Abstract
Abstract
Background
Prostate cancer remains the most prevalent malignancy and the second-leading cause of cancer-related death in men in the USA. Radiation therapy, typically with androgen suppression, remains a mainstay in the treatment of intermediate- and high-risk, potentially lethal prostate cancers. However, local recurrence and treatment failure remain common. Basic and translational research has determined the potential for using androgen receptor (AR) ligands (e.g., dihydrotestosterone and flutamide) in the context of androgen-deprived prostate cancer to induce AR- and TOP2B-mediated DNA double-strand breaks (DSBs) and thereby synergistically enhance the effect of radiation therapy (RT). The primary aim of this study is to carry out pharmacodynamic translation of these findings to humans.
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.
Funder
Patrick C. Walsh Prostate Cancer Research Fund
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Medicine (miscellaneous)
Reference21 articles.
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Prostate Cancer, Version 3.2016 (2016). Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. (Accessed: 1st January 2016)
2. Fosså SD, et al. Ten- and 15-yr prostate cancer-specific mortality in patients with nonmetastatic locally advanced or aggressive intermediate prostate cancer, randomized to lifelong endocrine treatment alone or combined with radiotherapy: final results of The Scandinavian Prostate Cancer Group-7. Eur Urol. 2016; https://doi.org/10.1016/j.eururo.2016.03.021.
3. Coen JJ, Zietman AL, Thakral H, Shipley WU. Radical radiation for localized prostate cancer: local persistence of disease results in a late wave of metastases. J Clin Oncol. 2002;20:3199–205.
4. Jemal A, Culp MB, Ma J, Islami F, Fedewa SA. Prostate cancer incidence 5 years after US Preventive Services Task Force recommendations against screening. JNCI J Natl Cancer Inst. 2021;113(1):64–71. https://doi.org/10.1093/JNCI/DJAA068.
5. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33. https://doi.org/10.3322/CAAC.21654.