METHODS: Patients with newly diagnosed, biopsy-confirmed localized prostatic
adenocarcinoma will be recruited.
Flutamide, an oral non-steroidal
androgen receptor ligand, will be administered orally 6-12 h prior to prostate biopsy (performed under
anesthesia prior to
brachytherapy seed implantation). Key study parameters will include the assessment of
DNA double-strand breaks by γH2A.x foci and AR localization to the nucleus. The initial 6 patients will be treated in a single-arm run-in phase to assess futility by establishing whether at least 2 subjects from this group develop γH2A.x foci in
prostate cancer cells. If this criterion is met, the study will advance to a two-arm, randomized controlled phase in which 24 participants will be randomized 2:1 to either
flutamide intervention or placebo standard-of-care (with all patients receiving definitive
brachytherapy). The key pharmacodynamic endpoint will be to assess whether the extent of γH2A.x foci (proportion of
cancer cells positive and number of foci per
cancer cell) is greater in patients receiving
flutamide versus placebo. Secondary outcomes of this study include an optional, exploratory analysis that will (a) describe
cancer-specific methylation patterns of
cell-free DNA in plasma and urine and (b) assess the utility of serum and urine samples as
a DNA-based
biomarker for tracking therapeutic response.
DISCUSSION: This study will confirm in humans the pharmacodynamic effect of AR
ligands to induce transient double-strand breaks when administered in the context of
androgen deprivation as a novel
therapy for
prostate cancer. The findings of this study will permit the development of a larger trial evaluating
flutamide pulsed-dose sequencing in association with fractionated external beam RT (+/-
brachytherapy). The study is ongoing, and preliminary data collection and recruitment are underway; analysis has yet to be performed.
TRIAL REGISTRATION: ClinicalTrials.gov NCT03507608. Prospectively registered on 25 April 2018.