1595MO - Phenotypic and genomic characterization of de novo metastatic prostate cancer: An ancillary study of the PEACE-1 phase III trial

Background

Recently, addition of abiraterone acetate/prednisone (AAP) to docetaxel and androgen deprivation therapy (ADT) became a standard of care for metastatic castration-sensitive prostate cancer (mCSPC) following results of PEACE-1 (Fizazi et al., Lancet 2022). In this ancillary study, we aim to identify prognostic and predictive biomarkers associated with radiographic Progression-Free Survival (rPFS) and Overall Survival (OS).

Methods

Immunochemistry (IHC) analyses were performed using validated antibodies staining luminal components (AR, NKX3.1), neuroendocrine (NE) features (synaptophysin, CD56, chromogranin A), tumor suppressors (p53, Rb, pTEN), Ki67 and ERG. Five phenotype subgroups were defined using luminal and NE status. A pre-specified statistical analysis plan was approved by the steering committee. Cox models were fitted with each IHC marker adjusted for age, tumor burden, Gleason score, ECOG and treatments received (radiotherapy, docetaxel and AAP) to evaluate their prognostic value. Interaction tests between AAP and biomarkers were performed to assess whether these factors were predictive of treatment benefit.

Results

From the 1172 de novo mCSPC patients (pts) randomized in PEACE-1 (NCT01957436), 595 pts had a paraffin-embedded sample collected and centrally reviewed. The distribution of clinical variables was similar between the full trial population and IHC populations. Among the 350 pts with an assessable phenotype, 150 (42.9%) were AR-high luminal, 97 (27.7%) AR luminal weak, 95 (27.1%) amphicrine, 3 (0.8%) double negative and 5 (1.4%) NEPC. No significant difference for rPFS or OS was found between these 5 subgroups but a trend from AR-high luminal (better prognosis) to NEPC (worse prognosis), mainly driven by the NE status. Pts with at least one NE positive marker had a shorter rPFS (HR=1.38, CI95%[1.06-1.81], p=0.017) and OS (HR=1.53, CI95%[1.14-2.06], p=0.005). ERG positive pts had a longer rPFS (HR=0.71, CI95%[0.53-0.94], p=0.019). None of the biomarkers were found to be predictive of response to AAP.

Conclusions

The phenotype assessed by IHC is strongly prognostic in mCSPC patients treated with ADT +/- docetaxel, with or without AAP. Genomic data will be further disclosed.

Clinical trial identification

NCT01957436.

Editorial acknowledgement

We acknowledge editorial assistance from Emilie Dasse, medical writer at Unicancer.

Legal entity responsible for the study

Unicancer.

Funding

Institut National du Cancer (INCA).

Disclosure

C. Pobel: Non-Financial Interests, Personal, Member: ESMO; Financial Interests, Personal, Sponsor/Funding: Chugai, Amgen, Sanofi; Financial Interests, Personal, Training: Sandoz, Janssen, Eisai, Actelion Pharmaceuticals, Vifor pharma, Ipsen. G. Roubaud: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Bayer; Financial Interests, Institutional, Advisory Board: Pfizer, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Coordinating PI: Bayer. A. Flechon: Financial Interests, Personal, Advisory Board: AstraZeneca, Astellas, Janssen, AAA, Bayer, MSD, Pfizer, Merck, BMS; Financial Interests, Personal, Invited Speaker: Novartis. B. Laguerre: Financial Interests, Personal, Other, ASCO GU symposium 2023 (travel and registration): Pfizer; Financial Interests, Personal, Other, honoraria: Astellas, Janssen, Pfizer, Eisai; Financial Interests, Personal, Other, registration ASCO virtual meeting 2022: BMS; Financial Interests, Personal, Other, registration ASCO GU symposium 2022 (virtual): MSD; Financial Interests, Personal, Other, registration and travel for ASCO meeting 2023: AstraZeneca. L. Mourey: Financial Interests, Personal, Advisory Board: Astellas, Janssen, MSD, BMS, Ipsen, AstraZeneca, Pfizer, AAA. S. Foulon: Financial Interests, Institutional, Advisory Board, Participation to the advisory board (statistical advice) of an epidemiological study performed by Gilead on real world data (medico-administrative data): Review and validation of the study protocol, validation of the study population, as well as the review and validation of the results and of the study report.: Gilead. 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. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck KgaA, Pfizer, Gilead, Seattle Genetics, Tahio; Financial Interests, Personal, Other, lectures, advisory boards: MSD, AstraZeneca, Astellas, Janssen; Financial Interests, Personal, Other, lectures, advisory boards: Roche, BMS; Financial Interests, Institutional, Research Grant: Janssen, Sanofi, MSD, Roche, Celsius; Financial Interests, Institutional, Steering Committee Member: Janssen; Financial Interests, Steering Committee Member: MSD, Astellas, Gilead/Immunomedics, Tahio; Financial Interests, Personal, Steering Committee Member: Basilea; Financial Interests, Institutional, Local PI: Pfizer, MSD, Janssen, Exelexis, AstraZeneca, Pfizer, Merck Kga, BMS, Astellas, Gilead, Incyte; Financial Interests, Institutional, Coordinating PI: Janssen; Non-Financial Interests, Member: ESMO, ASCO, AACR; Non-Financial Interests, Other, scientific committee: ARC. All other authors have declared no conflicts of interest.