Prostate Specific Anti-androgen Therapy for Localized Prostate Cancer

摘要 前列腺癌是全世界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癌切除术、前列腺癌放射治疗或主动监测。 高危患者可在放射治疗的同时进行全身抗雄激素治疗。 患有晚期或转移性前列腺癌的男性也是如此。来自ACTE试验的有希望的数据表明 第二代抗雄激素药物苯扎鲁胺的荷尔蒙疗法可能会使男性在服用安慰剂时受益。 监视系统。每天口服苯扎鲁胺一年可以降低前列腺癌的进展速度，但 相当大的系统性副作用的代价。因此，既有未得到满足的需求，也有机会界定 早期前列腺癌的新治疗策略。我们建议通过以下方式解决这一未得到满足的需求 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癌 目标是提供持续的抗雄激素治疗，同时将全身副作用降至最低。 在广泛的临床前测试和临床原则研究中，我们已经表明，我们可以提供短期- 前列腺术前和联合放射治疗的治疗剂量比卡鲁胺。利用 根据我们以往的经验，因此我们建议开发一种长期给药的种子植入剂，其中包含 第二代抗雄激素对早期前列腺癌男性患者的积极监测。最优的 种子植入物将选择性地将治疗药物水平输送到前列腺至少两年，并将 通过在社区实践环境中进行的微创手术植入。 在两个目标中，我们在目标1中建议为三个批准的每一个开发一种优化的铅植入物配方 第二代抗雄激素(苯扎鲁胺、阿帕鲁胺和达鲁他胺)，并在目标2中进行评估 体内植入种子的短期可行性研究(AIM 2a)和长期体内研究以确定 种子植入制剂(Aim 2b)在体内的药代动力学和药效学研究 大鼠的前列腺。第一项为期两周的短期研究将包括三组优化的铅种植入物 含有苯扎鲁胺、阿帕鲁胺和达鲁他胺的制剂以及与比卡鲁胺的一个对照队列 植入以评估前列腺、血浆和其他组织中PK的安全性、可行性和短期特征。长的- 对相同四个队列的学期研究将评估药物在前列腺、抗雄激素组织中的分布。 效应和回收的种子植入物中的残留药物含量来估计2，4和6的累积药物洗脱 月份。所有植入物都将设计成易于手术插入。该数据将允许选择最多 有希望的种子植入物将推进对早期男性PH1临床试验的进一步IND研究 并启动与行业合作伙伴的合作，以进行临床开发和商业化。

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.