LBA86 - Androgen receptor pathway inhibitors or taxanes for patients with metastatic castration-resistant prostate cancer: A direct comparison in ProBio, a randomized, outcome-adaptive, biomarker-driven platform trial

Background

The Prostate Biomarker (ProBio) trial is an international biomarker-driven, randomized, outcome-adaptive platform trial in men with metastatic castrate resistant prostate cancer (mCRPC) evaluating multiple agents.

Methods

We used outcome-adaptive randomization to compare biomarker-driven treatment selection (experimental arms) against physician’s choice standard-of-care (SOC; control arm), and to compare agents against each other within the experimental treatment arms. Men with mCRPC were randomized based on genomic alterations in circulating tumor DNA in five biomarker signatures: (1) AR wt and TP53 wt; (2) TP53 mut; (3) DRD; (4) TMPRSS2:ERG fusion; (5) all biomarkers signatures combined. Androgen receptor pathway inhibitors (ARPi; abiraterone and enzalutamide) and taxanes (docetaxel and cabazitaxel) were evaluated, using progression-free survival, by no longer clinically benefiting per PCWG3 criteria (PFS), as primary endpoint. Enrollment in the experimental group was stopped when the Bayesian probability of superiority reached prespecified thresholds (“graduation”).

Results

In total, 219 men were randomized: 92 to SOC, vs. 76 and 51 to taxanes and ARPi, respectively, in the biomarker-driven arms. ARPi graduated in the “signature all”, i.e. a signature encompassing all biomarkers. The median estimated PFS was 11.3 months (90% Bayesian credible interval [CI], 9.8 to 13.1) for ARPi compared with 7.2 months (90% CI, 6.5 to 8.1) in the SOC arm, for a hazard ratio (HR) of 0.52 (90% CI 0.37 to 0.72). ARPi demonstrated superiority to taxanes within the experimental arms (HR 0.54; 90% CI 0.38 to 0.76). We observed suggestive differential treatment effects for patients with TP53 mut and TMPRSS2:ERG fusion disease. The median estimated overall survival (OS) was 37.3 months (CI, 27.7 to NA) for ARPi compared with 20.2 months (90% CI, 18.4 to 23.0) taxanes within the experimental arms.

Conclusions

ARPi increases PFS and OS both compared to SOC and taxanes in patients with mCRPC. These are directly randomized data for ARPi and taxanes, showing the first evidence of a difference in PFS and OS for these agents in the mCRPC setting.

Clinical trial identification

NCT03903835.

Editorial acknowledgement

Legal entity responsible for the study

Karolinska Institutet.

Funding

Janssen Pharmaceuticals, AstraZeneca.

Disclosure

H. Grönberg: Financial Interests, Personal, Ownership Interest: A3P Biomedical; Financial Interests, Institutional, Funding: AstraZeneca, Janssen; Financial Interests, Personal, Invited Speaker: Janssen, Astellas, Bayer, AstraZeneca. A. Ullén: Financial Interests, Institutional, Funding: Merck KGaA; Financial Interests, Personal, Advisory Role: Merck KGaA, Astellas Pharma. A. Mortezavi: Financial Interests, Institutional, Funding: Janssen; Financial Interests, Personal, Stocks or ownership: STOICH GmbH; Financial Interests, Personal, Advisory Role: Janssen, Myriad; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Other: Janssen. P. Ost: Financial Interests, Institutional, Funding: Varian; Financial Interests, Personal, Advisory Role: AAA, Bayer, Janssen, Novartis. G. Enblad: Financial Interests, Personal, Advisory Role: Gilead, Pierre Fabre. J. Oldenburg: Financial Interests, Personal, Other: Astellas Oncology, AstraZeneca, Name of Entity: Relationship: Delete : Name of Entity: Relationship: Delete : Astellas Oncology You ABayer Germany, Ipsen, BMS Norway, Eisai, Roche, Janssen Oncology, Merck, MSD; Financial Interests, Personal, Advisory Role: Merck, BMS Norway, Bayer Germany, Roche, Janssen, Eisai, AstraZeneca, Astellas Oncology; Financial Interests, Personal, Speaker’s Bureau: Astellas Oncology, Janssen, Bayer. J. Sandzén: Financial Interests, Institutional, Funding: Reassure. M.N. Vigmostad: Financial Interests, Personal, Other: Pfizer, Janssen, Dagens Medisin. M.E. Hjälm-Eriksson: Financial Interests, Personal, Advisory Role: Astellas. M. Eklund: Financial Interests, Personal, Stocks or ownership: A3P Biomedical AB; Financial Interests, Personal, Other: A3P Biomedical AB. All other authors have declared no conflicts of interest.