Paradoxical PSA Association With Mortality After Radical Prostatectomy — In men with PSA persistence, higher pre-op PSA tied to lower mortality, suggesting overtreatment, MedPage Today, by Charles Bankhead, Senior Editor, MedPage Today, March 14, 2025
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Key Takeaways:
Among men with PSA persistence after radical prostatectomy, a higher preoperative PSA surprisingly was linked to lower mortality.
Men with PSA persistence and preoperative PSA >20 ng/mL had 31% lower all-cause and 59% lower cancer-specific mortality.
Findings suggest potential for overtreatment and need to reconsider post-surgery PSA testing guidelines.
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Among men who had persistent prostate-specific antigen (PSA) after radical prostatectomy (RP), a higher preoperative PSA appeared prognostic for lower mortality risk, a large retrospective cohort study showed.
Counterintuitively, men with pre-RP levels >20 ng/mL had a 31% lower risk of all-cause mortality (ACM) and a 59% lower risk of prostate cancer-specific mortality (PCSM) over a median follow-up of more than 6 years, as compared with lower preoperative PSA levels. The result persisted after adjustment for multiple factors.
The more favorable outcomes in men with preoperative PSA >20 ng/mL could represent a higher proportion of patients who could have reached undetectable post-RP PSA levels with longer follow-up, reported Anthony V. D'Amico, MD, PhD, of Brigham and Women's Hospital and Dana-Farber Cancer Institute in Boston, and coauthors in JAMA Oncology.
Notably, the median time to salvage radiotherapy and/or androgen deprivation therapy (ADT) was less than the median time to undetectable PSA (2.96 vs 3.37 months), the authors added. The findings suggest a potential for overtreatment and warrant reconsideration of current clinical guideline recommendations for post-RP PSA testing.
"According to the American Urological Association, you should get a PSA in the 6- to 8-week window [after prostatectomy]," D'Amico told MedPage Today. "That's been convention and it's just been accepted, one of those things that got grandfathered in without any proof from studying it formally."
"What we learned is that if you check the first PSA within the first couple of months, you will find that many people, especially those whose preoperative PSA was greater than 20, actually take longer to clear the PSA compared to those who have lower preoperative PSAs," he continued. "That stands to reason because clearance of PSA from the bloodstream is on a fixed interval, and the higher your PSA before surgery, the longer it takes to clear."
The investigators did not expect to find that men who had a higher preoperative PSA, and persistently detectable PSA after surgery, would have better survival.
"How could that be?" said D'Amico. "How can someone with a pre-op PSA of 50 do better than somebody with a pre-op PSA of 15? The only way that could happen is if that guy with the pre-op PSA of 50 was called persistent when he really was on his way to becoming undetectable. As a result, he got overtreated."
PSA testing should be repeated 3 months after surgery, he continued. If the PSA is detectable but still decreasing, repeat PSA testing at 4 months.
"You can see that the people who were observed and not treated, if they had a pre-op PSA over 20, the average time to undetectable was three and a half months," said D'Amico. "That was the average. Some took longer, some took a little shorter."
The findings came from an analysis of 43,000 men with localized prostate cancer treated by RP. More than 30,000 patients were treated from 1992 to 2020 at University Hospital Hamburg-Eppendorf in Germany and represented the study cohort. The remaining 12,000-plus men were treated from 1990 to 2017 at Johns Hopkins Medical Institutions in Baltimore and served as a validation cohort.
The study participants were followed through November 2023. During follow-up, patients typically had PSA tests every 2 to 3 months after RP for the first year, and then every 6 months for another 4 years. The primary objective was to determine the time necessary for accurate documentation of persistent PSA following RP.
The data showed that 1,418 (4.7%) patients in the study cohort had persistent PSA (≥0.10 ng/mL) at a median 2.17 months after RP. In the validation cohort, 320 (2.5%) patients had persistent PSA, and 850 (6.6%) died after a median follow-up of 5 years.
Significantly more patients with persistent PSA at first post-RP assessment had preoperative PSA levels >20 ng/mL (14% vs 3.6% for ≤20 ng/mL, P20 ng/mL.
Men with preoperative PSA >20 ng/mL more often had salvage RT and/or ADT (54.7% vs 34.8%), and the salvage therapy started sooner (2.68 vs 3.30 months after RP). The median time to treatment was shorter as compared with median time to undetectable PSA in patients followed for at least 6 months (2.96 vs 3.37 months).
In the study cohort, 2,310 patients died during a median follow-up of 6.3 years, and prostate cancer accounted for 454 (19.7%) of the deaths. Overall, persistently detectable PSA after radical prostatectomy was associated with worse prognosis.
Data analysis revealed a significant interaction between post-RP PSA persistence and preoperative PSA levels >20 versus ≤20 ng/mL, resulting in statistically significant reductions in the ACM hazard (HR 0.69, 95% CI 0.51-0.91, P=0.01) and the PCSM hazard (HR 0.41, 95% CI 0.25-0.66, P<0.001). No significant interaction existed for patients with undetectable post-RP PSA.
After multiple adjustments, estimated ACM and PCSM remained lower in the patients with persistent post-RP PSA and preoperative PSA >20 ng/mL. The 8-year estimated ACM was 12.15% for the >20 ng/mL subgroup versus 15.84% for the ≤20 ng/mL subgroup. The 8-year estimated PCSM was 4.33% versus 8.32%, respectively.
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Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow
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Disclosures:
D'Amico reported no relevant relationships with industry. A co-author reported relationships with Amgen, Apogepha, AstraZeneca, Astellas, A3P Biomedical, Bayer, Exact Sciences, Johnson & Johnson, Ipsen, Novartis, Pfizer, Roche, Veracyte, and Takeda.
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Primary Source: JAMA Oncology
Source Reference: Tilki D, et al "Persistent prostate-specific antigen following radical prostatectomy for prostate cancer and mortality risk" JAMA Oncol 2025; DOI: 10.1001/jamaoncol.2025.0110.
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