How Low Does PSA Need to Go? New VA Data Point to a Tenfold Stricter Target in Advanced Prostate Cancer

A new retrospective analysis of nearly 4,900 Veterans Health Administration patients has found that the prostate-specific antigen (PSA) threshold most closely tied to survival in metastatic castration-sensitive prostate cancer is roughly ten times lower than the target many physicians report using in practice. The study, led by investigators at Cedars-Sinai and published in Cancer, suggests that the difference between a partial and a complete PSA response is not a matter of degree but a matter of outcome.

Key Takeaways

• Among 4,890 VA patients with metastatic castration-sensitive prostate cancer (mCSPC), those who reached a PSA below 0.2 ng/mL within 9 months of starting androgen deprivation therapy (ADT) had a 54% lower risk of death than those who did not [1].
• A 90% or greater PSA decline alone, without dropping below 0.2 ng/mL, was not associated with improved survival or delayed disease progression [1].
• Adding an androgen receptor pathway inhibitor (ARPI) to ADT more than doubled the odds of reaching the 0.2 ng/mL threshold compared with ADT alone [1].

A Real-World Test of a Trial-Derived Threshold

PSA has served as a working proxy for treatment response in prostate cancer since long before molecular subtyping and imaging-based staging became routine, and its behavior under androgen suppression is well characterized: levels fall sharply once testosterone-driven signaling to the tumor is cut off [2]. What has been less settled is exactly how far PSA needs to fall, and by which measure, before that decline can be trusted as a marker of a favorable disease trajectory rather than simply a partial response.

Several phase 3 trials in mCSPC, including ARCHES (ClinicalTrials.gov identifier NCT02677896) [3], ARANOTE (NCT04736199) [4], ARASENS (NCT02799602) [5], LATITUDE (NCT01715285) [6], and TITAN (NCT02489318) [7], have each reported that reaching an undetectable or near-undetectable PSA nadir, generally defined as below 0.2 ng/mL, correlates with reduced risk of progression to castration-resistant disease, radiographic progression, and death. Those associations, however, come from clinical trial populations that skew toward higher-volume, de novo disease and are not necessarily representative of the more heterogeneous patients seen in day-to-day oncology and urology practice. A physician survey published in 2024 found that most clinicians treating mCSPC rely on percentage PSA decline rather than an absolute nadir to judge treatment success, with a median target decline of only 50% [8]. Among clinicians who do use an absolute PSA value, the study authors report, the typical target is a full order of magnitude higher than the level the trial literature has flagged as optimal.

That gap between what trials suggest and what practice reports using is the specific question this new VA analysis was designed to test in a broad, real-world cohort.

Study Design: Two PSA Metrics, Landmarked at Nine Months

The investigators used the VHA Corporate Data Warehouse to identify adult patients diagnosed with mCSPC between 2018 and 2023 who initiated ADT, with or without additional systemic therapy, and had documented PSA values at baseline and during follow-up while on their initial treatment [1]. Patients with any prior evidence of castration resistance, prior ARPI or docetaxel use, or prior definitive local therapy combined with long-term ADT were excluded, in an effort to isolate a genuine first-line mCSPC population.

Two PSA-response definitions were compared: a decline of 90% or more from baseline, and an absolute PSA below 0.2 ng/mL, both assessed within 9 months of starting treatment. The 9-month landmark was chosen to align roughly with the 6-to-7-month assessment windows used in trials such as ENZAMET and TITAN, while accounting for the somewhat less frequent PSA testing typical of routine VA care [1]. From that landmark forward, the study measured overall survival and a composite disease progression endpoint encompassing PSA progression, treatment change, castration resistance, or death, using Cox regression models adjusted for age, race, region, comorbidity burden, metastatic site, and other baseline characteristics.

Of the 4,890 patients included, 47% received ADT alone, 40% received ADT plus an ARPI (with or without a first-generation antiandrogen), and the remainder received other combinations, including docetaxel-containing regimens [1]. Median age was 74 years, and median baseline PSA was 27 ng/mL, reflecting a real-world population with substantial disease and comorbidity heterogeneity compared with the more selected patients enrolled in registration trials [1].

A Ten-Fold Gap Between ‘Good’ and ‘Optimal‘

The results draw a sharp line between the two response definitions. Overall, 44% of patients reached a PSA below 0.2 ng/mL within 9 months, while 74% achieved a 90% or greater decline from baseline [1]. Patients who reached the lower absolute threshold had a substantially reduced risk of death (adjusted hazard ratio 0.46, 95% CI 0.40–0.54) and of disease progression (adjusted HR 0.45, 95% CI 0.40–0.50) compared with those who did not [1]. Median overall survival was not reached in the group that achieved that nadir, versus 37 months in those who did not [1].

The picture for the percentage-based metric was markedly different. Achieving a 90% or greater PSA decline was associated with only a modest survival benefit (adjusted HR 0.78, 95% CI 0.66–0.91) and showed no significant association with disease progression at all (HR 0.93, 95% CI 0.81–1.06; p=0.28) [1]. When the two metrics were examined together, the pattern became clearer still: patients who reached the 0.2 ng/mL threshold benefited whether or not they had also achieved a 90% decline, while patients who reached a 90% decline but stayed above 0.2 ng/mL had outcomes statistically indistinguishable from patients who met neither target (HR 0.88, 95% CI 0.74–1.04; p=0.13) [1]. Three-year survival illustrated the same divide: 78% to 83% among patients who reached the absolute PSA nadir, compared with 48% to 51% among those who did not, regardless of their percentage decline [1].

The study’s authors describe this as evidence that percentage decline, however dramatic, is not an adequate substitute for an absolute PSA target, and that patients whose PSA falls by 90% but plateaus above 0.2 ng/mL should not be regarded as having achieved an optimal response.

Treatment Intensification Changed Who Reached the Target

The analysis also examined which initial treatment strategies were most likely to get patients to the lower PSA threshold. Patients started on ADT plus an ARPI were significantly more likely to reach a PSA below 0.2 ng/mL within 9 months than those on ADT alone (53% versus 41%; adjusted odds ratio 2.36, 95% CI 1.97–2.83) and reached that nadir considerably faster (median 9 months versus 20 months; HR 1.71, 95% CI 1.55–1.88) [1]. Even so, nearly half of ARPI-treated patients did not reach the target within that window, a finding the authors interpret as evidence that a meaningful subset of real-world mCSPC patients may need still more aggressive treatment, potentially including triplet regimens combining ADT, an ARPI, and docetaxel, an approach already being tested prospectively in patients with a suboptimal PSA response in the ongoing TRIPLE-SWITCH trial (NCT06592924) [1].

Where the Gap Between Trial Data and Practice May Matter Most

The authors point to a specific and testable explanation for why real-world PSA targets have historically run higher than what the data now support: patients whose PSA falls under 2 ng/mL on ADT alone may appear, by an older and less stringent standard, to be responding well enough that clinicians do not pursue treatment intensification. If the 0.2 ng/mL threshold identified in this analysis is the more clinically meaningful one, then a substantial number of patients currently managed with ADT alone, on the basis of a PSA decline that looks satisfactory by percentage or by a higher absolute cutoff, may be undertreated relative to what the data suggest they could achieve.

The authors frame this as a case for using the PSA nadir observed within 9 months of starting treatment as a decision point: those who cross below 0.2 ng/mL might reasonably be considered candidates for the treatment de-intensification strategies now being tested in trials such as LIBERTAS (NCT05884398), the EORTC GUCG 2238 De-Escalate study (NCT05974774), and A-DREAM/Alliance A032101 (NCT05241860), while those who do not may be better candidates for earlier treatment intensification [1].

Study Limitations

The authors are explicit about the constraints of a retrospective, single-system analysis. The VA data set lacked information on tumor grade and disease volume, both established prognostic factors that could not be adjusted for. Administrative coding for mCSPC carries inherent inaccuracy, testosterone levels were not routinely available to confirm castration sensitivity, and PSA assessment intervals varied across patients rather than following a fixed trial schedule. The findings also come from a predominantly male, VA-enrolled population that may not generalize fully to broader community oncology settings. The authors note these constraints directly and describe the study as hypothesis-supporting rather than practice-mandating, calling for further real-world evaluation across age and comorbidity subgroups.

What Remains Unanswered

The study does not establish that pursuing a stricter PSA target would, if applied prospectively, improve outcomes; it demonstrates an association between reaching that nadir and better survival in patients whose treatment course was determined by their own physicians under real-world conditions, not by a PSA-guided protocol. Whether systematically intensifying treatment for patients who fail to reach 0.2 ng/mL would translate into improved survival is the question the ongoing prospective and pragmatic trials cited above, including TRIPLE-SWITCH, LIBERTAS, and the EORTC De-Escalate study, are designed to address directly.

Clinical Trials

• A Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC) (ARCHES) – ClinicalTrials.gov ID NCT02677896
• Darolutamide in Addition to ADT Versus ADT in Metastatic Hormone-sensitive Prostate Cancer (ARANOTE) – ClinicalTrials.gov ID NCT04736199Darolutamide in Addition to Standard Androgen Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer (ARASENS) – ClinicalTrials.gov ID NCT02799602
• A Study of Abiraterone Acetate Plus Low-Dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Participants With High-Risk, Metastatic Hormone-Naive Prostate Cancer (mHNPC) – ClinicalTrials.gov ID NCT01715285
• A Study of Apalutamide (JNJ-56021927, ARN-509) Plus Androgen Deprivation Therapy (ADT) Versus ADT in Participants With mHSPC (TITAN)
  – ClinicalTrials.gov ID NCT02489318

References

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[2] Cleutjens KB, van der Korput HA, van Eekelen CC, van Rooij HC, Faber PW, Trapman J. An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter. Mol Endocrinol. 1997 Feb;11(2):148-61. doi: 10.1210/mend.11.2.9883. PMID: 9013762.

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[4] Saad F, Briganti A, Haresh KP, Vjaters E, Olmos D, Littleton N, Testa I, Srinivasan S, Verholen F, Shore N. A Deep Prostate-specific Antigen Response to Darolutamide plus Androgen Deprivation Therapy Is Associated with Better Clinical Outcomes in the Phase 3 ARANOTE Trial in Patients with Metastatic Hormone-sensitive Prostate Cancer. Eur Urol Oncol. 2025 Oct;8(5):1321-1332. doi: 10.1016/j.euo.2025.06.010. Epub 2025 Aug 22. PMID: 40846621.

[5] Saad F, Hussain MHA, Tombal B, Fizazi K, Sternberg CN, Crawford ED, Nordquist LT, Bögemann M, Tutrone R, Shore ND, Belkoff L, Fralich T, Jhaveri J, Srinivasan S, Li R, Verholen F, Kuss I, Smith MR. Deep and Durable Prostate-specific Antigen Response to Darolutamide with Androgen Deprivation Therapy and Docetaxel, and Association with Clinical Outcomes for Patients with High- or Low-volume Metastatic Hormone-sensitive Prostate Cancer: Analyses of the Randomized Phase 3 ARASENS Study. Eur Urol. 2024 Oct;86(4):329-339. doi: 10.1016/j.eururo.2024.03.036. Epub 2024 Apr 21. PMID: 38644146.

[6] Matsubara N, Chi KN, Özgüroğlu M, Rodriguez-Antolin A, Feyerabend S, Fein L, Alekseev BY, Sulur G, Protheroe A, Li S, Mundle S, De Porre P, Tran N, Fizazi K. Correlation of Prostate-specific Antigen Kinetics with Overall Survival and Radiological Progression-free Survival in Metastatic Castration-sensitive Prostate Cancer Treated with Abiraterone Acetate plus Prednisone or Placebos Added to Androgen Deprivation Therapy: Post Hoc Analysis of Phase 3 LATITUDE Study. Eur Urol. 2020 Apr;77(4):494-500. doi: 10.1016/j.eururo.2019.11.021. Epub 2019 Dec 13. PMID: 31843335.

[7] Chowdhury S, Bjartell A, Agarwal N, Chung BH, Given RW, Pereira de Santana Gomes AJ, Merseburger AS, Özgüroğlu M, Juárez Soto Á, Uemura H, Ye D, Brookman-May SD, Londhe A, Bhaumik A, Mundle SD, Larsen JS, McCarthy SA, Chi KN. Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer. Ann Oncol. 2023 May;34(5):477-485. doi: 10.1016/j.annonc.2023.02.009. Epub 2023 Feb 27. PMID: 36858151.

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This article is intended for informational purposes for healthcare professionals and does not constitute medical advice. The study discussed is a retrospective real-world analysis and does not establish that prospectively targeting a lower PSA threshold improves outcomes; findings should be interpreted alongside ongoing prospective trials referenced above.

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