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.
Public Health Relevance Statement: Public Health Relevance Prostate cancer remains the most common malignancy in men, and hormonal therapy has clearly shown to benefit many of these men, however, systemic side effects often countervail the benefits. We have devised a novel means to selectively deliver anticancer therapy to the prostate only, for men with early stage prostate cancer. In preclinical studies we will now evaluate and prepare the most promising anti-androgen eluting seed implants for clinical readiness.
Project Terms: Accounting; Anti-Androgen; Anti-Androgen Agents; Antiandrogen Agents; Antiandrogens; androgen inhibitor; Androgen Antagonists; Animals; Anxiety; Autopsy; necropsy; postmortem; Biological Assay; Assay; Bioassay; Biologic Assays; Biopsy; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Clinical Trials; Disease; Disorder; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Dropout; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Fright; Fear; Goals; Human; Modern Man; Impotence; impotent; Incidence; Inflammation; Lead; Pb element; heavy metal Pb; heavy metal lead; Libido; sex drive; sexual drive; Longitudinal Studies; long-term study; longitudinal outcome studies; longterm study; Magnetic Resonance Imaging; MR Imaging; MR Tomography; MRI; MRIs; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Zeugmatography; men; Mus; Mice; Mice Mammals; Murine; Patients; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Polymers; polymer; polymeric; Prostate; Prostate Gland; Prostatic Gland; Prostatectomy; Radiation therapy; Radiotherapeutics; Radiotherapy; radiation treatment; treatment with radiation; Rattus; Common Rat Strains; Rat; Rats Mammals; Risk; Safety; Testing; Tissues; Body Tissues; Urinary Incontinence; Generations; doubt; Uncertainty; Prostatovesiculectomy; Radical Prostatectomy; Clinical; Residual; Residual state; Phase; Evaluation; bone mass; muscle bulk; muscle mass; muscle form; Disease Progression; Endocrine Therapy; Hormonal Therapy; hormone therapy; Anti-androgen Therapy; Anti-androgen Treatment; Antiandrogen Treatment; Antiandrogen Therapy; Collaborations; MALD-MS; MALDI; MALDI-MS; Spectroscopy, Mass, Matrix-Assisted Laser Desorption-Ionization; matrix assisted laser desorption ionization; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Casodex; Cosudex; Bicalutamide; Therapeutic; Infiltration; Nature; Malignant neoplasm of prostate; Malignant Tumor of the Prostate; Malignant prostatic tumor; Prostate CA; Prostate Cancer; Prostate malignancy; Prostatic Cancer; Oral; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Visit; experience; cohort; melting; Histopathology; Sterility; sterile; Structure; novel; Radiation; Modeling; response; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; cancer diagnosis; Metastatic Prostate Cancer; Prostate Carcinoma Metastatic; Metabolic syndrome; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; irradiation; Address; Dose; Data; Preclinical Testing; pre-clinical testing; in vivo; Community Practice; Local Therapy; Localized Therapy; Seed Implantation; Seed Implant; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Monitor; Preparation; preparations; Characteristics; Adjuvant; Development; developmental; Image; imaging; pre-clinical; preclinical; preclinical study; pre-clinical study; cost; sexual functioning; Sex Functioning; designing; design; LNCaP; drug distribution; anti-cancer activity; anticancer activity; innovate; innovative; innovation; biocompatible polymer; Implant; comparative; prototype; commercialization; high risk; public health relevance; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; new treatment approach; new treatment strategy; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; novel therapeutic intervention; minimally invasive; product development; industrial partnership; industry partnership; industry partner; Sterilization; screenings; screening; prostate biopsy; Formulation; clinical development; prostate cancer progression; practice setting; lead optimization; lead candidate; in vivo testing; in vivo evaluation; side effect; PK/PD; pharmacokinetics and pharmacodynamics; efficacious intervention; enzalutamide; Xtandi; manufacture; technology platform; technology system; clinic ready; clinical ready
