Canadian Cancer Trials Group (CCTG) IND.234/223: PC_BETS (Prostate Cancer Biomarker Enrichment and Treatment Selection)–A molecularly selected cooperative group platform study.

Abstract

5066 Background: PC-BETS registered patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) for circulating tumour (ct)DNA-based genomic screening to biomarker select and stratify pts for enrolment in a multi-arm platform trial testing clinical activity of investigational therapies. Methods: Pts (≥ 18 years old, ECOG PS 0-1, life expectancy ≥ 6 months) had mCRPC, disease progression (PD), no CNS involvement or serious illnesses and had received AR pathway inhibitor therapy +/- chemotherapy. Eligible pts were registered and screened using plasma ctDNA and enrolled to a substudy (SS) based on the presence (or absence) of a prespecified biomarker (BM), using a prespecified algorithm and a virtual web-based Molecular Tumour Board (MTB). ctDNA testing used an established targeted sequencing approach customised for mCRPC. Pts without BM positive genomic alteration(s) for an open SS were randomized to a BM negative SS cohort; pts who were never enrolled were followed for outcomes. Pts without detected ctDNA were not eligible for enrolment but could be rescreened after >8 weeks. Pts who discontinued a SS could be rescreened. Primary endpoint was clinical benefit rate (CBR; PSA50 response, RECIST CR/PR, or SD ≥12 weeks). Eight SS opened between 2017-2020. Results: From 2017-2024, 568 pts were screened from 11 centres across Canada. Pts: median age 71.5 (range 47.7-94.7), prior chemotherapy in 47.0%, and median ctDNA fraction was 7%. 216 pts were enrolled to 1 or more SS (3 pts enrolled to >1). See Table for summary of results. For all SS, toxicities were as expected. In SS-E, 1 pt had CBR and 1 pt received 25 cycles but did not meet CBR (both pts had AKT mutations). Clinical and genomic correlations will be presented. SS C, F and G are reported separately. Conclusions: Biomarker selected platform designs are an efficient way to screen potential new therapeutics, are well suited to multi-centre cooperative group settings and are strongly supported by patients advocates. CBRs were not reported for SS 223, B and D while modest clinical activity was seen for SS A (in the BM- cohort only) and E. Clinical trial information: NCT03385655 . Total Screens / N pts 606 / 565 ctDNA+ screen / pts 443 / 426 N pts enrolled to SS 216 SS 223 A B C D E F G Drug/s Palbociclib Adavosertib Savolitinib Darolutamide CFI-40095 Ipatasertib Durvalumab / tremelimumab Carboplatin Target/pathway CDK 1 BRCA/ATM 2 MET AR PTEN PIK3CA/AKT TMB high BRCA/ATM 2 Drug supplied by Pfizer AstraZeneca Bayer 3 Treadwell Hoffman-La Roche 3 AstraZeneca 3 - Enrolled to SS(BM+/-) 19 (9/10) 25 (11/14) 16 (6/10) 72 (53/19) 18 (9/9) 8(BM+) 25 (15/10) 35(18/17) CBR (BM+) 0 0 0 0 1 CBR (BM-) 0 3 0 0 1 CDK4/6/CCND1 amplification or CDK12 mutations; 2 or other HRR-related defects; 3 Plus partial funding to support SS.