Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naive metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies.
We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes.
Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4-weeks of first-line ARPI treatment during two prospective multi-centre observational studies (NCT02426333;NCT02471469). CtDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy number profiles. Samples were classified into detected vs. undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Non-durable treatment response was defined as PFS ≤ 6 months.
CtDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. CtDNA fraction for samples with detected ctDNA was lower at 4-weeks vs. baseline (median 5.0% vs. 14.5%, P=0.017). PFS and OS was shortest for patients with persistent ctDNA at 4 weeks (univariate hazard ratio 4.79 (95%CI, 2.62-8.77) and 5.49 (95%CI, 2.76-10.91), respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4-weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. CtDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying non-durable responses.
Early changes in ctDNA% are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Mar 30 [Epub ahead of print]
Sofie H Tolmeijer, Emmy Boerrigter, Takayuki Sumiyoshi, Edmond M Kwan, Sarah Ng, Matti Annala, Grainne Donnellan, Cameron Herberts, Guillemette E Benoist, Paul Hamberg, Diederik M Somford, Inge M van Oort, Jack A Schalken, Niven Mehra, Nielka P van Erp, Alexander W Wyatt
Radboud University Nijmegen, Nijmegen, Netherlands., Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands., Kyoto University, Kyoto, Japan., Vancouver Prostate Centre, Vancouver, BC, Canada., Vancouver Prostate Centre, Vancouver, Canada., Tampere University and Tays Cancer Centre, Tampere, Finland., University of British Columbia, Vancouver, British Columbia, Canada., Deventer Hospital, Deventer, Netherlands., Franciscus Gasthuis, Rotterdam, Netherlands., Canisius-Wilhelmina Ziekenhuis, Nijmegen, Netherlands.