Data from Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition

<div>Abstract<p>Biomarkers for more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib in metastatic prostate cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole-exome sequencing of serial circulating cell-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95% CI, 0.06–0.56; <i>P</i> = 0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (χ<sup>2</sup> <i>P</i> < 0.001). At disease progression, following response to olaparib, multiple subclonal aberrations reverting germline and somatic DNA repair mutations (<i>BRCA2, PALB2</i>) back in frame emerged as mechanisms of resistance. These data support the role of liquid biopsies as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancer.</p><p><b>Significance:</b> We report prospectively planned, serial, cfDNA analyses from patients with metastatic prostate cancer treated on an investigator-initiated phase II trial of olaparib. These analyses provide predictive, prognostic, response, and resistance data with “second hit” mutations first detectable at disease progression, suggesting clonal evolution from treatment-selective pressure and platinum resistance. <i>Cancer Discov; 7(9); 1006–17. ©2017 AACR.</i></p><p><i>See related commentary by Domchek, p. 937</i>.</p><p><i>See related article by Kondrashova et al., p. 984</i>.</p><p><i>See related article by Quigley et al., p. 999</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 920</i></p></div>