(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting featured a session on prostate cancer, and a discussant presentation by Dr. Gerhardt Attard titled “Prognosis is in the Blood” discussing the following two abstracts: “A clinical-genetic circulating tumor DNA (ctDNA)-based prognostic model for predicting overall survival in men with metastatic castrate-resistant prostate cancer (mCRPC) treated with potent androgen receptor inhibition (Alliance)” by Dr. Susan Halabi, and “Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore” by Dr. Johann De Bono.
Dr. Attard started his presentation by highlighting several clinical opportunities for ctDNA:
- Prognostication: predict the likely outcome independent of treatment
- Prediction: predict the benefit of treatment A versus treatment B (biomarker-treatment interactions)
- Response assessment: Early indication of treatment benefit based on ctDNA dynamics
- Molecular classification: identify patients harboring a drug target, for example BRCA1/2 alterations for PARP inhibition
- Early detection/risk stratification: requires very high sensitivity for ctDNA detection in PSA-screened populations and validation requires long follow-up
Dr. Attard notes that there is a range of prostate cancer ctDNA abstracts at ASCO 2024, as highlighted in the following figure:
With regards to ctDNA analysis, Dr. Attard notes that despite high detection rates, we are pushing technology to its limit due to (often) low tumor fractions. One word of caution is that we must beware of bespoke assays/computational pipelines performing differently, especially in challenging technical conditions (ie. low tumor fractions). Historical work dating back nearly a decade has shown us that ctDNA is prognostic:
However, there remains several important questions, which may have been answered in the data presented today. 1) How does ctDNA perform in a clinically implementable model including prognostic features? 2) Is ctDNA clinically relevant with recently approved therapies such as LuPSMA? The work presented by Dr. Halabi identified 16 ctDNA genetic factors, with the top predictors of overall survival being: gains in AR and the AR enhancer, MYC, and RSPO2; losses of ZBTB16, PTEN, and MSH6. Time-dependent area under the receiver operating characteristic curves in clinical and clinical genetic models were 0.72 (95% CI 0.72-0.73) and 0.77 (95% CI 0.76-0.77), respectively:
Additionally, Dr. Halabi was able to develop the following three- and four- prognostic risk groups for median overall survival:
Dr. Attard notes that ctDNA features to improve the C-index, thus it is important for us to understand the ctDNA potential and the biology. However, the model needs to be externally validated with modern-day treatment paradigms, such as after androgen receptor pathway inhibitor + ADT treatment in the mHSPC setting, and in LuPSMA trials. The work presented by Dr. de Bono showed that baseline ctDNA fraction is prognostic in PSMAfore:
Additionally, early ctDNA clearance was associated with longer radiographic progression free survival:
Thus, the hypothesis is that ctDNA dynamics/burden after one cycle of treatment is an early marker of treatment inefficacy and could inform treatment change. Dr. Attard notes that in this analysis, there are relatively small numbers and the endpoint is radiographic progression free survival rather than overall survival. It is therefore important to support prospective clinical trials where ctDNA fraction informs treatment continuation and change.
Dr. Attard then discussed a poster presented at ASCO 2024 by Kwan et al. assessing ctDNA fraction in the TheraP clinical trial [1]. ctDNA fraction was prognostic for progression free survival among patients treated with LuPSMA, but was not among patients that were treated with cabazitaxel:
Moreover, undetected ctDNA independently predicted superior progression free survival for LuPSMA versus cabazitaxel (p = 0.035):
Dr. Attard concluded his discussant presentation with the following take-home messages:
- ctDNA testing in important trials captured a significant percentage of (but not all) patients
- These are important contributions to the ctDNA genomic landscape of advanced prostate cancer
- ctDNA dynamics are associated with outcome and can improve accuracy of prediction
- There are different bespoke assays, which limit the inter-trial comparison and future clinical implementation
- The next steps are to:
- Conduct trials of ctDNA biomarkers that will result in treatment change and ultimately improve patient outcomes
- Perform prospective validation with the current management paradigms
Presented by: Gerhardt Attard, MD, PhD, University College London, London, UK
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.
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