Exploring CDK4/6 Endocrine Therapy for Low-Grade Serous Ovarian Cancer

The phase 2 GOG 3026 (NCT03673124) study presented at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting assessing ribociclib (Kisqali) and letrozole (Femara) in patients with low-grade serous ovarian cancer showed that CDK4/6 inhibition elicited a greater response rate than the best available agent for this patient population, according to Kathleen N. Moore, MD, MS.

CancerNetwork® spoke with Moore, Virginia Kerley Cade Endowed Chair of Cancer Development, associate director of Clinical Research at the Stephenson Cancer Center, director of the Oklahoma TSET Phase I Program and professor in the Section of Gynecologic Oncology the University of Oklahoma Health Sciences Center, about key clinical trials she believed might disrupt current standard of care.

She initially stated that multiple clinical trials were evaluating CDK4/6 inhibition in patients with low-grade serous ovarian cancer. Moore further highlighted an oral presentation of the GOG 3026 at the 2023 SGO Annual Meeting by Brian Slomovitz, MD, director of gynecologic oncology at Mount Sinai Medical Center, where treatment with ribociclib in combination with letrozole elicited a response rate of 24%, the highest response rate for this patient population.

Noting the favorable tolerability of the regimen, Moore expressed that breast cancer trials helped to establish understanding of maintaining patient quality of life (QOL) and benefit which help to mitigate and manage adverse effects associated with CDK4/6 inhibition. She further suggested that the combination would likely appear in the NCCN guidelines, given its inclusion in a growing number of frontline neoadjuvant studies.

Moore questioned as to what setting CDK4/6 inhibition would derive the most benefit, noting that the questions would likely be assessed in the next generation of clinical trials evaluating this therapy in low-grade serous ovarian cancer. She further expressed that CDK4/6 inhibition was available as an off-label option but warned against inducing financial toxicity for patients.

Although trials were still comparing the efficacy of individual CDK4/6 regimens, Moore was grateful to access any of them given their off-label status. She concluded by stating that the current treatment paradigm has not identified a preferred treatment order for CDK4/6 inhibition and endocrine therapy.

Transcript:

We have seen in the recurrent setting several clinical trials [involving] CDK4/6 inhibitor and endocrine therapy. We saw Brian Slomovitz, MD, present [results from a study evaluating] ribociclib and letrozole at the 2023 SGO Annual Meeting a couple of years ago. The response rate was around 24%, but we have to remember that with chemotherapy, our response rates are less than 10%. Our most active drug is a MEK inhibitor alone with a 17% response rate, and that’s your most effective therapy in an all-comer [cohort]. [The combination elicited a response rate that was] above 20% with shrink with RECIST responses.

It is noteworthy, especially when it’s a well-tolerated regimen. There are [adverse] effects with CDK4/6 and endocrine [therapy] that we have to acknowledge do impact quality of life [QOL]. Our breast cancer colleagues have paved the way for us to understand how to use these combinations safely and maintain QOL and patient benefit. That’s something you will see on NCCN soon, and that’s already bumped up into these frontline neoadjuvant studies.

My question is, is that a better maintenance [option] with a higher risk? Is that something I use in the neoadjuvant setting? Is that something I use for someone who got debulked but has residual disease? What else will we need to add? Maybe letrozole maintenance is all you need, and patients do great if they are fully resected. Where that CBK4/6 [inhibition] best fits in the next generation of trials is an active question.

Right now, in the current setting, that is absolutely an option. It’s off-label, though. I want to emphasize that. We have to be cautious about not inducing financial toxicity for our patients. There is strong data of efficacy and whether or not there are differences between the CDK4/6 [inhibitors]; certainly, we believe that's true of breast cancer. We have seen some recent data on that in low-grade [ovarian cancer] was abemaciclib [Verzenio] better than palbociclib [Ibrance] or ribociclib? We do not have anything to say [to that end]. I am just grateful to get any of them because they are off-label.

When I get a CDK4/6 [inhibitor], we will get to a point where we can put them in efficacy order. Being the same is true of the endocrine therapies, I do not know why I have this bias that fulvestrant [Faslodex] is better. Is a selective estrogen receptor degrader [SERD] better than an aromatase inhibitor? It is better than tamoxifen [Soltamox] when we have shown that. Of the CDK4/6 [inhibitors] and endocrine [therapies], [regarding] how to order them, we are not quite there yet.

Reference

Slomovitz B, Deng W, Killion J, et al. GOG 3026 a phase II trial of letrozole + ribociclib in women with recurrent low-grade serous carcinoma of the ovary, fallopian tube or peritoneum: a GOG foundation study (001). Gynecol Oncol. 2023;176(suppl 1):S2. doi:10.1016/j.ygyno.2023.06.466