Abstract CT007: PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-06, Vol.82 (12_Supplement), p.CT007-CT007
• Main Authors: Yap, Timothy A., Im, Seock-Ah, Schram, Alison M., Sharp, Adam, Balmana, Judith, Baird, Richard D., Brown, Jessica S., Schwaederle, Maria, Pilling, Elizabeth A., Moorthy, Ganesh, Linardopoulos, Spiros, Dowson, Adam, Pound, Carol, Lukacs, Edit, Cosulich, Sabina, Luen, Stephen J.
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-CT007

Background: AZD5305 is a potent, highly selective PARP1 inhibitor and trapper with superior preclinical tolerability, target engagement and efficacy vs 1st generation dual PARP1/2 inhibitors (PARPi). This is the first report of the ongoing Phase 1/2a PETRA (NCT04644068) trial. Methods: Pts with advanced breast, ovarian, prostate or pancreatic cancer bearing germline or somatic BRCA1/2, PALB2 or RAD51C/D mutations received AZD5305 QD PO until disease progression. ECOG PS 0-2 and Hb ≥9.0 g/dL were required. Prior PARPi and platinum therapy were permitted. The primary objective was safety; secondary objectives included pharmacokinetics (PK) and pharmacodynamics in tumor and/or blood samples and response by RECIST v1.1, CA125 or PSA. Exploratory genomic analyses included zygosity evaluation and ctDNA response monitoring. Results: At data cutoff (Nov 17, 2021), 46 pts received AZD5305 10-90 mg QD (43.5% had prior PARPi; median 3.5 prior lines of therapy). AZD5305 was well tolerated across all doses without DLTs (Table). PK exposures were dose-proportional. Steady-state Ctrough was higher than 1st generation PARPi: specifically 6.3 and 31.9 fold above target effective concentration at 10 and 90 mg, respectively. PARylation inhibition was ≥90% at 10-40 mg QD (PBMCs) confirming target engagement. 7/25 (28%) pts had objective responses: 5 RECIST PRs (3 confirmed) and 2 additional pts with PSA50 responses (1 confirmed), including platinum- and PARPi-resistant pts. 13/22 (59%) RECIST-measurable pts had SD or PR up to 51+ weeks. ctDNA declined on treatment in 7/13 (54%) evaluable pts (3 complete, 4 >50% reductions) across doses. Conclusions: AZD5305 is a highly selective PARP1 inhibitor and trapper with excellent physiochemical properties and a wide therapeutic index. It led to maximal target engagement and showed promising clinical activity with favorable tolerability at exposures surpassing those of 1st generation PARPi. AZD5305 10 mg/d (n=8) AZD5305 20 mg/d (n=19) AZD5305 40 mg/d (n=13) AZD5305 60 mg/d (n=3) AZD5305 90 mg/d (n=3) Total (N=46) Most common (>10%) TRAEs, n (%) Any grade Any grade Any grade Any grade Any grade Grade ≥3 Any grade Nausea 3 (37.5) 5 (26.3) 1 (7.7) 1 (33.3) 0 0 10 (21.7) Anemia* 2 (25.0) 4 (21.1) 1 (7.7) 0 0 6 (13.0) 7 (15.2) Neutropenia* 3 (37.5) 2 (10.5) 1 (7.7) 0 1 (33.3) 2 (4.3) 7 (15.2) Thrombocytopenia* 1 (12.5) 2 (10.5) 2 (15.4) 0 0 1 (2.2) 5 (10.9) Fatigue and asthenia* 2 (25.0) 2 (10.5) 0 1 (33.3) 0 0 5 (10.9) Any TRAE leading to