Markman Underscores Unanswered Questions in Ovarian Cancer Management

Although advancements were “simple” to track for more than 40 years and left few questions open for evaluation in the ovarian cancer treatment paradigm, new questions have begun to develop with many pending considerations impacting the complexity of care, according to Maurie Markman, MD.¹

Markman, president of medicine and science at City of Hope, and editor-in-chief of OncologyLive®,presented on decision-making in ovarian cancer at the 41st Annual CFS®, an event hosted by Physicians’ Education Resource, emphasizing into how care for ovarian cancer has evolved and the current questions that investigators are seeking to answer.

Prior Standards of Care in Ovarian Cancer Treatment

Markman, who is also a 2018 Giant of Cancer Care® inductee in the gynecologic cancer category, highlighted the advances seen over the last few decades in care beginning with how ovarian cancer was managed with a single alkylating agent, with or without doxorubicin, which was later replaced in the 1970s with the development of platinum agents.¹

Over the next 40 years, the field shifted to use cisplatin and cyclophosphamide with or without doxorubicin, then moved to carboplatin and cyclophosphamide. The standard of care (SOC) for treating ovarian cancer then became the combination of cisplatin and paclitaxel, which came before the current regimen most oncologists reach for: carboplatin and paclitaxel.

He noted that, in the past, it was simple for oncologists to follow which agents were to be used in the practice setting, because clinical trials had shown no benefit with higher dose regimens, extending duration of treatment, substituting for paclitaxel, or adding a third cytotoxic agent.

“There were multiple trials during this period of time that showed no benefits for other strategies including high-dose chemotherapy—doubling the dose didn’t work. We had very standard therapies for ovarian cancer as far as dose,” Markman explained. “We even had a trial [with] 5 different platinum-based regimens in the frontline setting several years ago that was reported, no different from any of the regimens, and carboplatin/paclitaxel was just as good and probably less toxic.”

He shifted to explain that the only questions regarding frontline therapy were the role of regional drug delivery and the neoadjuvant strategy.¹

The Current Landscape

Carboplatin plus paclitaxel remains a key regimen in ovarian cancer and is the primary chemotherapeutic backbone. Markman highlighted that there are several unanswered questions, many of them centered around the role of PARP inhibitors as well as bevacizumab (Avastin).

“Even though [these questions are] based on randomized phase 3 trial data, we don’t know the role of bevacizumab or the optimal patient population to be employed, and there’s debate about when you [use] bevacizumab or not. What about the role of PARP inhibitors in the frontline setting? [This is] BRCA mutation defined, but how long do we give the therapy [and] do we give it with bevacizumab? What about the role of regional therapy, the role of HIPEC?”

Neoadjuvant approaches, the best treatment approach for elderly patients, and the role of molecular signatures to help define optimal therapy are also areas that need further investigation. The role of retreatment with bevacizumab is also unknown.¹

Regarding retreatment with a PARP inhibitor, he asked: “What about a patient who has received PARP therapy and is doing well, if they continue on the PARP inhibitor indefinitely, is that safe? [We’re] certainly concerned about secondary acute leukemia, but what about retreatment? Do they respond again, and do they respond well? We don’t know.”

He also said that an appropriate definition of platinum-sensitive vs platinum-resistant for patients who received bevacizumab or PARP inhibitors is needed.

Pending Considerations

Determining the optimal treatment for patients with ovarian cancer also becomes more complex when one considers the role of immunotherapy, antibody-drug conjugates (ADCs), the standard for molecular testing, clinical pathways, and defining the optimal sequence of therapies, according to Markman.

In November 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx (Elahere)for the treatment of adult patients with FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received 1 to 3 prior systemic treatment regimens, presents another therapeutic option in the paradigm.²

“There are half a dozen other drugs in the pipeline that will also be tumor agnostic almost certainly—how do they get incorporated [into treatment]?”¹

Additionally, Markman noted that in ovarian cancer clinicians are “waiting to understand why checkpoint inhibitors aren’t active…[however,] ADCs are part of the new world in ovarian cancer.”

He stressed the importance of defining optimal drug use and sequencing, such as randomized phase 3 trials have done over the years. He referenced a phase 3 trial which demonstrated that the combination of cisplatin and paclitaxel would stay the preferred initial treatment option after single-agent cisplatin, paclitaxel monotherapy, and cisplatin plus paclitaxel all demonstrated similar overall survival (OS) results.³

Regarding recurrent platinum-sensitive ovarian cancer, he also highlighted a phase 3 trial which revealed that pegylated liposomal doxorubicin (PLD) was significantly superior to topotecan. Patients given PLD (n = 239) experienced a median OS of 108.0 weeks vs 71.1 weeks for those given topotecan (n = 235; P =.008).⁴

Finally, the first randomized study that showed increased OS with third-line therapy was a phase 3 trial demonstrating that median OS was superior with PLD or topotecan vs canfosfamide.⁵

A solution to choosing and sequencing therapies optimally, Markman said, may be conducting pragmatic clinical trials. He added that organization structure is also a relevant area to revisit when thinking about how to best optimize and enhance the delivery of health care services.¹

“Pragmatic clinical trials specifically designed and conducted to address the most relevant ‘real world’ questions unanswered through existing regulatory/academic/commercial clinical research paradigms [are key], he said. “It is critical that study populations reflect ‘real world’ patients seen in routine community-based practice.”

“Conceptually, it is not unreasonable to suggest that the study end points be somewhat less strict statistically compared with the typical regulatory focused efforts,” he concluded.

References

1. Markman, M. Current complexity of decision-making in ovarian cancer management. Presented at: 41st Annual CFS®; November 8-10, 2023; New York, NY.
2. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. FDA. November 14, 2022. Accessed November 9, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mirvetuximab-soravtansine-gynx-fra-positive-platinum-resistant
3. Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2000;18(1):106-115. doi:10.1200/JCO.2000.18.1.106
4. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19(14):3312-3322. doi:10.1200/JCO.2001.19.14.3312
5. Vergote I, Finkler N, del Campo J, et al. Phase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer. Eur J Cancer. 2009;45(13):2324-2332. doi:10.1016/j.ejca.2009.05.016