Background:
Docetaxel (Doce) is effective for metastatic (M1) PC but its effect is varied. Combining Doce and hormone therapy can improve overall survival (OS) but is not appropriate for all. We previously reported the mRNA Decipher test predicts benefit from Doce. We then used transcriptome-wide data to interrogate differential associations with outcome for biologically-relevant pathways.
Methods:
PTEN inactivation using a previously described signature (Liu et al JCI, 2021; active score <= 0.3, inactive: score > 0.3) and Decipher score (high > 0.8, lower <= 0.8) was determined from transcriptome-wide expression data generated in a clinically-accredited lab on prostate tumor from M1 patients (pts) randomized 1:1 to ADT vs ADT + Doce +/- zoledronic acid (ZA) or ADT vs ADT + Abi (abiraterone acetate + prednisone) in the STAMPEDE protocol (Oct 2005-Jan 2014). Cox survival models were fitted with an interaction between treatment allocation and PTEN activity, adjusted for age, WHO PS, pre-ADT PSA, Gleason score, T-stage, N stage (N0, N1), metastatic volume (CHAARTED definition, high [HV] or low [LV]). Hypotheses were tested using partial likelihood ratios. Primary endpoint was OS.
Results:
We generated transcriptome-wide profiles on 832 M1 pts with no notable differences from the full M1 trial cohort (N=2224). 657 (79%) were reported to have died. 50% of tumors were classified as PTEN inactive (N=419). PTEN mRNA score distribution was similar across HV and LV disease (p=0.310). PTEN inactivity associated with shorter OS in pts allocated ADT+Abi (N=182; HR=1.56, 95%CI: 1.06-2.31) but not in pts allocated ADT+Doce+/-ZA (N=279; HR=0.93, 95%CI: 0.70-1.24). We found strong evidence (p=0.002) of an interaction between PTEN inactivation and Doce sensitivity: PTEN inactive pts benefited from Doce (HR=0.57, 95% CI 0.42-0.76) unlike PTEN active pts (HR=1.05, 95% CI 0.77-1.43). This was consistent in LV (N=244; PTEN inactive HR=0.53, 95% CI 0.33-0.86; PTEN active HR=0.82, 95% CI 0.48-1.40) and HV (N=295; PTEN inactive, HR=0.59, 95% CI 0.39-0.88; PTEN active HR=1.23, 95% CI: 0.83-1.81). In pts randomized to Abi, treatment effect was uniform (PTEN inactive HR=0.52, 95% CI 0.36-0.73; PTEN active HR=0.55, 95% CI 0.39-0.77; p=0.784). We estimated adding Doce for tumors classified as PTEN inactive and high Decipher reduced the hazards of death by 45% (HR 0.55, 99% CI 0.34-0.89).
Conclusions:
Prostate tumors classified as high Decipher and PTEN inactive have a 45% reduction in hazard of death when Doce is added to ADT. This biomarker should be tested in pts considered for triplet therapy of ADT + Abi + Doce.