Androgen receptor cfDNA longitudinal mutational analysis in metastatic castrate-resistant prostate cancer.

Abstract

197 Background: Androgen receptor (AR) mutations commonly occur in metastatic castrate resistant prostate cancer (mCRPC). Methods: Circulating tumor DNA (ctDNA) data were obtained from Guardant 360 assays throughout the clinical course of mCRPC patients (pts). Retrospective analysis for any pt with ≥ 3 Guardant assays at least 4 weeks apart were reviewed. Patients must have at least 1 AR mutation or amplification to qualify for inclusion. Statistical analyses, including chi-sq and longitudinal analyses, were conducted. Results: Of the 259 patients with Guardant testing, a total of 88 patients had at least 3 Guardant tests; of these, 59 (67%) had at least one AR alteration. Patients had a median of 4 Guardant assays (range 3-10). Patients with AR amplification, AR mutation or both were identified (23, 20, 16 respectively). The most common and clinically relevant AR mutations found alone or in combination with amplification were T878A (22%), L702H(19%), W742C (19%), and H875Y (10%). These particular functional AR mutations occurred alone in 16 patients. Only 3 patients had neither amplification nor common AR mutation. 17/59 patients were found to have at least one common AR mutation and amplification at some point (on same or different Guardant). One patient had seven different AR mutations with no amplification and two other patients had 3 AR mutations. Remainder of patients had either AR amplification or ≤ 2 alternative mutations. Patients with an AR amplification were 0.1138x (95% Cl 0.0289 - 0.4491) significantly less likely of having a common known functional mutation (p <0.002) at any point. Conclusions: Patients with the most frequently identified known functional AR mutations are less likely to have AR amplification in pts with mCRPC; these common AR mutations have been shown to be associated with resistance to 2nd generation androgen deprivation. Further clinical correlation between treatment regimen and %cfDNA of these and other non-AR driver mutations is planned.