An exploratory analysis of the TITAN trial investigated the role of early PSA response in predicting treatment efficacy for patients with metastatic hormone-sensitive prostate cancer (mHSPC). The study, focusing on patients treated with ADT with or without apalutamide, found that achieving a PSA level of ≤ 0.2 ng/mL by 6 months (early PSA response) served both as a causal mediator and a predictor of treatment effect from ADT plus apalutamide on overall survival (OS). This was not observed at the 3-month mark, highlighting the importance of the 6-month timeframe. Notably, patients who achieved early PSA response experienced significantly favorable treatment effects with ADT plus apalutamide, while those who did not had poor survival outcomes irrespective of the treatment received. This suggests that early PSA response can be a powerful tool for identifying patients who are most likely to benefit from apalutamide in addition to ADT.
Longer time to PSA response within the first 6 months was associated with improved OS in the ADT plus apalutamide arm, while a shorter time to response, surprisingly, was linked with a worse prognosis. This seemingly paradoxical association could be explained by the rapid ablation of androgen receptors with intensified hormone therapy, leading to prostate cancer dedifferentiation and early emergence of an androgen-resistant phenotype. While the depth of early PSA response was prognostic in the ADT plus apalutamide arm, it was not predictive of treatment effect.
The study also highlights the potential of using early PSA response to guide future clinical trials and treatment strategies. For instance, suboptimal PSA response by 6 months could be used as a selection criterion for trials investigating treatment intensification or novel drugs. Additionally, this information could be valuable in personalizing treatment decisions, such as determining which patients would benefit from triplet therapy with docetaxel. By incorporating early PSA response into clinical practice, clinicians can potentially improve treatment outcomes for mHSPC patients. The authors acknowledge limitations inherent to exploratory analyses, including potential misspecification bias and the need for validation in other trials and real-world populations.

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