There are many treatment intensification strategies for advanced prostate cancer, the majority of which are guided by disease risk biology, as well as age and performance status. Increasingly, molecular factors are helping guide treatment, including TP53/RB1/PTEN loss, SPOP, MSI-H/CDK12/ARID1A, BRCA1/2, ATM/ATR, genomic instability, methylation status, and PD-L1+ status.
Dr. Wise started by discussing Abstract 5506 “Baseline circulating tumor cell (CTC) count as a prognostic marker of PSA response and progression in metastatic castrate sensitive prostate cancer (mCSPC).” Indeed, CTC number is a validated biomarker for overall survival in mCRPC, and baseline CTC correlates with PSA response in smaller studies. But whether baseline CTC predicts better response to treatment in a larger study has not been determined until the current study. SWOG S1216 found that CTC count at the start of treatment for mCSPC was highly prognostic of a 7-month PSA response (intermediate endpoint for OS) and of PFS at 2 years. According to Dr. Wise, the take-home points from this study are that baseline CTCs correlate with outcomes in a large prospective study, and these results show promise for identifying a “high-risk” cohort (CTC count of 5 or more) of men. The next steps after this study are to (i) validate the CTC cut points, (ii) correlate with the primary endpoint of TAK-700 benefit, and (iii) qualify the biomarker to demonstrate clinical utility.
The second study Dr. Wise discussed was Abstract 5508 “Circulating tumor DNA (ctDNA) Dynamics Associate with Treatment Response and Radiological Progression-Free Survival (rPFS). This study looked at the abundance of ctDNA relative to total cell-free DNA (cfDNA). The primary finding was that patients who remained ctDNA negative had the best radiographic PFS, followed by patients experiencing a reduction in ctDNA; higher post-treatment ctDNA significantly correlated with worse radiographic PFS (ctDNA increase vs always ctDNA negative: HR 2.89, 95% CI 1.74-4.78). Dr. Wise notes that a circulating assay for PTEN loss is needed given that PTEN expression is heterogeneous in primary prostate cancer, and PTEN alteration are the dominant mechanism of PI3K/AKT activation in mCRPC. Dr. Wise’s take-home point is that this study shows an impressive signal for ctDNA as a baseline prognostic factor and early on-treatment response indicator. The next steps include (i) validating “positive” and “negative” ctDNA cut points and (ii) investigating copy number variants in ctDNA, which has implications for PTEN.
The final study Dr. Wise discussed was abstract 5507 “The comprehensive methylation landscape of metastatic castration-resistant prostate cancer (mCRPC) identifies new phenotypic subtypes”. This study found that hypermethylation clusters are enriched for somatic mutations, especially DNMT3B and TET2. Dr. Wise suggests that identifying hypermethylated regions (cluster 3 + CMP) can be translated to a circulating biomarker whereby there is emerging data suggesting that plasma DNA methylation profiles are feasible for diagnosing and monitoring human diseases.1 Dr. Wise’s take-home points for this study are that methylation profiles correlate with clinical outcomes, but the question remains if these subtypes will translate to precision therapy. As follows are several ongoing trials highlighted by Dr. Wise utilizing methylation status:
Presented by: David R. Wise, MD, PhD, Department of Urology, NYU Langone's Perlmutter Cancer Center, New York, NY
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.
- Moss J, Magenheim J, Neiman D, et al. Comprehensive Human Cell-Type Methylation Atlas Reveals Origins of Circulating Cell-Fre DNA in Health and Disease. Nat Commun 2018 Nov 29;9(1):5068.