A Pilot Study of Parenteral Testosterone and Oral Etoposide as Therapy for Men With Castration Resistant Prostate Cancer

Based on our preclinical data, high levels of androgens can lead to significant growth suppressive effects in prostate cancer cells in vitro and in vivo. Mechanistic data in in vitro models suggests that this growth suppression may be due to the accumulation of androgen induced TOP2B mediated double strand breaks at AR target sites occurring after stimulation of prostate cancer cells with high levels of androgens. Provocatively, the number of double strand breaks was significantly increased (Figure 3 B) if the cells were treated with etoposide, an agent that leads to formation of double strand breaks at TOP2 target sites, concurrently with high-dose androgen stimulation. We hypothesize that co-administration of testosterone with etoposide could produce high levels of double strand breaks in prostate cancer cells, overwhelming DNA repair and survival mechanisms and leading to cancer cell death or growth arrest. To test whether this possibility holds promise for therapy of advanced prostate cancer, we propose the following clinical trial of parenteral testosterone therapy in combination with oral etoposide in men with evidence of progressive prostate cancer during chronic androgen ablation.

Inclusion criteria

• Performance status ≤2
• Documented adenocarcinoma of the prostate with histologic confirmation
• Treated with continuous androgen ablative therapy (either surgical castration or LHRH agonist for ≥ 1 year)
• Documented castrate level of serum testosterone (<50 ng/dl)
• Evidence of rising PSA on two successive dates > 1 month apart
• Treatment with ≤ 2 prior chemotherapeutic regimens allowed
• Treatment with ≤2 prior second line hormone therapies allowed.
• Prior treatment with ketoconazole is allowed.
• Patients must be withdrawn from antiandrogens for ≥ 6 weeks and have documented PSA increase after the 6 week withdrawal period.
• Patients with rising PSA only or ≤ 5 sites of asymptomatic bone metastases and < 10 total sites of disease including bone and soft tissue documented within 28 days of enrollment on trial.
• Patients will considered for repeat treatment with testosterone if they meet the following criteria:

• Had either PSA decline from baseline following treatment with testosterone or had return of PSA levels to pretreatment baseline once serum testosterone reached a castrate level.
• Must continue to meet inclusion/exclusion criteria as described above
• Must have been off testosterone therapy for ≥ 3 months
• Must have castrate level of serum testosterone
• Must have evidence of rising PSA on two occasions at least 2 weeks apart
• Are allowed to have had additional treatment with up to 2 additional hormonal therapies that include anti-androgens (e.g. flutamide, bicalutamide, nilutamide, enzalutamide), CYP17 inhibitors (e.g. ketoconazole, abiraterone acetate) or other investigational hormonal therapies.

Exclusion criteria

• Evidence of disease in sites or extent that, in the opinion of the investigator, would put the patient at risk from therapy with testosterone (e.g. femoral metastases with concern over fracture risk, spinal metastases with concern over spinal cord compression, lymph node disease with concern for ureteral obstruction)
• Abnormal liver function (bilirubin, AST, ALT ≥ 2 x upper limit of normal)
• Abnormal kidney function (serum creatinine ≥ 2 x upper limit of normal)
• Inability to provide informed consent