Phase II Trial of the PARP Inhibitor, Niraparib, in BAP1 and Other DNA Damage Response Pathway-Deficient Neoplasms

Abstract

Purpose: BRCA1-associated protein 1 (BAP1) is a critical cell cycle and DNA damage response (DDR) regulator with mutations (mBAP1) causing a functional protein loss. PARP inhibitors (PARPis) demonstrate synthetic lethality in mBAP1 preclinical models, independent of underlying BRCA status. This study aimed to explore the clinical activity of niraparib in patients with advanced tumors likely to harbor mBAP1.

Methods: This was a phase II multicenter trial in which refractory solid tumor patients were assigned to cohort A (histology-specific tumors likely to harbor mBAP1) or cohort B (histology-agnostic tumors with other known non-BRCA-confirmed DDR mutations). All patients received niraparib 300 mg orally once daily on a 28-day cycle. The primary end point was objective response rate, and secondary end points included progression-free survival (PFS) and overall survival.

Results: From August 2018 through December 2021, 37 patients were enrolled with 31 evaluable for response (cohort A, n = 18; cohort B, n = 13). In cohort A, the best response was one partial response (PR; 6%), eight stable disease (SD; 44%), and nine progressive disease (PD; 50%). This cohort stopped at the first stage following the prespecified Simon's design. mBAP1 was confirmed in 7/9 patients (78%) with PR or SD but in only 3/9 (33%) in those with PD. The median PFS in patients with mBAP1 (n = 10) was 6.7 months (95% CI, 1.0 to 9.2) versus 1.8 months (95% CI, 0.9 to 4.5) for wild-type (n = 8; P = .020). In cohort B, the best response was six SD (46%) and seven PD (54%), with SD in those with ATM, CHEK2, PTEN, RAD50, and ARID1A mutations.

Conclusion: Niraparib failed to meet the prespecified efficacy end point for response. However, clinical benefit was suggested in a proportion of patients who had a confirmed mBAP1, supporting further investigation.

Trial registration: ClinicalTrials.gov NCT03207347.

FIG 1.

CONSORT diagram. Cohort A included patients with histologic diagnosis of mesothelioma, uveal melanoma, renal cell carcinoma, or cholangiocarcinoma. Cohort B included patients with confirmed histologic diagnosis of malignancy and known somatic mutation of component of DNA damage repair pathway. Both cohorts received niraparib 300 mg orally once daily on each day of the 28-day cycle. If patients' baseline body weight <77 kg or baseline platelet count <150,000 μL, niraparib 200 mg/d orally once daily was administered.

FIG 2.

Waterfall plot of cohort A patients showing best tumor responses (n = 17). One patient with cholangiocarcinoma (BAP-negative) with multiple new progressive lesions not shown above. ^aPatients had overall PD with <20% increase in target lesions but had new nontarget lesions. ^bBAP1 mutation. PD, progressive disease; PR, partial response; SD, stable disease.

FIG 3.

(A) Kaplan-Meier PFS curves for cohorts A and B. (B) PFS by BAP1 status for cohort A. 95% CIs are indicated in parentheses. PFS, progression-free survival; WT, wild-type.

FIG 4.

(A) Kaplan-Meier OS curves for cohorts A and B. (B) OS by BAP1 status for cohort A. 95% CIs are indicated in parentheses. OS, overall survival; WT, wild-type.