Circulating tumor DNA responses to high-dose testosterone injections in CRPC patients.

Abstract

173 Background: Some proportion of men with CRPC have favorable responses to high doses of testosterone (HDT) and some do not. Genomic determinants of these responders and non-responders are poorly understood. Herein ctDNA predictors of response are assessed using a responder/non-responder analysis. Methods: All men with CRPC had been pretreated with abiraterone, enzalutamide, or both. A ctDNA test was obtained prior to high doses of testosterone (administered as a dose of 400 mg IM testosterone cypionate every 3-4 weeks). Guardant 360 was used to analyze ctDNA (with an allelic fraction cut-off of > 0.5%) to ascertain the presence or absence of pathogenic mutations. Lower allelic fractions were not analyzed. Responders had a PSA decline of 50% or more (N = 16), non-responders received at least two doses of testosterone but never had any PSA decline at all (N = 20). All patients were treated at Tulane Cancer Center. Results: AR amplifications were more commonly detected (p = 0.036) pre-treatment in the ctDNA of responders (5/16) as compared to non-responders (1/20). No differences were found in those with common AR mutations; T878A was detected in 2/16 responders and 2/20 non-responders, L702H was detected in 1/16 responders and 2/20 non-responders. No differences were seen with regard to TP53 mutations, 6/20 non-responders and 7/16 responders. Non- AR/non- TP53 mutations were not distinct in the two groups but trended (P = 0.15) toward being more common in non-responders (5/16 in responders versus 11/20 non-responders). Pre- and post- ctDNA analyses were conducted in 5/6 patients for those with AR amplification at baseline. In all 5 of these patients, the degree of AR amplification diminished after testosterone injections. Conclusions: In this analysis of CRPC patients who were responders and non-responders to 400 mg testosterone cypionate q 3-4 weeks (post-abiraterone and/or enzalutamide), only AR amplifications in ctDNA were predictive of response. In all measured patients, the degree of AR amplification in the ctDNA diminished after testosterone injections.