PSA kinetics and predictors of PSA response in metastatic hormone-sensitive prostate cancer treated with androgen receptor signaling inhibitors.

Abstract

Background: PSA response is a key prognostic tool in metastatic hormone-sensitive prostate cancer (mHSPC). Data from SWOG 9346 and TITAN post-hoc analyses demonstrated the prognostic value of PSA thresholds at 6-7 months after androgen deprivation therapy (ADT) or ADT plus apalutamide. However, variability in thresholds and timing highlights the need to explore PSA kinetics in real-world cohorts. This study investigates PSA dynamics and their predictors following Androgen Receptor Signaling Inhibitors (ARSI) initiation.

Methods: This multicenter study included mHSPC patients treated with ADT+ARSI between June 2017 and October 2024. Exclusions included ADT monotherapy, triplet therapy, or ARSI initiation >6 months post-ADT. PSA kinetics were analyzed over 12 months, focusing on SWOG (0.2-4 ng/ml) and TITAN (0.02-0.2 ng/ml) thresholds. Logistic regression and SHAP (SHapley Additive exPlanations) analysis identified predictors of achieving low (<0.2 ng/ml) or ultralow (<0.02 ng/ml) PSA at 6 months.

Results: Among 586 mHSPC patients (median follow-up: 23 months), most had synchronous (58%), low-volume (58%), and ISUP grade 4-5 (64%) disease. At 6 months, 74%, 19%, and 7% achieved PSA <0.2 ng/ml, 0.2-4 ng/ml, and >4 ng/ml (SWOG cutoffs), while 36%, 35%, and 29% achieved PSA <0.02 ng/ml, 0.02-0.2 ng/ml, and >0.2 ng/ml (TITAN cutoffs). Baseline PSA <50 ng/ml and metachronous disease were strong predictors of ultralow PSA.

Conclusion: SWOG and TITAN thresholds offer distinct PSA stratifications, with SWOG grouping more patients into the lowest PSA category and TITAN providing a more balanced distribution. Baseline PSA and metachronous disease are key predictors of favorable PSA responses, emphasizing their importance in guiding management.