Real-world data support PSA below 0.2 ng/mL as key response threshold in mCSPC

Achieving a prostate-specific antigen (PSA) level below 0.2 ng/mL within 9 months of initiating androgen deprivation therapy (ADT) was associated with longer overall survival (OS) among patients with metastatic castration-sensitive prostate cancer (mCSPC), according to a retrospective analysis of Veterans Health Administration (VHA) data published in the journal Cancer.¹

The findings, based on 4890 patients treated with ADT with or without additional therapy, builds on prior work linking PSA decline with improved survival and suggests that PSA response may be used to guide treatment de-intensification strategies in this setting.

“These data show that we need to target a PSA below 0.2 ng/ml as our metric of success to optimize outcomes for our patients with metastatic prostate cancer,” said lead author Stephen J. Freedland, MD, professor of urology at Cedars-Sinai Medical Center and staff physician at the Durham VA Medical Center, in a news release on the results.²

PSA response associated with survival outcomes

For the study, investigators evaluated VHA data from patients with mCSPC who initiated ADT, either alone or with other treatments, and had PSA measurements available before and after treatment initiation. The analysis used a 9-month landmark to examine associations between PSA response and subsequent OS using adjusted Cox proportional hazards models.

Of the 4890 patients included, 47% received ADT alone, 40% received ADT plus an androgen receptor pathway inhibitor (ARPI), 7.4% received ADT plus a nonsteroidal antiandrogen, and 5.8% received ADT plus docetaxel with or without an ARPI or nonsteroidal antiandrogen. The median follow-up was 25 months, and the median PSA follow-up was 15 months.

During PSA follow-up, 44% of patients achieved a PSA below 0.2 ng/mL, and 74% experienced a PSA decline of at least 90% from baseline. Patients who achieved a PSA below 0.2 ng/mL within 9 months of treatment initiation had a 54% lower risk of death after the 9-month landmark compared with those who did not reach that threshold (adjusted HR, 0.46; 95% CI, 0.40 to 0.54).

The association remained when the PSA <0.2 ng/mL response was examined according to the magnitude of PSA decline. Among patients who reached a PSA below 0.2 ng/mL, the adjusted HR for death was 0.43 (95% CI, 0.35 to 0.52) among those who also had a PSA decline of at least 90% and 0.36 (95% CI, 0.23 to 0.56) among those with a decline of less than 90%, compared with patients who did not reach a PSA below 0.2 ng/mL.

“In comparison, patients who achieved ≥90% PSA decline but did not reach a PSA of <0.2 ng/mL had OS outcomes on par with patients who had neither a ≥90% PSA decline nor a PSA of <0.2 ng/mL (HR, 0.88; 95% CI, 0.74 to 1.04; P = .13),” the authors noted.

Further, patients who achieved a PSA decline below 0.2 ng/mL within 9 months of treatment initiation also demonstrated a significant reduction in the risk of disease progression vs those who did not. As with OS, this reduction was observed among patients who achieved at least a 90% decline in PSA (HR, 0.50; 95% CI, 0.42 to 0.59; P < .001) and in those who did not (HR, 0.45; 95% CI, 0.32 to 0.62; P < .001).

The analysis also found that patients who received ADT plus an ARPI were more likely to achieve a PSA below 0.2 ng/mL during PSA follow-up than those receiving ADT alone (odds ratio, 2.36; 95% CI, 1.97 to 2.83; P < .001).

Findings build on prior PSA response data

The prognostic importance of a low PSA level after treatment initiation is not new. A landmark analysis of the phase 3 CHAARTED trial (NCT00309985) previously found that patients with mCSPC who reached a PSA level of 0.2 ng/mL or less at 7 months had substantially longer OS than those with PSA levels above 4 ng/mL (P < .001). Median survival was 60.4 months vs 22.2 months, respectively.³

Similarly, analyses from the phase 3 SWOG S1216 study used PSA response categories of 0.2 ng/mL or less, greater than 0.2 to 4 ng/mL, and greater than 4 ng/mL as prognostic measures for patients receiving ADT-based therapy, showing that 3- and 7-month PSA response was strongly associated with OS.⁴ An analysis of the phase 3 TITAN trial further evaluated deeper PSA responses among patients receiving apalutamide plus ADT. In that post hoc analysis, achieving PSA levels of 0.2 ng/mL or less—and particularly levels at or below 0.02 ng/mL—was associated with longer radiographic progression-free survival, OS, and time to castration resistance.⁵

The new VHA analysis extends these observations to a large real-world population.

Based on the results, the investigators suggested that patients who fail to achieve a PSA below 0.2 ng/mL within 9 months could represent a population warranting closer assessment and potentially intensified treatment strategies. They note that several ongoing trials are assessing PSA response–guided treatment de-escalation in mCSPC, including the phase 3 LIBERTAS trial (NCT05884398), the EORTC GUCG 2238 De-Escalate study (NCT05974774), and the phase 2 A-DREAM/Alliance A032101 study (NCT05241860).

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