EAU 2021: Are PSA Kinetics and Other Biomarkers Able to Replace per Protocol Biopsies?

(UroToday.com) Dr. Antti Rannikko from Finland reviewed the potential for PSA kinetics and other biomarkers as potential replacements for per protocol prostate biopsies for men on active surveillance.

First, the EAU guidelines recommend

Confirmatory biopsy within 12 to 24 months of diagnosis unless the initial biopsy was based on MRI targeted and systematic biopsy
Repeat biopsies for progression on MRI, DRE, or PSA

Most cohorts have “untriggered” routine biopsies every 1-4 years on top of that.

These biopsies are recommended due to the small ~1-2% risk of true progression vs. much higher risk of sampling error.

However, despite these recommendations, the reality is that repeat biopsies are rarely done in a compliant fashion. Biopsy rate tapers off the further out from diagnosis the patient is.¹ This is due to patient hesitance (discomfort, pain, bleeding, sepsis) and physician reticence (expensive).

He then addressed PSA kinetics as a biomarker to replace prostate biopsy and trigger treatment.

PSA doubling time < 3 years was assessed as a trigger for treatment ² – but was found to not be predictive of unfavorable pathologic outcomes at RP. ~50% of men had favorable pathology.
Study by Cooperberg et al.³ on PSA kinetics (relatively complex calculation based on linear mixed-effect model) was a significant predictor of reclassification – but it was a complex model with no clear threshold.

Ultimately, he concluded that while there are numerous ways to calculate PSA kinetics and they can be used to trigger further tests such as biopsy, none have been shown to predict important patient outcomes sufficient enough to replace a prostate biopsy.

MRI as a biomarker for AS is an important adjunct tool. However, it has not yet reached the mainstream of replacing biopsy altogether, as there are multiple studies demonstrating missed cancer with MRI targeted biopsies alone (indicating that MRI does not identify all cancer) and there remains significant institutional and inter-reader variability.⁴

MRI does assist in better patient selection – there are fewer failures of AS in men who had an MRI guided confirmatory biopsy than men who did not.⁴
MRI during AS also increases probability of GG reclassification and potentially better selection

But ultimately it is not yet possible to replace biopsy with MRI Inman on active surveillance for prostate cancer.

Beyond these several biomarkers have been tested in prostate cancer. These include blood-based (PSA, PHI, 4K score, Sthlm-3), tissue-based (Prolaris, Oncotype Dx, Decipher, PTEN), and urine-based (PCA3, SelectMDx). Most have been tested at diagnosis to help select patients for active surveillance, but have not been utilized during active surveillance.

Current guidelines do not endorse the use of biomarkers as a substitute for follow-up biopsies in active surveillance

While AS protocols can be tailored to individual risk using a compilation of clinical data into an algorithm/tool (as described by Cooperberg et al.⁵), there remains significant unexplained heterogeneity between centers’ progression rates despite accounting for clinical variables.⁶

In conclusion,

PSA kinetics MRI and biomarkers cannot yet replace per protocol biopsies and active surveillance
Due to improved initial risk ratification with contemporary diagnostics, “early” protocol based biopsies less likely important
Due to excellent prognosis of low-risk Pca, all studies have used surrogate endpoints with questionable clinical relevance. None of these studies have used important patient outcomes (MFS, OS)
Effectiveness of AS itself (as opposed to watchful waiting) has yet to be shown for intermediate-risk PCa

But de-escalation and individualization of AS protocols is mandatory to reduce overtreatment.

Presented by: Antti S. Rannikko, University of Helsinki, Helsinki, Finland

Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

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