Beyond Chemotherapy: Evaluating the Efficacy of Ribociclib, Letrozole in LGSOC

Although high-grade serous ovarian cancer (HGSOC) remains the most common focus of gynecologic oncology, low-grade serous ovarian cancer (LGSOC) presents a distinct clinical and molecular challenge. Characterized by younger patient age at onset and a unique molecular profile—often featuring p53 wild-type status, KRAS mutations, and high estrogen receptor positivity—LGSOC typically demonstrates poor sensitivity to conventional cytotoxic chemotherapy.

Historically, treatment for LGSOC has been extrapolated from HGSOC protocols, often with disappointing results. Results from the phase 2 GOG 3026 trial (NCT03673124),¹ published in the Journal of Clinical Oncology,² show that the combination therapy of ribociclib (Kisqali) and letrozole (Femara) in patients with recurrent LGSOC of the ovary, fallopian tube, or peritoneum achieved meaningful response rates and durable disease control, meeting the study’s primary end point.

In an interview with Brian M. Slomovitz, MD, lead author of the study, he discusses a shift in the treatment paradigm that looks toward the "breast cancer model" of care. By targeting the CDK 4/6 pathway in combination with letrozole, researchers are exploring a nonchemotherapy approach aimed at improving both efficacy and quality of life for this patient population. Slomovitz is director of gynecologic oncology and cochair of the clinical research committee at Mount Sinai Medical Center in Miami Beach, Florida. He is also the clinical trial lead for uterine cancer for GOG Partners.

Targeted Oncology: What were the rationale or unmet needs that prompted this line of research?

Brian M. Slomovitz, MD: In this line of research, we're looking at a rare subtype of ovarian cancer, something called low-grade serous ovarian cancer. It affects younger women, and biologically and molecularly, it has a different makeup than what we call the typical high-grade ovarian cancers, or the high-grade serous ovarian cancers. These have, or normally have, estrogen receptor positivity. Occasionally, they have KRAS mutations, are p53 wild type, and most high-grade tumors are p53 mutated.

When we look at the best treatment options for these patients, it's much more limited than it is for the typical type of ovarian cancers. Response rates to chemotherapy are very, very, very low. Then the next best test agents for these are hormonal type agents like letrozole, and even then, the response rates aren't great.

There was an unmet need for this population of patients, and oftentimes their treatments were based on the typical ovarian cancer treatments. It just doesn't work well for these patients. When we think of these tumors, they're more like hormone receptor–positive breast cancers than they are like ovarian cancers.

We know that the CDK4/6 pathway can be exploited in these tumors. So the strategy was to use a good breast cancer regimen.

We wanted to use a CDK4/6 inhibitor plus letrozole. In addition, an unmet need for a lot of these patients is a nonchemotherapy regimen. So, this also gave an opportunity to get rid of chemotherapy, just for 2 reasons. One, the [adverse] effect profile and the toxicity associated with chemo[therapy], but No. 2, the lack of efficacy that we see chemotherapies have against these types of tumors.

What are the key findings from the study?

The primary objective of the study was to evaluate for response rate, and the response rate in the study was 31%. In addition, we looked at the duration of response, and that was 21 months. Now it's interesting, we reported these data originally in 2023, and at that time, the response rate was about 20%. So when we look at these tumors, they're a slow and indolent course. Even their responses to these types of therapies, they don't melt away like chemotherapy. The response is slow and steady, and we saw [patients] after 7 or 8 cycles get a response. The response rate went from 20% to 30% over 2 years. It's just because it took a while for some of these patients to respond. There are about 7 or 8 patients who are still on study getting their treatment based on how well the combination works.

We also saw a clinical benefit rate of 84%, median progression-free survival is 14.5 months, and overall survival is 44 months. So really, when we compare to other treatment options out there, it's the best one.

What are the implications or major takeaways that you think oncologists should know?

Our hope for this study is for it to be recognized and acknowledged by the NCCN, and hopefully it'll get an NCCN listing. These are drugs that are past their life. The likelihood of getting a randomized phase 3 study for these specific agents is low, but we do know further investigation with CDK 4-6 inhibitors in ovarian cancer would be worthwhile.

What are the next steps in this line of research?

We're continuing to evaluate nonchemotherapy regimens for the management of this disease. As far as CDK 4/6 inhibitors in particular, we'll be having to look for newer agents, next generation, in order to further investigate this, because of the limitations we have, the cycling of this drug is older.

This was a recurrent trial. I think one of the things that will be important to look at is in the first line. If, based on results in the second line, we could translate those into positive results in the first line.

Ultimately, we want to see more and more women taking this medicine because if the results play out to what we see in the real world, it'll yield an overall survival advantage and something that's pretty tolerable.

REFERENCES

1. Ribociclib and letrozole treatment in ovarian cancer. ClinicalTrials.gov. Updated December 23, 2025. Accessed January 20, 2026. https://www.clinicaltrials.gov/study/NCT03673124

2. Slomovitz B, Weroha SJ, Deng W et al. Phase II trial of ribociclib plus letrozole in women with recurrent low-grade serous carcinoma of the ovary, fallopian tube, or peritoneum: a GOG partners trial (GOG 3026). J Clin Oncol. 2026:44(3):153-163. doi:10.1200/JCO-25-01348