Prostate Specific Anti-androgen Therapy for Localized Prostate Cancer

Abstract Prostate cancer is the most common malignancy in men worldwide and its incidence is steadily rising. Treatment options for early-stage prostate cancer include radical prostatectomy, prostate irradiation, or active surveillance. Systemic anti-androgen hormonal therapy is offered to high-risk patients in combination with radiation therapy

and in men with advanced or metastatic prostate cancer. Promising data from the ENACT trial has suggested that hormonal therapy with a second-generation anti-androgen, enzalutamide, may benefit men on active surveillance. Daily oral enzalutamide for one year reduced the rate of prostate cancer progression but came at

the cost of considerable systemic side effects. Thus, there is an unmet need as well as an opportunity to define novel therapeutic strategies for early-stage prostate cancer. We propose to address this unmet need by developing polymer-based drug loaded seed implants. These seed will be surgically placed into the prostate with

the goal to provide sustained anti-androgen therapy while minimizing systemic side effects. In extensive preclinical testing and clinical proof of principle studies, we have shown that we can deliver short- term therapeutic doses of bicalutamide pre-prostatectomy and in combination with radiation therapy. Leveraging

our prior experience, we therefore propose to develop a long-term drug delivering seed implant containing a second-generation anti-androgen for men with early-stage prostate cancer on active surveillance. The optimal seed implant would deliver therapeutic drug levels selectively to the prostate gland for at least two years and will

be inserted via a minimally invasive surgery performed in a community practice setting. In two aims we propose in Aim 1 to develop an optimized lead implant formulation of each of the three approved 2nd-generation antiandrogens (enzalutamide, apalutamide and darolutamide) and in Aim 2 to evaluate these

seed implants in a short-term feasibility in vivo rat study (Aim 2a) and a long-term in vivo rat study to determine the pharmacokinetic and pharmacodynamic profile of seed implant formulations (Aim 2b) when deployed into the rat prostate. The first, short-term, 2-week study will include three cohorts of optimized lead seed implant

formulations containing enzalutamide, apalutamide and darolutamide and one control cohort with a bicalutamide implant to evaluate safety, feasibility, and short-term PK profiles in prostate, plasma, and other tissues. The long- term study with the same four cohorts will evaluate drug distribution across the prostate, anti-androgen tissue

effects, and residual drug content in recovered seed implants to estimate cumulative drug elution at 2, 4 and 6 months. All implants will be designed for easy surgical insertion. This data will allow the selection of the most promising seed implants to advance to further IND-enabling studies for Ph1 clinical trials in men with early-stage

prostate cancer and initiate collaborations with industry partners for clinical development and commercialization.