Background
Metastatic renal cell carcinoma (RCC) comprises a wide set of heterogenous tumors, many of which are increasingly recognized with alterations that affect genomic instability. Several studies demonstrated that DNA repair pathways are frequently disrupted in RCC. Recent In vitro studies have shown that RCC cells are sensitive to PARP inhibitors, with subsequent increased DNA replication stress, DNA synthesis suppression and eventual increased cell cycle arrest. In addition, other studies demonstrated reduced repair of double stranded DNA (dsDNA) breaks following conditional knockout of BAP-1 suggesting that PARP inhibitors may result in synthetic lethality in the setting of BAP-1 inactivation. In light of this we have initiated a phase 2 clinical trial to examine the activity of the PAPR inhibitor olaparib in metastatic RCC with BAP-1 and select DNA repair gene alterations.
Methods
This is an open-label, single-arm, investigator-initiated phase II trial of olaparib in patients with metastatic RCC (NCT03786796). Eligibility criteria include age ≥18 years; histologically confirmed, unresectable, locally advanced or mRCC; disease progression after at least one VEGF targeted therapy or immune-checkpoint inhibitor, evidence of deleterious somatic or germline DDR gene alteration (BAP1, ATM, BRCA1, BRCA2, PALB2, CHEK2, BRIP1, RAD51C, BARD1, CDK12, CHEK1, FANCL, PP2R2A, RAD51B, RAD51D, or RAD54L). A total of 20 patients will be enrolled with the primary endpoint of disease control rate (defined as complete response [CR], partial response [PR], or stable disease [SD]) at six months of treatment) according to RECIST version 1.1. Patients will be treated with olaparib at an initial dose of 150mg by mouth twice daily. If olaparib is tolerated without any grade > 3 adverse events after one month, the dose will be increased to the FDA-approved dose of 300mg by mouth twice daily. Patients will be followed monthly with clinic visits, safety labs, and toxicity assessments. Treatment will be continued until radiographic progression (RECIST version 1.1) or unmanageable toxicity requiring drug cessation. Secondary endpoints include progression-free survival, best overall response, and safety. The study is currently open to enrollment. Clinical trial information: NCT03786796.