Impact of androgen deprivation therapy (ADT) on circulating tumor DNA (ctDNA) detection in de novo metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Kwan Edmond Michael , Murtha Andrew J , Tu Wilson , Vasquez Rios Carlos , Bernales Cecily Q. , Arviola Shannen Keith , Donnellan Gráinne , Parekh Karan , Annala Matti , Maurice-Dror Corinne , Vandekerkhove Gillian , Chi Kim N. , Wyatt Alexander William 
Published: January 2024

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Background: Plasma ctDNA is detected in most patients with metastatic castration-resistant prostate cancer, enabling minimally invasive tumor genotyping that informs prognosis and therapy decisions. However, most patients with de novo mCSPC will commence ADT before referral for genomic testing, reducing ctDNA fraction (ctDNA%), potentially limiting its clinical utility. Here, we identify clinical predictors of ctDNA%, and assess its association with clinical outcomes in patients with de novo mCSPC. Methods: From a prospective British Columbia biobank, we identified patients with de novo mCSPC that provided blood prior to or within 50 days of ADT commencement. Plasma cell-free DNA and matched white blood cell DNA underwent deep targeted sequencing and ctDNA% was estimated (detection threshold ≥2%) using validated mutation- and copy number-based methods. Associations between clinical factors were related to ctDNA detection using 𝛘2 or Fisher's exact test. Time to castration-resistance (TTCR) and overall survival (OS) were stratified by ctDNA parameters (detected vs not detected, and by ctDNA% groups <2% vs 2-30% vs >30%), and compared using Kaplan-Meier and Cox regression analyses. Results: We examined 188 samples from 179 patients. Median age was 68 years, 87% received treatment intensification, and disease burden was consistent with typical de novo mCSPC (79% high-volume). CtDNA was detected in 66% (29/44) of ADT-naive samples compared to 26% (37/144) of ADT-exposed samples. The strongest predictor of ctDNA detection was duration of ADT exposure. CtDNA reduced over time, most evident >7 days after ADT commencement (1-7 days: 88% detected; 8-14: 31%, 15-50: 15%; p<0.001). Significant associations for ctDNA detection were also observed for abnormal hemoglobin (OR 3.5, p<0.001) and visceral (liver/lung) disease (OR 3.0; p=0.012), but not CHAARTED/LATITUDE criteria, PSA, or Gleason grade group. At a median follow-up of 48 months (mo), detected ctDNA and higher ctDNA% were associated with shorter TTCR irrespective of ADT exposure (ADT-naive: HR 3.6, 95% CI 1.2-11, p=0.02; ADT-exposed: HR 1.9, 95% CI 1.2-3, p=0.01; interaction p= 0.35), with outcomes poorest in the ADT-exposed group with high ctDNA% (median TTCR 32 vs 8.4 mo in <2% and >30% ctDNA groups, respectively). Only ADT-exposed ctDNA detection and ctDNA% were associated with OS (median 58 vs 29 mo in ctDNA– and ctDNA+ groups, respectively; HR 1.9, 95% CI 1.1-3.1, p=0.02). Conclusions: ADT exposure is the strongest predictor of ctDNA non-detection in de novo mCSPC. However, a quarter of patients will have detectable ctDNA despite receiving up to 50 days of ADT, indicating a window for complementing tumor tissue-based genotyping with ctDNA tests. Persistent ctDNA after ADT administration is prognostic and a potential biomarker to identify patients for treatment intensification.