Hormonal Maintenance Therapy Offers Deescalated Option for Low-Grade Serous Ovarian Cancers

Patients with low-grade serous ovarian carcinoma historically have demonstrated a benefit with hormonal maintenance therapy following cytoreductive surgery and platinum-based chemotherapy.^1,2 Additionally, studies have demonstrated that patients with this rare histologic subtype have relatively poor response to treatment with chemotherapy, leading investigators to question whether patients may be overtreated in the adjuvant setting.² However, a lack of data supporting either approach has left both as viable options for treatment of patients with stage II to IV disease.³ Those who experience disease recurrence have a poor prognosis, therefore investigators have aimed to identify the optimal adjuvant treatment to mitigate detrimental survival outcomes.

Histological Barriers to Treatment

Despite serous classification being the most common histologic subtype of epithelial ovarian cancer, low-grade disease is relatively rare and presents with different clinical presentation, pathogenesis, and diagnostic hurdles than its high-grade counterpart.² “Low-grade serous carcinoma of the ovary or perineum is considered a rare epithelial ovarian cancer. It constitutes only approximately 2% to 3% of all epithelial ovarian malignancies, and approximately 5% of all serous cancers, which is the most common epithelial ovarian cancer subtype,” Amanda Nickles Fader, MD, said in an interview with OncologyLive^®. Fader is the vice chair of gynecologic surgical operations and director of the Center for Rare Gynecologic Cancers at Johns Hopkins Medicine and an associate professor of gynecology and obstetrics in the Department of Gynecology and Obstetrics and the Sidney Kimmel Cancer Center in Baltimore, Maryland.

“What we know about low-grade serous carcinoma is that it’s very different in many respects to its more common counterpart, highgrade serous ovarian carcinoma,” Fader said. “The molecular expression in the tumors is different, the epidemiology is different, and low-grade serous tumors often develop in younger women compared with high-grade serous [tumors] where most women are post menopausal. The disease course and the prognosis can be a little bit different as well.” Fader noted that women with low-grade serous ovarian carcinoma have longer survival but tumors are often diagnosed in advanced stages and those who have disease recurrence have poor prognosis.^2,3 “One of the reasons for that is that low-grade serous tumors are indolent in their growth patterns and don’t respond as well to chemotherapy. Therefore, we have to be a little bit more creative in identifying best treatment strategies,” Fader said.

Hormonal Therapy Shows Early Promise

Low-grade serous tumors are like many breast cancers in that they are rich in estrogen and progesterone receptor expression, according to Fader. “[The tumors] have high endocrine receptor expression and we [want] to leverage that by looking at endocrine or hormonal therapies that we can use to inhibit those receptors, such as with the aromatase inhibitor letrozole,” Fader said. “Two studies were performed looking at use of letrozole in the treatment of women with upfront adverse or primary advanced stage, low-grade serous ovarian carcinoma or carcinoma of the peritoneum,” Fader noted, citing institutional analyses of hormonal maintenance therapy for this population.

The first was a single-center study conducted at The University of Texas MD Anderson Cancer Center in Houston that compared outcomes of women who received hormonal maintenance therapy or underwent routine observation.¹ Following primary cytoreductive surgery and platinum-based therapy, 133 patients were placed in observation and 70 received hormonal therapy, (54.3% received letrozole). The median duration of hormonal therapy was 33.3 months (range, 1.0-223.2).¹

The median follow-up was 70.8 months for the entire cohort, 80.3 months for those under observation, and 54.9 months for those in the intervention group. The median progression-free survival (PFS) was 26.4 months (95% CI, 21.8-31.0) in the observational group compared with 64.9 months (95% CI, 43.5-86.3) in the hormonal therapy group (P < .001).¹

“The landmark study from Gershenson et al… showed that when you added letrozole maintenance therapy after a woman had undergone surgery and received standard carboplatin and paclitaxel therapy for 6 cycles, compared with women who only got the [chemotherapy], the women who received [hormone therapy] had a significantly improved PFS. So that was exciting to see,” Fader said.

The median age was 47 years with all patients having received a median of 6 cycles of chemotherapy. The primary site of the tumor was in the ovary for 68.9% of patients who received hormonal therapy and in 78.2% of patients who underwent observation. Nearly all patients (95.7% and 96.2%, respectively) were estrogen receptor (ER) positive, and most patients (66.7% and 54.9%, respectively) were progesterone receptor (PR) positive. At baseline, most patients in the observation arm (91.7%) had no evidence of disease after chemotherapy compared with 40% of patients in the experimental arm.¹

A subgroup analysis showed that for those who were clinically disease free after chemotherapy, the median PFS for those who underwent observation was 30.0 months (95% CI, 24.9-35.1) vs 81.1 months (95% CI, 54.9-107.2) for those who had received hormonal therapy. An improvement was also consistent in those with persistent disease at 15.2 months (95% CI, 7.6-22.9) and 38.1 months (95% CI, 17.8-58.4), respectively. Of note, no significant improvement was observed in overall survival (106.8 vs 102.7 months, respectively).¹

The second retrospective study, conducted at Johns Hopkins University and Cleveland Clinic in Ohio, omitted chemotherapy altogether in this population.⁴ All 27 patients, who had stage II to IV low-grade serous carcinoma and had undergone underwent primary cytoreductive therapy, received maintenance hormonal therapy. One patient proceeded to chemotherapy following treatment with hormonal therapy.⁴

“We looked at similar women and there was a smaller study of 27 patients. But we looked at women [mostly] with stage III and IV low-grade serous ovarian carcinoma who had undergone upfront surgical debulking and then went on letrozole therapy alone with no chemotherapy and we found that they did very well,” said Fader, who was the lead study author on the trial.

Most patients had stage IIIC (n = 18) or stage IIIA (n = 6) disease with a median age of 47.5 years. Among all patients, 85.2% had no residual disease following surgery, 96% of patients were ER positive, and 32% were PR positive. At 2 years, the median PFS and OS were not reached. The 2-year PFS rate was 82.8% and the 2-year OS rate was 96.3%, with 3-year PFS and OS rates of 79.0% and 92.6%, respectively. At a median follow-up of 41 months, 22% (n = 6) of patients had recurrent disease.⁴

NRG-GY019

Spurred by these results, the phase 3 NRG-GY019 randomized trial (NCT04095364) has been initiated to evaluate wheth maintenance therapy with letrozole monotherapy will elicit noninferior PFS to intravenous paclitaxel/carboplatin plus maintenance letrozole.⁵

“A study that I’m very privileged to lead, NRG-GY019 is a randomized, controlled, noninferiority trial that’s looking at women with stage II to IV low-grade serous ovarian carcinoma of the ovary or their peritoneum,” Fader said. “Women must have undergone an attempt at maximal cytoreductive surgery, and then the women are [randomly assigned] to receive carboplatin/ paclitaxel followed by letrozole maintenance therapy or letrozole alone. We believe it’s the first ovarian cancer trial in the advanced-stage setting that does not have chemotherapy in one of the treatment arms and we’re trying to study if we can omit chemotherapy altogether in this population of women who have very low-grade indolent tumors, or [whether] the chemotherapy is important and the letrozole should be added to those patients.”

Specifically, patients enrolled in NRG-GY019 will be randomly assigned to carboplatin/paclitaxel for 6 cycles followed by letrozole 2.5 mg daily until disease progression or letrozole alone at 2.5 mg daily until disease progression.5 At baseline, tumors will be assessed for TP53, which is present is nearly all high-grade serous carcinomas, with nearly all low-grade tumors being wild type.^2,5

Investigators aim to enroll approximately 450 patients, which presents a challenge, Fader noted. “We’re actively enrolling and this trial is open now in 4 countries, which we’re very excited about,” she said. “In order to power the trial to look at the primary end point of PFS, we need 459 patients…. We’re approximately 50% of the way there, the trial has been open for 3 years, and we have about 225 patients enrolled to date. It’s important that we enroll the total number of patients needed to have the power to answer this question."

The primary end point of the study is PFS with secondary objectives including toxicity, objective tumor response, OS, and patient adherence to orally administered letrozole.5 For the analysis, patients will be stratified by region (United States/Canada vs Asia/Europe) and residual disease following surgery (microscopic vs any gross disease).⁶

“We’re grateful to the sites that have already opened the study, and we’d love to encourage more sites to consider it so that we can learn whether we’re possibly overtreating our patients in this setting,” Fader said.

References

1. Gershenson DM, Bodurka DC, Coleman RL, Lu KH, Malpica A, Sun CC. Hormonal maintenance therapy for women with lowgrade serous cancer of the ovary or peritoneum. J Clin Oncol. 2017;35(10):1103-1111. doi:10.1200/JCO.2016.71.0632
2. Moujaber T, Balleine RL, Gao B, Madsen I, Harnett PR, DeFazio A. New therapeutic opportunities for women with low-grade serous ovarian cancer. Endocr Relat Cancer. 2021;29(1):R1-R16. doi:10.1530/ERC-21-0191
3. NCCN. Clinical Guidelines in Oncology. Ovarian cancer/fallopian tube cancer/primary peritoneal cancer, version 1.2023. Accessed April 11, 2023. https://www.nccn.org/professionals/physician_ gls/pdf/ovarian.pdf
4. Fader AN, Bergstrom J, Jernigan A, et al. Primary cytoreductive surgery and adjuvant hormonal monotherapy in women with advanced low-grade serous ovarian carcinoma: reducing overtreatment without compromising survival? Gynecol Oncol. 2017;147(1):85-91. doi:10.1016/j.ygyno.2017.07.127
5. Letrozole with or without paclitaxel and carboplatin in treating patients with stage II-IV ovarian, fallopian tube, or primary peritoneal cancer. ClinicalTrials.gov. Updated November 3, 2022. Accessed April 14, 2023. https://clinicaltrials.gov/ct2/show/ NCT04095364
6. A randomized phase III, two-arm trial of paclitaxel/carboplatin/ maintenance letrozole monotherapy in patients with stage II-IV, primary low-grade serous carcinoma of the ovary or peritoneum: a NRG oncology study. Poster presented at Society of Gynecologic Cancers 2023 Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, FL