PSA response to predict progression in metastatic hormone-sensitive prostate cancer (mHSPC) patients. When is the...

The combination of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) has transformed the treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC), becoming one of the most widely used standard treatment options. The depth of PSA declines following initiation of ADT plus ARPI-typically defined as a PSA ≤0.2 ng/ml-has shown promise as a reliable prognostic marker for risk stratification in mHSPC patients. This study aimed to identify the most informative time point for PSA response to predict disease progression.

Retrospective multicenter study of mHSPC patients treated with ADT+ARPI between June 2017 and October 2024, registered in a real-world clinical database. Patients receiving ADT monotherapy, triplet therapy or initiating ARPI more than 6 months after starting ADT were excluded. The primary objective was to assess the predictive value of PSA response at 3, 6, and 9 months for disease progression within 18 months of treatment initiation. Predictive performance was evaluated using discriminant analysis. Groups were defined based on time cut-offs. Patients were classified as biochemical complete response (BCR, PSA ≤0.2 ng/ml) or nonresponse (PSA >0.2 ng/ml) at each time point. Secondary objectives included comparing progression-free survival (PFS) between BCR and NR groups at 6 and 9 months and identifying clinical predictors of progression.

A total of 599 mHSPC patients were included, with a median follow-up of 24 months. Median age at diagnosis was 72 years, and median baseline PSA was 20 ng/ml. BCR rates at 3, 6, and 9 months were 48%, 60%, and 53%, respectively. PSA response demonstrated strong predictive accuracy for progression at 18 months, with the 9-month cutoff showing the highest discriminative ability (AUC = 0.87). The negative predictive value (NPV) was high across all time points (0.92, 0.95, and 0.97), while the positive predictive value (PPV) remained limited (0.44, 0.38, and 0.38). Kaplan-Meier analysis showed significantly longer PFS in BCR versus NR groups at both 6 and 9 months (p < 0.0001). Multivariable analysis identified NR status and high-volume disease as independent predictors of progression.

PSA response at 9 months was the most accurate time point for identifying patients unlikely to experience progression at 18 months. Its high negative predictive value (NPV) supports its potential role in risk stratification, while the limited positive predictive value highlights the need for additional markers to better guide treatment decisions.