PR-Driven Approaches to Treating Granulosa Cell Tumors

Granulosa cell tumors (GCT) are a rare form of ovarian cancer. Two different subtypes of GCT exist: adult (AGCT) and juvenile (JGCT). AGCTs are more frequent and often produce estrogen and progesterone, which can cause symptoms such as abnormal vaginal bleeding or breast tenderness. AGCTs are usually diagnosed in perimenopausal women between ages 50 and 54, although it can occur throughout the adult woman’s lifespan. GCTs account for 2-5% of all ovarian malignancies and it is estimated that there are approximately 5,000 patients with recurrent disease in the United States and European Union.

GCT tumors exhibit morphological, biochemical, and hormonal features similar to proliferating granulosa cells of the preovulatory follicle, including estrogen and inhibin synthesis. A somatic missense mutation in the forkhead box L2 (FOXL2) gene is unique to AGCT, and absent in most other ovarian cancers. Due to the slow growth and distinguishable hormonal symptoms, AGCTs are generally diagnosed at an early stage.

Treatment of Advanced GCT of the Ovary

GCT tumors have a low mitotic ratio and generally have a more indolent course, which limits the effectiveness of chemotherapeutic and precision medicine approaches. Cytoreductive surgery (CRS) in combination followed by either observation or platinum-based chemotherapy is recommended as the first line of treatment for patients. Recurrences are characterized by disseminated peritoneal metastasis. Treatment options upon recurrence are not standardized, and may include systemic chemotherapy, secondary CRS, endocrine therapy, anti-angiogenesis therapy, or clinical trials.

Unmet Need

Even though most early stage AGCT patients experience an excellent outcome, up to 33% of patients will eventually develop a tumor relapse. Recurrence may be detected many years after the initial treatment, thus prolonged surveillance is necessary. Incomplete CRS is one of the primary determinants of recurrence.

Upon recurrence, there are limited treatment options for patients and those that do exist are lacking. There are currently no FDA-approved treatments for GCT tumors of the ovary in the recurrent setting, and few, if any, open clinical trials. This may be attributed to the rarity of the disease.

Historical Trials

During the last decade, our understanding of the molecular pathogenesis of GCTs has improved, whereas the developments of chemotherapeutic regimens and targeted therapies have remained modest. Treatment today consists largely of treatments regimens borrowed from other ovarian cancer subtypes, leading to suboptimal outcomes. Thus, the completeness of CRS remains the most important factor in the treatment of both primary and relapsed GCTs.

There is a lack of prospective trial data in GCT, making trial comparisons challenging. Combination chemotherapy, bevacizumab, and aromatase inhibitors are options in recurrent GCT that have been explored. Much of the clinical data generated to date has been from single-site retrospective analyses over long periods of time. While initially promising, retrospective data has thus far not been replicated in prospective trials. This may be due in part to the rarity of the disease, small trial sizes, or selection of patients by treating clinicians.

A retrospective review of case studies and small clinical trials by van Meurs et al (2014) of 19 trials evaluating hormonal agents in advanced GCT determined a pooled objective response rate (ORR) of 71%.¹ However, in a prospective trial by Banerjee et al (2019) evaluating anastrozole, the ORR was found to be 2.5%, significantly lower than the retrospective analysis.²

Targeting Progesterone Receptor

Almost all GCT tumors are progesterone receptor (PR) positive, while 45-65% are estrogen receptor (ER) positive. Therefore, hormonal treatments have been used empirically to treat patients with recurrent GCT who have progressed on or cannot tolerate chemotherapy. The treatment modalities have included progestins, gonadotrophin releasing hormone agonist, selective estrogen receptor modulators, and aromatase inhibition.

Progesterone Receptor Antagonism

Progesterone receptors (PR), and associated signaling pathways, play a diverse role in reproductive tissues and are increasingly gaining attention for their emerging role as critical regulators of breast, ovarian, and endometrial cancer.One such example of PR gene regulation comes from a recent publication by Park et al. (2020), wherein the authors determined that PR downregulates Ptgs2 (COX-2) expression in granulosa cells, thereby identifying a link between PR and inflammatory signaling in these cells. PR disruption may therefore result in aberrant and prolonged inflammatory signaling within granulosa cells that could over time lead to cancer.³

Puechl et al (2019) found that PR expression is correlated with both decreased recurrence-free and overall survival in patients with GCT.⁴ Recently, Roze et al (2021) evaluated the in vitro activity of ulipristal, an antiprogestin approved for emergency contraception and uterine fibroids, in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN).⁵ Ulipristal was found to be growth inhibitory across these cell lines.

Current Trials Underway

At Memorial Sloan Kettering Cancer Center, we continue to seek opportunities to further evaluate the potential for improved outcomes for patients with GCT.

To that end, we’re exploring the potential of onapristone extended release (ONA-XR) in women with recurrent GCT who have progressed following prior therapy. ONA-XR is an investigational medicine that prevents progesterone signaling by blocking the interaction between progesterone and its binding partner, progesterone receptor.

Given that GCT tumors are hormone driven, it is plausible that complete hormone blockade via antiprogestin and antiestrogen therapy may provide a therapeutic benefit to patients. Preclinical data in models of ovarian cancer suggests that treatment with ONA-XR and anastrozole in combination provides more complete hormone blockade than either therapy alone.

Our ongoing Phase 2 trial, has completed enrollment to treatment with ONA-XR monotherapy and the combination arm of the aromatase inhibitor anastrazole, in combination with ONA-XR is now open to accrual

Conclusion

There remains a pressing need for a GCT treatment in the recurrent setting that provides both a therapeutic benefit and a high quality of life for patients. Combination antihormonal therapy presents one such approach. GCT tumors are hormone-dependent and preclinical data indicates that combination antihormonal therapy may provide a therapeutic benefit to patients.

_REFERENCES:

_{1. van Meurs H, Lonkhuijzen L,, Limpens J, et al. Hormone therapy in ovarian granulosa cell tumors: a systematic review. Gynecol Oncol. 2014;134(1):196-205. doi: 10.1016/j.ygyno.2014.03.573}

_{2. Shah PD, Wethington SL, Pagan C, et al. Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer. Gynecol Oncol. 202i;4;S0090-8258(21)01322-6. doi: 10.1016/j.ygyno.2021.08.024}

_{3. Park CJ, Lin P, Zhou S, et al. Progesterone Receptor Serves the Ovary as a Trigger of Ovulation and a Terminator of Inflammation. Cell Rep. 2020;31(2):107496. doi: 10.1016/j.celrep.2020.03.060.}

_{4. Puechl AM, Edwards J, Suri A, et al. The association between progesterone receptor expression and survival in women with adult granulosa cell tumors. Gynecol Oncol. 2019;153(1):74-79. doi: 10.1016/j.ygyno.2019.01.016.}

_{5. Roze J, Garvi EJ, Stelloo E, et al. In vitro systematic drug testing reveals carboplatin, paclitaxel, and alpelisib as a potential novel combination treatment for adult granulosa cell tumors. Cancers (Basel). 2021;13(3):368. doi: 10.3390/cancers13030368.}