International journal of gynecological cancer : official journal of the International Gynecological Cancer Society · 2026
PARAGON-II cohort C: a phase II basket study of letrozole plus ribociclib in hormone receptor-positive, platinum-resistant, high-grade epithelial ovarian cancer.
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Lee Chee Khoon, Zebic Danka S, O'Connell Rachel L, Lee Yeh C, Francis Katherine E, Gao Bo, Goh Jeffrey C, Baron-Hay Sally, Kasherman Lawrence, Srivastav Ratnesh, Steer Christopher, Meniawy Tarek, Simon Sandy, Mathur Deepa, Cheung Leanna, Wall Margaret, Scott Clare L, Davis Alison, De Fazio Anna, Yip Sonia, Friedlander Michael
Аннотация
OBJECTIVE: Hormone receptor expression is common in epithelial ovarian cancer, and endocrine therapy is included in guidelines for recurrent disease. Dysregulation of the cyclin-dependent kinase 4 and 6 pathway is frequent in high-grade serous carcinoma, providing a rationale for evaluating cyclin-dependent kinase 4 and 6 inhibition with endocrine therapy in hormone receptor-positive epithelial ovarian cancer. PARAGON-II Cohort C assessed letrozole plus ribociclib in hormone receptor-positive, PIK3CA wild-type, platinum-resistant ovarian cancer.
METHODS: PARAGON-II is a multi-center, phase II basket trial. Participants received letrozole 2.5 mg daily continuously plus ribociclib 600 mg (3-weeks-on/1-week-off) until progression or unacceptable toxicity. The primary end point was objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 or Gynecologic Cancer InterGroup CA125 criteria. Secondary end points included disease control rate, progression-free survival, patient-reported outcomes, and safety.
RESULTS: Thirty-two participants were enrolled (median age 64 years; 97% high-grade serous histology). Patients were heavily pre-treated: 56% had ≥3 prior lines, 69% had prior bevacizumab, and 25% prior Poly (ADP-ribose) polymerase inhibitors. Among 25 participants with measurable disease, the objective response rate was 4.0% (95% confidence interval 0.1 to 20.0; 1 partial response). There was 1 Gynecologic Cancer InterGroup CA125 response (3.3%; 95% confidence interval 0.1 to 17.2). In evaluable participants (n = 30), the 12-week disease control rate was 27.0%. Median progression-free survival was 1.9 months, with a 6-month progression-free survival rate of 16.0%. Grade ≥3 toxicities were mainly hematologic. Over half of the participants reported moderate-severe baseline abdominal symptoms, which were associated with significantly shorter survival. Patient-reported outcome scores declined over time, consistent with disease progression.
CONCLUSIONS: Letrozole plus ribociclib demonstrated minimal clinical activity in heavily pre-treated hormone receptor-positive, PIK3CA wild-type, platinum-resistant ovarian cancer. These findings do not support further evaluation of this specific endocrine therapy and cyclin-dependent kinase 4 and 6 inhibitor combination in this population, although alternative endocrine-based strategies targeting different biological mechanisms may warrant investigation.
METHODS: PARAGON-II is a multi-center, phase II basket trial. Participants received letrozole 2.5 mg daily continuously plus ribociclib 600 mg (3-weeks-on/1-week-off) until progression or unacceptable toxicity. The primary end point was objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 or Gynecologic Cancer InterGroup CA125 criteria. Secondary end points included disease control rate, progression-free survival, patient-reported outcomes, and safety.
RESULTS: Thirty-two participants were enrolled (median age 64 years; 97% high-grade serous histology). Patients were heavily pre-treated: 56% had ≥3 prior lines, 69% had prior bevacizumab, and 25% prior Poly (ADP-ribose) polymerase inhibitors. Among 25 participants with measurable disease, the objective response rate was 4.0% (95% confidence interval 0.1 to 20.0; 1 partial response). There was 1 Gynecologic Cancer InterGroup CA125 response (3.3%; 95% confidence interval 0.1 to 17.2). In evaluable participants (n = 30), the 12-week disease control rate was 27.0%. Median progression-free survival was 1.9 months, with a 6-month progression-free survival rate of 16.0%. Grade ≥3 toxicities were mainly hematologic. Over half of the participants reported moderate-severe baseline abdominal symptoms, which were associated with significantly shorter survival. Patient-reported outcome scores declined over time, consistent with disease progression.
CONCLUSIONS: Letrozole plus ribociclib demonstrated minimal clinical activity in heavily pre-treated hormone receptor-positive, PIK3CA wild-type, platinum-resistant ovarian cancer. These findings do not support further evaluation of this specific endocrine therapy and cyclin-dependent kinase 4 and 6 inhibitor combination in this population, although alternative endocrine-based strategies targeting different biological mechanisms may warrant investigation.