SAN JUAN, Puerto Rico – A negative study in low-grade serous ovarian cancer has opened a path toward more effective treatments for a large subgroup of patients, according to NRG-GY019 tests.
The randomized study established chemotherapy plus letrozole as the standard of care for low-grade serous ovarian carcinoma (LGSOC), as letrozole monotherapy failed to meet non-inferiority requirements for progression-free survival (PFS). However, a subgroup analysis showed a 50% reduction in recurrence with single-agent letrozole in patients who had no gross residual disease after surgery. Analysis of that subgroup – which included approximately two-thirds of patients randomized to letrozole monotherapy – yielded a hazard ratio (HR) within the non-inferiority range.
Median PFS was not yet reached in both arms and preliminary analysis of overall survival (OS) showed that more than 90% of patients remained alive after more than 2 years of follow-up. Letrozole alone was much better tolerated, as patients treated with chemotherapy were four times more likely to develop grade ≥3 adverse events (AEs), Amanda Fader, MD, of Johns Hopkins Medicine in Baltimore, reported at the Society of Gynecologic Oncology (SGO) meeting.
“It is worth considering that in the letrozole monotherapy arm, recurrence with any residual disease was markedly higher, approximately double that seen in those patients with no gross residual disease after cytoreductive surgery,” Fader said. “We believe this disparity likely contributed to the inability to establish non-inferiority of chemotherapy and letrozole versus letrozole monotherapy in the prospectively treated population.”
He added, “However, this trial is the first to practice defining and establishing a definitive standard of care for patients being treated in the frontline setting with advanced low-grade serous ovarian carcinoma.” “Nevertheless, in a prespecified, hypothesis-generating analysis of patients without gross residual disease, which we know is a better prognostic group … the rate of disease progression did not differ significantly between treatment arms, and the hazard ratio for progression in the letrozole monotherapy group was also relatively favorable. These findings suggest that a clinically relevant subgroup of patients may be suitable candidates for letrozole monotherapy.”
‘Biology matters’
Ongoing follow-up will include intratumoral molecular analyzes to provide context for the results and possibly clarify which patients benefit most from chemotherapy and whether letrozole alone may be a reasonable option for select patients, Fader said.
NRG-GY019 reflects ongoing efforts to move away from chemotherapy and toward more personalized treatments for LGSOC, said SGO invited discussant Roisin O’Cairbhail, MD, of Memorial Sloan Kettering Cancer Center in New York City.
“Low-grade serous have traditionally not been well responded to by chemotherapy,” O’Cearbhail said. “Although (the study) was stopped early due to futility, it may be possible, with careful discussion and patient selection, that there is a subgroup of patients that we can spare from chemotherapy.”
“We’re learning that biology matters,” she added. “Low-grade serous ovarian carcinoma and endometrioid cancer are separate entities and should be treated and studied separately. We have learned that there is a certain subgroup of patients who certainly still require chemotherapy, but great efforts should continue in terms of endocrine and targeted strategies, as these are increasingly viable as early-line options, especially for younger patients in the early-line setting. “Non-chemotherapy approaches used in breast cancer may also inform mechanisms of resistance and activity.”
LGSOC is considered a rare cancer, accounting for 2-5% of all epithelial ovarian carcinomas and about 10% of SOC, Fader said. LGSOC is epidemiologically, pathologically, molecularly, and clinically distinct from high-grade SOC. Historically, patients with any type of SOC have been treated similarly despite obvious biological differences and treatment responses.
LGSOC has a slow growth rate and is relatively chemoresistant to platinum/taxane therapy, Fader added. The risk of recurrence of this condition is high, and persistent disease after primary cytoreductive surgery is strongly associated with worse survival.
Approximately 85–90% of LGSOC express estrogen receptors and half express progesterone receptors. Several studies have produced encouraging results with post-cytoreduction endocrine therapy and National Comprehensive Cancer Network Chemotherapy plus endocrine therapy or endocrine therapy alone has been advocated as frontline for advanced LGSOC.
“Despite these encouraging retrospective results, prospective randomized data on frontline management have been lacking until now,” Fader said. “Questions remain about the optimal initial therapy and whether chemotherapy can be omitted without compromising oncological outcomes.”
key findings
Eligible NRG-G019 patients had previously untreated stage II-IV LGSOC, page53 Wild type, maximum cytoreductive surgery attempt, and no prior chemotherapy. Patients were randomized to receive six cycles of chemotherapy followed by oral letrozole or daily maintenance alone for six cycles followed by oral letrozole until disease progression or toxicity. The primary endpoint was investigator-assessed PFS in the intention-to-treat (ITT) population.
The trial ended nonsignificantly after randomization of 450 patients, and all 450 were included in the ITT analysis. The trial had a prespecified HR for non-inferiority of 1.18 for the comparison of letrozole monotherapy versus chemotherapy. When the trial ended the ITT analysis showed a HR of 1.30.
But the absolute PFS numbers were similar, Fader said, as 77.9% of the chemotherapy group and 71.9% of the letrozole monotherapy group remained alive and progression-free. OS data were incomplete but showed no significant difference between treatment arms after a median follow-up of 27.3 months (95% vs 92%).
During the first six cycles of therapy, 46.9% of the chemotherapy group had at least one grade ≥3 AE, compared with 17.6% with letrozole monotherapy, translating to an odds ratio of 3.99 (95% CI 2.57–6.18). P<0.001).
The prespecified analysis of patients with no gross residual disease after surgery included 286 patients (64% of the total). The analysis showed that 29 of 142 patients had PFS events, as did 27 of 144 patients in the chemotherapy arm, a difference that translated to a HR of 1.15. Further inspection of the data showed a recurrence rate of 41.5% with letrozole alone in patients with gross residual disease, compared with 20.5% in patients with no gross residual disease.
