ORCHID: A phase II study of Olaparib in Metastatic Renal Cell Carcinoma Patients HarborIng a BAP1 or Other DNA Repair Gene Mutations

BACKGROUND: DNA damage repair genes alterations (DDRa) are frequent events in renal cell carcinoma (RCC), including BAP1 and other DDRa. Olaparib is a poly ADP ribose polymerase inhibitor (PARPi) that is FDA-approved for the treatment of several malignancies with DDRa. Preclinical models demonstrated synthetic lethality with PARPi in RCC cell lines including BAP1 mutant lines. Here we report an interim analysis of the ORCHID study investigating the clinical activity of single agent olaparib in patients (pts) with advanced RCC (aRCC) harboring BAP1 other select DDRa. METHODS: We conducted a single center, single arm, investigator-initiated Phase 2 trial of olaparib in pts with aRCC. Eligible pts harbored select DDRa and had prior therapy with immune checkpoint inhibitors (ICIs) and/or VEGF-TKI. Pts were treated with olaparib at an initial dose of 150mg twice which was increased to 300mg twice daily after one month if well tolerated. The primary endpoint is disease control rate (DCR) by RECIST v1.1 (including complete response (CR), partial response (PR), and stable disease (SD) >6 months). Secondary endpoints included objective response rate (ORR), progression free survival (PFS), and safety. RESULTS: Eleven pts were enrolled with a median age of 59 years (48-72) including 9 pts with clear cell RCC and 2 pts with unclassified RCC. Most pts had BAP1 mutations (Table). 36% of pts had history of brain metastasis. Median number of prior lines of therapies was 2 (1-6) and all pts received prior ICI. The study met the pre-specified Simon’s 2 stage design for the first stage with 22% DCR in the evaluable pts (2/9), including deep PR (>70% reduction in tumor volume) and SD of 10 months. Both pts harbored BAP1 mutations. An additional pt with BRCA1 mutation had 20% decrease in measurable disease. There were no treatment related adverse events resulting in study discontinuation. CONCLUSIONS: This is the first study investigating single agent PARPi in RCC with the interim trial analysis indicating promising activity of olaparib in aRCC pts with BAP1 mutations including one pt with deep PR. These results support further development of PARPi in this setting.