team understands how to address key operational issues and mitigate risks in these trials, helping sponsors optimize their likelihood of study success.

[1] Gynecologic Oncology. 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), 2020.

[2] Cancer Biology & Medicine. Epidemiology of ovarian cancer: a review, 2017.

[3] Medidata. COVID-19 and Clinical Trials: The Medidata Perspective, 2020.

[4] U.S. Food & Drug Administration. FDA Approves New Imaging Drug to Help Identify Ovarian Cancer Lesions, 2021.

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

[6] Journal of Clinical Oncology, 2021 ASCO Annual Meeting Abstract. Maintenance vigil immunotherapy in newly diagnosed advanced ovarian cancer: Efficacy assessment of homologous recombination proficient (HRP) patients in the phase IIb VITAL trial.

[7] Memorial Sloan Kettering Cancer Center. To Detect Ovarian Cancer Early, Researchers Look to Nanotechnology, 2021.