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
Bibliographic record
Abstract
Abstract 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 dose reduction 1 (12.5) 0 0 0 0 1 (2.2) Any TRAE leading to discontinuation 0 0 0 0 0 0 AE, adverse event; TRAE, treatment-related adverse event *Grouped Terms Citation Format: Timothy A. Yap, Seock-Ah Im, Alison M. Schram, Adam Sharp, Judith Balmana, Richard D. Baird, Jessica S. Brown, Maria Schwaederle, Elizabeth A. Pilling, Ganesh Moorthy, Spiros Linardopoulos, Adam Dowson, Carol Pound, Edit Lukacs, Sabina Cosulich, Stephen J. Luen. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT007.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.015 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".