1839P - Circulating tumor DNA (ctDNA) low pass whole genome sequencing (lpWGS) studies identify genomic alterations associating with taxane outcomes in prospective phase III taxane trials for metastatic castration resistant prostate cancer (mCRPC) sufferers

Background

Taxanes are a standard of care for mCRPC and no clinically qualified biomarker has as yet been identified for these. lpWGS of ctDNA identifies copy-number alterations (CNAs) common in advanced PC and may identify mCRPC subtypes most responsive to taxane therapy. ctDNA lpWGS identified genomic aberrations associating with treatment outcomes for participants of three prospective Phase III taxane trials (CARD, FIRSTANA and PROSELICA).

Methods

Genomic alterations in ctDNA were assessed for correlations with overall survival (OS), radiologic progression-free survival (rPFS), and PSA or radiological response rate (RR) using univariable and multivariable mixed-effect regression models to study CNAs significantly associated with differential outcomes of prognostic and predictive significance.

Results

Genome-wide analysis identified several genomic alterations that were significantly associated with worse OS in these taxane-treated individuals including chromosome 2p, 9p and 13 deletions. Several CNAs remained independently significant (Chr2p HR 2.89, p<0.01; Chr9p HR 2.9, p<0.01, Chr12q HR 2.06, p<0.01) following multivariable analyses incorporating PSA, LDH, haemoglobin, the presence of visceral metastases and tumour fraction estimate. Conversely, several loci including 20q and X gain, and 15q loss associated with worse rPFS and OS on the CARD control arm (abiraterone post enzalutamide or vice versa) but exhibited no difference in rPFS and OS on the cabazitaxel-treated arm. To confirm these results, we explored the association of CNAs with response rate in the FIRSTANA and PROSELICA study cohorts and found that several loci were associated with higher taxane-response rates in biomarker-positive individuals.

Conclusions

These ctDNA lpWGS studies in mCRPC patients have identified genomic alterations in ctDNA of prognostic and predictive significance in men suffering from mCRPC receiving taxane treatment. Prospective validation will facilitate treatment selection and identify potential clinical biomarkers associated with outcome.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The Institute of Cancer Research.

Funding

Sanofi Aventis; Prostate Cancer UK.

Disclosure

N. Mehra: Financial Interests, Personal, Advisory Board: Pfizer, Roche, MSD, AstraZeneca, Astellas, JNJ; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Funding: Astellas, Pfizer; Financial Interests, Personal and Institutional, Funding: Janssen; Financial Interests, Institutional, Coordinating PI: BMS, Janssen, BMS; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS; Non-Financial Interests, Leadership Role, Head of the Prostate Cancer Working group: Dutch Uro-Oncology Study Group; Non-Financial Interests, Principal Investigator, co-PI: Prospective Bladder Cancer Infrastructure (Netherlands); Non-Financial Interests, Leadership Role: Castration-resistant Prostate Cancer Registry. M. Eisenberger: Financial Interests, Personal, Member of Board of Directors: VERU Inc; Financial Interests, Personal, Stocks/Shares: VERU Inc; Financial Interests, Personal, Advisory Board: Merck, Seagen, BMS. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Personal, Advisory Board, February 2022: Arvinas; Financial Interests, Personal, Advisory Board, April 2022: Macrogenics; Financial Interests, Institutional, Research Grant, Trial chair: Pfizer, Bayer, AstraZeneca, Orion, MSD, BMS, Janssen; Non-Financial Interests, Principal Investigator, Chair of the 7DX phase 3 trial: BMS; Non-Financial Interests, Principal Investigator, Chair of the Docetaxel-pembrolizumab phase 3 trial: Merck; Non-Financial Interests, Principal Investigator, Chair of the Darolutamide BCR phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the PSMAfore phase 3 trial: AAA/Novartis; Non-Financial Interests, Principal Investigator, Chair of the CYPIDES ODM-208 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the STESIDES ODM-209 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the CAPITELLO 281 phase 3 trial: AstraZeneca; Non-Financial Interests, Principal Investigator, Chair of the TALAPRO-2 and TALAPRO-3 phase 3 trials: Pfizer; Non-Financial Interests, Principal Investigator, Chair of the RADIANT phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the TRITON-3 phase 3 trial: Clovis. B. Tombal: Financial Interests, Personal, Advisory Board: Astellas, Bayer, Amgen, Janssen, Sanofi, Myovant, Novartis (AAA), Pfizer, Astellas, MSD, AstraZeneca; Financial Interests, Personal, Invited Speaker: Astellas, Amgen, Ferring; Non-Financial Interests, Member of Board of Directors, Past President: European Organisation of Research and Treatment of Cancer (EORTC); Non-Financial Interests, Member of Board of Directors, Education in the field of Oncology: ISSECAM. C.N. Sternberg: Financial Interests, Personal, Advisory Board, AD board and speaker at ESMO: Pfizer; Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, Astellas, Sanofi-Genzyme, Roche-Genentech, Foundation Medicine, Immunomedics, Janssen; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Advisory Board, Was the head if the oversignt committee, of Phase III trial but last meeting over 1 year ago: Seattle Genetics; Financial Interests, Personal, Other, AD board: BMS; Financial Interests, Personal, Other, Speaker, owned by Prostate Cancer Foundation: Uro Today; Financial Interests, Personal, Other, Speaker, CME activities: Medscape. D.E. Castellano Gauna: Financial Interests, Personal, Advisory Board: Pfizer, Roche, BMS, Janssen, Astellas, MSD, Ipsen, AstraZeneca Novartis, GSK; Financial Interests, Institutional, Local PI: Pfizer, Roche, MSD, BMS, AstraZeneca Janssen, Astellas, Ipsen, Exelisis, Eisai, Lilly, Bayer, GSK, CLOVIS, QED Therapeutics; Non-Financial Interests, Personal, Other, Executive member: SOGUG (Spanish Oncology Genito-Urinary Group) Foundation. S. Oudard: Financial Interests, Personal, Speaker, Consultant, Advisor, honoraria, travel expenses: AstraZeneca, Astellas, BMS, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Sanofi, Bayer; Financial Interests, Personal, Advisory Board, travel expenses: Roche. O. Sartor: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: AstraZeneca, Bayer, Janssen; Financial Interests, Personal, Speaker, Consultant, Advisor: Clovis Oncology, Invitae, Pfizer. C. Geffriaud-Ricouard: Financial Interests, Personal, Full or part-time Employment, I am a full time employee at Sanofi (global medical lead): Sanofi. M. Chadjaa: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi. S. Mace: Financial Interests, Personal, Full or part-time Employment: Sanofi. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Menarini Silicon Biosystems, ImCheck Therapeutics, Crescendo; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi Sankyo, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics, Menarini Silicon Biosystems; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Crescendo, ImCheck Therapeutics; Non-Financial Interests, Institutional, Product Samples: Daiichi Sankyo, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GSK. All other authors have declared no conflicts of interest.