Advanced ovarian and endometrial carcinomas present the greatest challenge in treating gynecologic cancer and, among the five types of female cancers, are responsible for the most U.S. deaths annually.1 With a combination of surgery, chemotherapy, and radiation; patients can go into remission, but the majority will have a recurrence after several months or years. There is a critical unmet need for better maintenance therapies to improve the quality of life and, ideally, achieve improvement in progression-free and overall survival for these women. Research has identified several useful specific agents, and biomarkers can help guide the selection of patients for maintenance therapy treatment.
Meaningful progress utilizing biomarkers
Between 2014 and 2020, considerable progress was made in the development of new maintenance therapies. A number of biomarkers were identified that are very valuable for women with ovarian cancer, including BRCA1, BRCA2, and related gene mutations – and these patients respond best to maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors. About 25 percent of patients have a phenotype that is either loss of heterozygosity or homologous recombination deficiency (HRD), and this also predicts a high likelihood of response. Those who are homologous recombination repair proficient (HR-proficient), who lack the biomarkers, typically have a minimal response to maintenance medications.
The development of PARP inhibitors for maintenance therapy has been a game-changer. In the trials that led to FDA approval, 90 percent of patients were able to stay on therapy for the duration. Patients reported a range of experiences – some had no side effects, while others had considerable nausea, fatigue, or blood count issues that required frequent clinic visits for blood draws. But overall, the impact of PARP therapy has been very positive. The FDA approved the PARP inhibitors without the need for biomarkers, since there is also a small benefit for the HR-proficient patient group.
The FDA considers three months of improvement in progression-free survival (PFS) the minimum bar for approving new therapeutics. For a patient with HRD, a PARP inhibitor can delay cancer recurrence for nine to 12 months. For a patient with a BRCA1 or BRCA2 mutation, PARP can delay a recurrence by one to three years on average. Many patients believe it is worth tolerating some side effects and decreased quality of life for this major clinical therapeutic benefit. However, oncologists must weigh how much benefit each patient may experience based on their biomarker status against how well they will tolerate the medication.
Other maintenance drugs
Bevacizumab, a VEGF inhibitor, is a first-generation intravenous antiangiogenic therapy. Following initial treatment with bevacizumab combined with chemotherapy for advanced ovarian cancer, patients are under expectant management (a watch-and-wait paradigm) and may enjoy perfect, or near-perfect, quality of life. They can continue with bevacizumab alone in a maintenance setting and potentially experience PFS of up to 18 months.2 Oral antiangiogenic agents are also being developed. If new interventions show a meaningful benefit with reasonable toxicity in clinical trials, they may supplant earlier therapies. But there is no biomarker for the antiangiogenics, so it’s currently a one-size-fits-all approach.
Other VEGF inhibitors are undergoing trials, e.g. different combinations of drugs across therapeutic areas, and sponsors are evaluating other compounds that could potentially be even more effective.
How long should patients continue on therapies?
In one study that led to the approval of the PARP inhibitor olaparib, patients took the drug for two years then stopped. A recent re-analysis of that data has shown that the survival benefit continues at five years, which is especially important for women with recurrent platinum-sensitive ovarian cancer. If patients had stayed on the drug for longer than two years, their outcomes might be even better. Many don’t want to stop taking a PARP inhibitor if they’re tolerating it well.
A paradigm shift may be happening: instead of taking an oncology maintenance drug for a discreet period of time and stopping, the clinical view may be evolving more toward the need to take insulin for diabetes – insulin provides a benefit, but you must take it indefinitely to control your disease. That transition is slowly happening based on real-world experience.
Commercializing innovative maintenance treatments
As sponsors develop new maintenance therapies, they must validate clinical effectiveness and continue to assess which subsets of patients will benefit the most, given the costs.
The uptake of FDA-approved gynecologic cancer maintenance drugs has been dramatic due to the overwhelmingly positive results from PARP inhibitor trials. Regarding reimbursement, insurers have been amenable to paying for drugs costing $10,000-$15,000 per month because they can be used for multiple indications including maintenance after first-line or subsequent lines of chemotherapy or as stand-alone treatment.
Also, patient assistance programs created by sponsors can help pay for expensive maintenance medicines. If private insurance or Medicare pays the majority of the cost, the patient assistance program covers the rest if the patient meets the financial qualifications. To some extent, the industry recognizes the financial burden of these therapies and has taken steps to ensure that patients who could benefit aren’t prevented access due to cost.
The world of gynecologic cancer treatment is complex right now because of the shift toward targeted therapies, which began with biomarkers and the development of checkpoint inhibitors. It’s an enormous change from the “more is better” approach in the old model for cancer trials based on FDA expectations.
We’ve learned that more isn’t necessarily better, and that this new path holds great promise for women with cancer.
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] National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts, 2021.
[2] U. S. Food and Drug Administration. FDA approves bevacizumab in combination with chemotherapy for ovarian cancer, 2018.
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