Androgen axis modulators, PARP inhibitors, and PSMA theranostics have all been demonstrated to increase overall survival in men with metastatic castrate-resistant prostate cancer. Clinically localized prostate cancer is one of the earliest disease phases when these and other therapies are tested. The therapeutic index and pharmacological impact become more noticeable when relocated earlier in the illness course. Because these treatments are molecularly based, patient subgroups with better oncological outcomes may be identified by cancer’s genetic fingerprints.

For a study, researchers looked for recognized signs of androgen receptor activity (AR-A), PTEN loss, homologous repair insufficiency, RB loss, immunological activity, and PSMA expression in the transcriptomes of 52,217 males with non-metastatic hormone-sensitive prostate cancer. They analyzed signature readouts across prostate cancer risk groups from the NCCN and EAU.

When it came to disease risk/stage, the median AR-A was greatest in individuals with highly low-risk prostate cancer and gradually declined after that (P<0.001). On the other hand, some markers indicating the loss of PTEN, a defect in homologous recombination, immunological activity, and PSMA expression all increased with the likelihood of illness (all P<0.001). Men eligible for active monitoring and those with unfavorable intermediate disease or more had approximately identical PTEN loss rates and homologous recombination deficit rates (7.5% vs. 15.3% and 32.2% vs. 59.7%, respectively, both P<0.001). RB loss rates for males with very high-risk diseases upon diagnosis increased, although they remained modest at 6.3%.

Agents that affect the androgen axis may be best suited for favorable risk disease when considering novel targeted therapeutics for localized prostate and cancer. In contrast, agents that target DNA damage repair deficient tumors, the PI3K/AKT pathway, and PSMA targeted agents are better suited for exploration in higher-risk patients.