Abstract 1983: Phase II study of rucaparib and nivolumab in patients with leiomyosarcoma

Introduction: Rucaparib, a small molecule inhibitor of PARP, is approved for treating patients with refractory deleterious BRCA mutations, while nivolumab, a human monoclonal antibody targeting PD-1, is approved for various cancers. This phase II study aimed to explore whether rucaparib could enhance the immune response of nivolumab in patients with leiomyosarcoma (LMS). Here, we present an exploratory analysis of circulating tumor DNA (ctDNA) dynamics and imaging-based responses. Methods: Twenty patients with LMS were enrolled in the trial and received rucaparib (600 mg twice daily for 28 days) in combination with nivolumab (480 mg day 1 of every 4-week cycle). Plasma samples were collected for ctDNA analysis at baseline and at weeks 5, 9, 17, 25, and the end of treatment, utilizing the MSK-ACCESS cfDNA assay to detect alterations across 129 genes. Matched tumor tissue was sequenced using MSK-IMPACT. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was efficacy, measured by best response by week 24, according to RECIST 1.1 criteria. Results: In this exploratory analysis in LMS patients, ctDNA was detected at baseline in 100% of samples. Concordance analysis between MSK-ACCESS and MSK-IMPACT revealed a baseline concordance of 63.6% in terms of the specific mutations detected, which increased to 72.7% when considering all plasma samples. The ctDNA dynamics were compared to RECIST imaging. Among the patients, eight exhibited RECIST-confirmed progression at the first imaging assessment, seven of whom had increasing ctDNA levels. Additionally, five patients discontinued the study due to clinical progression despite RECIST indicating stable disease, with 80% (4 of 5) showing rising ctDNA levels. This study highlights the limitations of using RECIST criteria and suggests that ctDNA dynamics may be a more sensitive indicator of disease progression. Baseline and post-chemotherapy cycle-2 ctDNA levels have been previously associated with survival outcomes in LMS. Consistently, our analysis revealed that ctDNA levels at week 5 predicted radiologic response, with 90% of patients experiencing disease progression showing increases in ctDNA. Notably, one patient who achieved a partial response demonstrated undetectable ctDNA at week 5, which remained so until treatment discontinuation due to toxicity. Conclusion: The combination of ctDNA dynamics with RECIST imaging shows potential for improving the monitoring of patient response and predicting disease progression in LMS. Overall, while the study underscores the limitations of the rucaparib and nivolumab combination, ctDNA appeared to predict early progression and response to therapy and was a useful adjunctive test in cases where the treatment benefit was unclear. Further study is needed to validate these findings. Citation Format: Carmelina Charalambous, Ronak H. Shah, Michael F. Berger, Sujana Movva. Phase II study of rucaparib and nivolumab in patients with leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1983.