Next-generation sequencing (NGS) of tumor tissue from >4000 men with metastatic castration-resistant prostate cancer (mCRPC): The PROfound phase III study experience.

195 Background: The PROfound study (NCT02987543) showed that olaparib provides a statistically significant improvement in radiographic progression-free survival versus physician’s choice of enzalutamide or abiraterone in mCRPC patients (pts) with alterations in genes with a direct or indirect role in the homologous recombination repair (HRR) pathway. This is the largest study to date with central, prospective tumor tissue testing in pts with mCRPC. Here, we report learnings during testing in the PROfound study. Methods: An investigational clinical trial assay, based on the FoundationOne CDx NGS test developed in partnership with Foundation Medicine, Inc (FMI), was used to prospectively identify pts with qualifying alterations in ≥1 of 15 prespecified genes, including BRCA1, BRCA2 or ATM. Tumor testing was conducted centrally using archival or recent biopsy from primary or metastatic tissue. Results: Of 4047 pts who submitted tumor samples, 2792 (69%) were successfully sequenced and yielded a biomarker status. Categories for test failure (n=1255; 31%) were pathology review failure in 277 (6.8%) pts (eg estimated tumor fraction <20% or tumor volume <0.2 mm 2 ), DNA extraction failure in 533 (13.2%) pts, and failure after DNA extraction in 280 (6.9%) pts, with 165 (4.1%) pts in >1 category. Regarding the sample disposition, approximately two-thirds of samples were from core needle biopsies, although higher success rates were observed with larger samples (ie prostatectomy). Samples were mainly from the prostate gland, with <5% from bone. Most samples were from archived tissue of primary tumors; only ~10% were from newly collected tissue. Test turnaround time, as well as representation of sample characteristics and country of origin relative to success rate, will be presented. Conclusions: The PROfound study has demonstrated that tissue testing to identify HRR alterations in men with mCRPC is feasible. Careful selection of high-quality tumor tissue samples is key to ensure success both at pathology review and during downstream steps of the NGS tissue testing process. Clinical trial information: NCT02987543.