Prostate Specific Anti-androgen Therapy for Localized Prostate Cancer

摘要 前列腺癌是世界范围内男性最常见的恶性肿瘤，其发病率正在稳步上升。治疗 早期前列腺癌的选择包括根治性前列腺切除术、前列腺放射或主动监测。 全身性抗雄激素激素治疗与放射治疗相结合提供给高危患者 以及晚期或转移性前列腺癌患者。ENACT试验的数据表明， 第二代抗雄激素药物恩杂鲁胺（enzalutamide）的激素治疗可能有益于活跃的男性， 监视每日口服Enzalutamide 1年可降低前列腺癌进展率，但 相当大的系统性副作用的代价。因此，有一个未满足的需求以及一个机会来定义 早期前列腺癌的新治疗策略。我们建议采取以下措施， 开发基于聚合物的载药种子植入物。这些种子将通过手术植入前列腺， 目的是提供持续的抗雄激素治疗，同时最大限度地减少全身副作用。 在广泛的临床前测试和临床原理验证研究中，我们已经证明，我们可以提供短- 长期治疗剂量的比卡鲁胺在前列腺切除术前以及与放射疗法联合。利用 根据我们先前的经验，我们因此建议开发一种长期的药物递送种子植入物， 第二代抗雄激素用于积极监测的早期前列腺癌男性。最优 种子植入物将选择性地向前列腺递送治疗药物水平至少两年， 通过在社区实践环境中进行的微创手术插入。 在两个目标中，我们在目标1中提出开发三种批准的电极导线植入物配方中的每一种的优化电极导线植入物配方 第2代抗雄激素药物（Enzalutamide、apalutamide和达罗鲁米特），目的2评价这些药物 在短期大鼠体内可行性研究（Aim 2a）和长期大鼠体内研究中， 种子植入制剂（目的2b）在植入后的药代动力学和药效学特征 老鼠的前列腺第一项为期2周的短期研究将包括3个优化的电极导线种子植入队列 含Enzalutamide、apalutamide和darolutamide的制剂和一个含比卡鲁胺的对照队列 植入以评价安全性、可行性和前列腺、血浆和其他组织中的短期PK特征。很长的- 一项包含相同4个队列的长期研究将评价药物在前列腺、抗雄激素组织中的分布 效果和回收的种子植入物中的残留药物含量，以估计2、4和6时的累积药物洗脱 个月所有植入物的设计均便于手术插入。这些数据将允许选择最 有希望的种子植入物，以推进进一步的IND使能研究，用于在早期男性中进行Ph 1临床试验 前列腺癌，并启动与行业合作伙伴的临床开发和商业化合作。

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.