Phase 1 Trial of High-Dose Exogenous Testosterone in Patients with Castration-Resistant Metastatic Prostate Cancer

Abstract

Background-Growth of selected castration-resistant prostate cancer (CRPC) cell lines and animal models can be repressed by reexposure to androgens. Low doses of androgens, however, can stimulate tumor growth.Objective-We performed a phase 1 clinical trial to determine the safety of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer (CRMPC).Design, setting, and participants-Patients with progressive CRMPC who had been castrate for at least 1 yr received three times the standard replacement dose of transdermal testosterone.Intervention-Cohorts of 3-6 patients received testosterone for 1 wk, 1 mo, or until disease progression. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: none.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Measurements-Toxicities, androgen levels, prostate-specific antigen (PSA) assays, computed tomography (CT) scans, bone scintigraphy, positron emission tomography (PET) scans, and metastatic tumor biopsy androgen receptor levels were assessed. NIH Public AccessResults and limitations-Twelve patients were treated-three in cohorts 1 and 2 and six in cohort 3. No pain flares were noted. One patient came off study because of epidural disease, which was treated with radiation. Average testosterone levels were within normal limits, although dihydrotestosterone (DHT) levels were supraphysiologic in cohort 3. One patient achieved a PSA decline of >50% from baseline. No objective responses were seen. For cohort 3, median time on treatment was 84 d (range: 23-247 d).Conclusions-We have demonstrated that patients with CRMPC can be safely treated in clinical trials using high-dose exogenous testosterone. Patients did not, on average, achieve sustained supraphysiologic serum testosterone levels. Future studies should employ strategies to maximize testosterone serum levels, use contemporary methods of identifying patients with androgen receptor overexpression, and utilize PSA Working Group II Consensus Criteria clinical trial end points.

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

“…Fowler and Whimore, (1981) observed that out of 52 metastatic prostate cancer patients who received ART, 45 exhibited increased cancer progression that could be reversed by androgen withdrawal, whereas 7 experienced symptomatic benefits. Other investigators have observed that in patients with castration-resistant metastatic prostate cancer, ART resulted in either little adverse effect on cancer progression or displayed some biochemical improvement or progression (Mathew, 2008;Morris et al, 2009;Szmulewitz et al, 2009). These clinical studies suggested that prostate cancer patients have differential responses to androgen/AR signals and ART might be able to improve the quality of life in selective prostate cancer patients with little impact on further progression of their prostate cancers.…”

Inhibition of Advanced Prostate Cancer by Androgens and Liver X Receptor Agonists

“…No adverse effect was reported. The serum testosterone ranged from 330-870 ng/dl (Morris et al 2009). This study suggested that patients with advanced prostate cancer can be safely treated with exogenous testosterone.…”

“…Bruchovsky et al showed that IAS therapy cause repeated differentiation of tumor with recovery of apoptotic potential, inhibition of tumor growth by rapid restoration of serum testosterone, and restraint of tumor growth by subnormal levels of serum testosterone (Bruchovsky et al 2000). They concluded that IAS is a viable treatment option for men with prostate cancer which affords an improved quality of life as well as reduced toxicity and costs (Bruchovsky et al 2000, Morris et al 2009, Pether et al 2003. A few studies have shown that androgen is safe and potentially effective for treatment of advanced prostate cancer.…”

Expression and Function of Stromal Androgen Receptor in Prostate Cancer

“…The permanent methods of androgen ablation such as surgical castration can be replaced by reversible methods of castration such as medical castration with LHRH analogues. Interestingly, some investigators have even observed that using androgen replacement therapy (ART) in metastatic CRPC displayed biochemical improvement in patients [24]. Newer therapies targeting the prostate cancer stromal cells should be evaluated.…”