PARAGON-II Cohort C: A phase II basket study of letrozole plus ribociclib in hormone receptor positive platinum-resistant high-grade epithelial ovarian cancer

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.