Prevalence of Potential Candidates for Targeted Therapies According to Treatment-related Transcriptomic Signatures Among 140 548 Patients with Nonmetastatic Prostate Cancer.

Abstract

Background and objective: Systemic therapies that have shown a benefit in advanced prostate cancer are being evaluated in earlier disease stages. We sought to determine the prevalence of transcriptomic changes in signatures related to treatment susceptibilities in patients with nonmetastatic prostate cancer.

Methods: Patients with nonmetastatic prostate cancer with Decipher genomic classifier and whole-transcriptome profiling data for biopsy specimens from October 2016 to February 2024 were included (n = 140 548). Predefined treatment-related signatures of androgen receptor activity (AR-A), PTEN loss, homologous recombination deficiency (HRD), RB loss, immune activity, and prostate-specific membrane antigen (PSMA; FOLH1) expression, along with Decipher scores and prostate cancer subtypes, were assessed.

Key findings and limitations: The prevalence of low AR-A scores and the basal subtype, which are associated with lower responsiveness to androgen deprivation therapy (ADT), increased with American Joint Committee on Cancer (AJCC) stage and Decipher genomic risk. The prevalence of cancers with a potential response to PI3K inhibitors, according to PTEN loss, and a response to PARP inhibitors, according to HRD status, also increased with AJCC stage and Decipher genomic risk score (all p < 0.001). The prevalence of high PSMA expression was greater in AJCC grade IIC-IIIC disease, so these patients would be potential candidates for PSMA radioligand therapies. More than 60% of patients with AJCC grade IIC-IIIC disease and very high Decipher scores (>0.85) are potential candidates for targeted therapies.

Conclusions and clinical implications: Treatment-related signature scores vary by AJCC stage and Decipher score and may be useful in guiding trials and selecting targeted therapies for nonmetastatic prostate cancer. Higher-stage prostate cancers appear to be more basal and androgen-independent, and thus may be more susceptible to intensified ADT + androgen receptor pathway inhibitors or therapies targeting PARP or PSMA.