PEACE-1 ancillary study: Biomarkers predict prognosis but not abiraterone benefit in mCSPC

Certain phenotypic and genomic biomarkers were found to be prognostic for radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with androgen deprivation therapy (ADT) plus abiraterone (Zytiga), according to the first results from an ancillary study of the PEACE-1 trial (NCT01957436) presented at the European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain.¹

Cedric Pobel, MD

However, predictive biomarkers have yet to be established to determine which patients will benefit from the addition of abiraterone acetate/prednisone (AAP).

Overall, data from the PEACE-1 trial demonstrated the benefit of adding AAP to ADT plus docetaxel in patients with de novo mCSPC. The median OS was not reached in the ADT plus docetaxel plus AAP arm, compared with 4.43 years in the ADT plus docetaxel arm (HR, 0.75; 95% CI, 0.59-0.95; P = .017). In total, the trial enrolled 1173 patients who were randomly assigned in a 1:1:1:1 fashion to receive either standard of care (SOC; n = 296), SOC plus abiraterone (n = 292), SOC plus radiotherapy (n = 293), or SOC plus abiraterone plus radiotherapy (n = 292).

The current ancillary study of the PEACE-1 trial sought to identify prognostic and predictive biomarkers associated with rPFS and OS in patients with mCSPC. From the 1172 patients who underwent randomization in PEACE-1, 595 had paraffin-embedded biopsies and were centrally reviewed for the ancillary analysis. Phenotypic and genomic characteristics were similar between cohorts in the full PEACE-1 trial and in the ancillary study.

Of the 595 patients included, 394 underwent immunochemistry (IHC) analysis and 119 underwent genomic analysis with next generation sequencing (NGS).

IHC stained for 10 markers, including luminal components (AR, NKX3.1), neuroendocrine (NE) features (synaptophysin, CD56, chromogranin A), tumor suppressors (p53, Rb, pTEN), Ki67, and ERG.From the IHC analysis, 5 phenotypes were defined based on luminal and NE status. These included AR-high luminal (AR-positive nuclear and NE-negative) AR luminal weak (AR-positive weak nuclear or AR-positive cytoplasmic and NE-negative) amphicrine (AR-positive and NE-positive) double negative (AR-negative and NE-negative) and NEPC (AR-negative and NE-positive).

In total, 150 patients (42.9%) were AR-high luminal, 97 (27.7%) were AR luminal week, 95 (27.1%) were amphicrine, 5 (1.4%) were NEPC, and 3 (0.8%) were double negative.

Overall, data showed that there was no significant difference in rPFS or OS between the 5 phenotypes. However, a trend was seen from better prognosis with AR-high luminal (median OS, 5.7 years) to worse prognosis with NEPC (median OS, 1.1 years), mainly driven by NE status.

In line with this finding, patients with at least 1 NE-positive marker were shown to have a worsened rPFS (HR, 1.38; 95% CI, 1.06-1.81; P = .017) and OS (HR, 1.53; 95% CI, 1.14-2.06; P = .005). Conversely, ERG-positive patients achieved an improved rPFS (HR, 0.71; 95% CI, 0.53-0.94; P = .019).

None of the biomarkers were shown to be predictive of survival benefit with AAP.

Findings from NGS also showed that multiple tumor suppressor gene alterations were associated with worse prognosis. In patients who had less than 2 alterations among the TP53, PTEN, and RB1 genes, the median OS was 5.4 years, compared with 2.2 years among patients with 2 or more alterations among those tumor suppressor genes (HR, 2.63; 95% CI, 1.10-6.30; P = .03).

Lead author Cedric Pobel, MD, of Gustave Roussy, Paris, France, concluded in the presentation at ESMO, “Both AR-positive and neuroendrocrine positive expression is displayed in 25% of mCSPC at baseline and predicts poor prognosis. Alterations in at least 2 tumor suppressor genes among TP53, PTEN, or RB1 also predicts poor prognosis. A predictive biomarker for abiraterone benefits remains to be established in mCSPC patients.”

Reference

1. Pobel C, Bargain C, Scoazec JY, et al. Phenotypic and genomic characterization of de novo metastatic prostate cancer: An ancillary study of the PEACE-1 phase III trial. Presented at: 2024 European Society for Medical Oncology Congress. Barcelona, Spain. September 13-17, 2024. Abstract 1595MO. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2024_abstracts/1595MO.html.pdf