Olaparib (O) in patients (pts) with colorectal cancer (CRC) with ATM mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Behl Deepti , Rothe Michael , Mangat Pam K. , Garrett-Mayer Elizabeth , Farrington Laura Catherine , Crysler Oxana V. , Dib Elie G. , Duvivier Herbert Leon , Hall Michael J. , Salmon John Stuart , Alese Olatunji B. , Marr Alissa S. , Ngirailemesang Isa , Polavaram Latha , Thota Ramya , Yang Eddy Shih-Hsin , O'Lone Raegan , Grantham Gina N. , Halabi Susan , Schilsky Richard L. 
Published: January 2023

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Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with CRC with ATM mut treated with O are reported. Methods: Eligible pts had advanced CRC with ATM mut, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was done in CLIA-certified, CAP-accredited labs. Recommended dosing for O was 300 mg twice daily (tablets) or 400 mg twice daily (capsules) until disease progression. Primary end point was disease control (DC), defined as complete or partial (PR) response per RECIST v. 1.1, or stable disease (SD) at 16+ weeks (wks) (SD16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 has DC, 18 more pts are enrolled; otherwise, cohort is closed for futility. If ≥7 of 28 pts has DC, the null DC rate is rejected. Secondary end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), duration of SD, and safety. DOR is defined as time from the pt’s first documented objective response (OR) until progressive disease (PD). Duration of SD is defined as time from start of tx to PD. Results: 30 pts with CRC and ATM mut were enrolled from Sept 2016 to Aug 2019. 3 pts were not included in efficacy outcomes: 2 pts had no post-baseline tumor evaluation; 1 pt was found to be ineligible after receiving 1 dose. 1 PR ( ATM P938fs*11 and RAD50 variant of unknown significance (VUS); DOR was 18.6 wks) and 3 SD16+ ( ATM R1875*, splice site 4237-11_4241del16, E522*; duration of SD was 19.7, 25.3 and 27.0 wks, respectively) were observed for DC rate of 23% (95% CI, 6% to 39%) and OR rate of 4% (95% CI, 0.1% to 19%). The null DC rate was not rejected (p=0.38). 6/30 pts had a BRCA2 co-alteration, but none of these pts achieved OR or SD16+; no pts had a BRCA1 co-alteration; aside from the pt with PR and RAD50 VUS, only 1 other pt who achieved OR or SD16+ had a co-alteration among the other homologous recombination-related genes examined ( ATR VUS). 7 pts had ≥1 Grade 3 adverse or serious adverse event (SAE) at least possibly related to O, including urinary tract infection, white blood cell decreased, febrile neutropenia (SAE), anemia (1 SAE), lung infection (SAE), fatigue (SAE), and nausea (SAE). Conclusions: Monotherapy O does not show sufficient antitumor activity in pts with advanced CRC with ATM mut to warrant further study. Clinical trial information: NCT02693535 . [Table: see text]