PSA Kinetics and Predictors of PSA Response in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Receptor Signaling Inhibitors

It all began with a curve. In 2006, the SWOG 9346 trial led by Hussain et al. delivered a game-changing message in metastatic hormone-sensitive prostate cancer (mHSPC): patients who achieved a PSA <0.2 ng/mL at 7 months after initiating androgen deprivation therapy (ADT) had a median overall survival exceeding 6 years, while those with PSA >4 ng/mL faced a far grimmer outcome. For the first time, depth of PSA response was recognized as a clinical compass—a simple biomarker that powerfully predicted survival.

Hussain et al. SWOG 9346.

Since then, the therapeutic landscape has evolved, and so have the thresholds. The once-standard <0.2 ng/mL has been challenged by newer targets: <0.1 ng/mL in abiraterone-treated cohorts, and the almost-undetectable <0.02 ng/mL “ultralow PSA” derived from TITAN post-hoc analyses with apalutamide. This multiplicity of benchmarks has generated confusion, leaving a key clinical question unanswered:

What is the expected PSA evolution in mHSPC patients treated with ADT + ARPI, and which threshold best predicts outcomes in the modern era?

To our knowledge, no previous study has systematically characterized first-year PSA kinetics in real-world patients receiving ARPI-based intensification. This multicenter study enrolled 586 men with mHSPC treated with ADT + ARPI (apalutamide, abiraterone, or enzalutamide) from 2017 to 2024. PSA was recorded at 3, 6, 9, and 12 months. We applied two historical stratification models:

The classical SWOG model (<0.2 / 0.2–4 / >4 ng/mL)
The TITAN model (<0.02 / 0.02–0.2 / >0.2 ng/mL)

At 6 months:

74% of our cohort achieved PSA <0.2 ng/mL (SWOG)
But only 36% reached an ultralow PSA <0.02 ng/mL (TITAN)

This raised a provocative question: If 60–70% of our patients meet the SWOG threshold, will they also enjoy the same 6-year survival seen in 2006? Or does the ARPI era demand stricter stratification?

Patients achieving <0.02 ng/mL had a non-reached median rPFS

Compared to 38, 24, and 11 months in progressively higher PSA categories (p<0.001). Notably, 20% of initially poor responders (<optimal PSA at 3 months) eventually reached deep responses by 9–12 months, significantly altering their prognosis.

Conclusion

SWOG and TITAN thresholds offer contrasting perspectives on PSA response: while SWOG classifies the majority as good responders, TITAN applies a more demanding and balanced approach. Our study shows that not all PSA declines are created equal, and that features such as low baseline PSA and metachronous disease make a significant difference. In the ARPI era, reaching the right threshold at the right time can redefine a patient’s prognosis.

Written by: Rocío Martínez-Corral,¹ Pedro De Pablos-Rodríguez,² Celia Bardella-Altarriba,³ Francisco Javier Vera-Ballesteros,⁴ Arnau Abella-Serra,⁵ Victor Rodríguez-Part,² María Elena Martínez-Corral,¹ Natalia Picola-Brau,³ Alicia López-Abad,⁴ Álvaro Gómez-Ferrer,² Manuel Beamud-Cortés,² José Francisco Suárez-Novo,³ Pedro Ángel López-González,⁴ Mireia García-Puche,⁵ Ana María Álvarez-Gracia,⁶ Daniel Pérez-Fentes¹

Department of Urology, Complejo Hospitalario Universitario de Santiago de Compostela, University of Santiago de Compostela, Spain.
Department of Urology, Instituto Valenciano de Oncología, Valencia, Spain.
Department of Urology, Hospital de Bellvitge, Barcelona, Spain.
Department of Urology, Hospital Virgen de la Arrixaca, Murcia, Spain.
Department of Urology, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.
Department of Radiation Oncology, Institut Català de Oncologia, Barcelona, Spain.

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