Drug implants containing PARP inhibitors and methods of use thereof

Abstract

Provided herein are drug implants comprising Pamiparib, Olaparib, or Niraparib for the treatment of disease in a subject. In some cases, the drug implant may comprise a polymer matrix and Pamiparib, Olaparib, or Niraparib disposed therein. Additionally provided are methods for manufacturing the drug implants and methods of treating diseases with the implants. In some cases, the drug implant may be used for the treatment of a proliferative disease.

Description

DRUG IMPLANTS CONTAINING PARP INHIBITORSAND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 737,373, filed December 20,2024, U. S. Provisional Application No. 63 / 737,384, filed December 20, 2024, and U. S. Provisional Application No. 63 / 737,392, filed December 20, 2024, each of which is incorporated herein by reference in its entirety.BACKGROUND OF THE DISCLOSURE

[0002] The burden of suffering from cancer in the United States is significant. For example, in 2009 approximately 192,000 men were diagnosed with prostate cancer, and 27,000 men were expected to die from this disease. Cancer is the second leading cause of death globally, accounting for an estimated 9.6 million deaths, or 1 in 6 deaths, in 2018. Lung, prostate, colorectal, stomach, and liver cancer are the most common types of cancer in men, while breast, colorectal, lung, cervical and thyroid cancer are the most common among women. Other tumors, such as pancreatic cancer, are rapidly rising.

[0002] PARP inhibitors are a group of therapeutics that inhibit the enzyme poly ADP ribose polymerase (PARP). PARP inhibitors have been approved for treating certain types of cancer by oral administration. However, systemic administration of PARP inhibitors is associated with serious adverse side effects.SUMMARY OF THE DISCLOSURE

[0003] There is an unmet need for drug implants containing PARP inhibitors, including Pamiparib, Niraparib, and Olaparib, for localized delivery of the PARP inhibitor to a target tissue, as well as methods for treating disease (e.g., cancer) in a subject by localized delivery of the PARP inhibitor and for reducing side effects associated with systemic administration of the PARP inhibitor. This disclosure meets this unmet need by providing drug implants containing a PARP inhibitor, and methods for using the implants for localized delivery of a PARP inhibitor to a target tissue.

[0004] Described herein, in some aspects, is drug implant comprising: a biocompatible polymer matrix; and Pamiparib dispersed in the biocompatible polymer matrix. In some embodiments, the Pamiparib is present in the drug implant at an amount from about 10% w / w to about 80% w / w. Insome embodiments, the Pamiparib is present in the drug implant at an amount of about 10% w / w. In some embodiments, the Pamiparib is present in the drug implant at an amount of about 30% w / w. In some embodiments, the Pamiparib is present in the drug implant at an amount of about 50% w / w. In some embodiments, the Pamiparib is present in the drug implant at an amount of about 70% w / w. In some embodiments, the drug implant releases the Pamiparib by zero order release. In some embodiments, at least 10%, at least 15%, at least 20%, at least 25%. or at least 50% of the Pamiparib remains in the biocompatible polymer matrix after 100 days of implantation. In some embodiments, at least 10%, at least 15%, at least 20%, at least 25%, or at least 50% of the Pamiparib remains in the biocompatible polymer matrix after 180 days of implantation. In some embodiments, the Pamiparib is in solid form. In some embodiments, the Pamiparib is in a crystalline form, a semi-crystalline form, or an amorphous form. In some embodiments, the Pamiparib is in a dissolved form. In some embodiments, the drug implant has a Shore A hardness of at least 20 durometer when loaded with Pamiparib. In some embodiments, the biocompatible polymer matrix comprises silicone. In some embodiments, the silicone is an acetoxy-cured silicone or a platinum-cured silicone. In some embodiments, the biocompatible polymer matrix comprises thermoplastic polyurethane. In some embodiments, the biocompatible polymer matrix comprises poly (ethylene vinyl acetate). In some embodiments, at least 99% by weight of the biocompatible polymer matrix remains in a target tissue of a subject after implantation for at least 12 months, at least 24 months, at least 36 months, at least 48 months, at least 60 months, or longer. In some embodiments, the drug implant is visible by ultrasound or MRI when disposed in a target tissue of a subject. In some embodiments, the drug implant inhibits modulation of the Pamiparib within the drug implant. In some embodiments, the modulation comprises degradation. In some embodiments, the drug implant is elongate. In some embodiments, the drug implant is cylindrical. In some embodiments, the drug implant is tubular. In some embodiments, the drug implant is rod-shaped. In some embodiments, the drug implant is circular. In some embodiments, the drug implant comprises one or more rods. In some embodiments, the one or more rods are connected. In some embodiments, the drug implant comprises a disk. In some embodiments, a diameter of the drug implant is from about 0.1 mm to about 5.0 mm. In some embodiments, a length of the drug implant is from about 1 mm to about 30 mm. In some embodiments, a volume of the drug implant is from about 0.1 mm3to about 30 mm3. In some embodiments, at least 50% of an outer surface of the drug implant is configured to directly contact a target tissue. In some embodiments, the drug implant is configured to be implanted into a target tissue or a tissue near or adjacent to the target tissue. In some embodiments, the target tissue is prostate tissue, bladder tissue, ovarian tissue, fallopian tissue, liver tissue, bone tissue, breast tissue,pancreatic tissue, lung tissue, gastric tissue, kidney tissue, gall bladder tissue, colon tissue, or a combination thereof. In some embodiments, the target tissue is prostate tissue. In some embodiments, the drug implant is configured to be delivered to the target tissue or the tissue near or adjacent to the target tissue using a lumen of a needle or a catheter. In some embodiments, the drug implant lacks at least one of a sheath, a scaffold, a retention member for retaining the drug implant within a target tissue, or a combination thereof. In some embodiments, the drug implant further comprises a coating. In some embodiments, the coating partially covers the drug implant. In some embodiments, the coating substantially covers the drug implant. In some embodiments, the coating contains comprises at least one additional therapeutic. In some embodiments, the at least one additional therapeutic comprises a cytotoxic therapeutic. In some embodiments, the at least one additional therapeutic comprises a hormonal therapeutic. In some embodiments, the at least one additional therapeutic comprises a biologic therapeutic. In some embodiments, the biocompatible polymer matrix comprises a non-biodegradable polymer. In some embodiments, the biocompatible polymer matrix comprises a biodegradable polymer. In some embodiments, the drug implant is not a nanoparticle. In some embodiments, the Pamiparib is not encapsulated in a nanoparticle.

[0005] Described herein, in some aspects, is a method of treating a tumor in a subject, the method comprising implanting, into the tumor or into a tissue adjacent to the tumor of the subject, at least one drug implant described herein. In some embodiments, the at least one drug implant continuously delivers the Pamiparib to the subject for at least 6 months, at least 12 months, at least 24 months, at least 60 months, or longer. In some embodiments, a total dose of the Pamiparib administered to the subject by the implanting is less than a total dose of the Pamiparib when administered to a subject by oral administration. In some embodiments, the implanting results in a blood plasma concentration of the Pamiparib that is less than a blood plasma concentration of the Pamiparib obtained when the Pamiparib is administered to a subject by oral administration. In some embodiments, the implanting occurs via transperineal administration. In some embodiments, the transperineal administration comprises using a template guided needle. In some embodiments, the implanting locally delivers the Pamiparib to the tumor. In some embodiments, the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof. In some embodiments, the method further comprises, after the implanting, administering to the subject at least one additional therapy to treat the tumor. In some embodiments, the method further comprises, after the implanting, recommending that the subject receive at least one additional therapy to treat the tumor. In some embodiments, the at least oneadditional therapy comprises radiation, chemotherapy, biologic therapy, immunologic therapy, hormonal therapy, or a combination thereof. In some embodiments, the at least one additional therapy comprises radiation. In some embodiments, the at least one additional therapy is more efficacious for treating the tumor after the implanting than after oral administration of the Pamiparib. In some embodiments, an amount of the at least one additional therapy needed to effectively treat the tumor is lower after the implanting, as compared to an amount of the at least one additional therapy needed to effectively treat the tumor in the absence of the Pamiparib. In some embodiments, the method results in decreased toxicity to the subject as compared to when the subject receives the at least one additional therapy without the Pamiparib. In some embodiments, the toxicity comprises weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity, or a combination thereof of the subject. In some embodiments, the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.

[0006] Described herein, in some aspects, is a method of manufacturing a drug implant of any one of the preceding, the method comprising: mixing an amount of polymer with an amount of the Pamiparib to generate a mixture; and molding or extruding the mixture of (a) to create the drug implant. In some embodiments, the polymer comprises uncured polymer. In some embodiments, the method comprises molding the mixture. In some embodiments, the method further comprises curing the drug implant for a period of time. In some embodiments, the amount of the Pamiparib is from 10% w / w to 80% w / w of the uncured polymer. In some embodiments, the polymer comprises silicone, thermoplastic polyurethane, polyethylene vinyl acetate), or a combination thereof. In some embodiments, the curing further comprises heating the mixture at a temperature from about 100 °C to about 175 °C for about 3 to about 8 minutes. In some embodiments, the mixture further comprises a solvent. In some embodiments, the solvent is selected from the group consisting of: pentane, dichloromethane, tetrahydrofuran, heptane, toluene, and hexane. In some embodiments, the mixture is molded by a transfer molding process or by extrusion through a tube. In some embodiments, the molding comprises extruding the mixture using a ram extruder or a twin screw extruder. In some embodiments, the molding comprises injection molding. In some embodiments, the method further comprises performing an analysis on the drug implant. In some embodiments, the analysis is selected from the group consisting of: differential scanning calorimetry (DSC), deployment of the drug implant in surrogate tissue, elution testing, rheology, high pressure liquid chromatography (HPLC), simulated in vivo stability assay, and dynamic mechanical analysis (DMA).

[0007] Described herein, in some aspects, is a kit comprising: a sterilized package comprising a drug implant described herein; and instructions for implanting the drug implant into a target tissue of a subject.

[0008] Described herein, in some aspects, is drug implant comprising: a biocompatible polymer matrix; and Niraparib dispersed in the biocompatible polymer matrix. In some embodiments, the Niraparib is present in the drug implant at an amount from about 10% w / w to about 80% w / w. In some embodiments, the Niraparib is present in the drug implant at an amount of about 10% w / w. In some embodiments, the Niraparib is present in the drug implant at an amount of about 30% w / w. In some embodiments, the Niraparib is present in the drug implant at an amount of about 50% w / w. In some embodiments, the Niraparib is present in the drug implant at an amount of about 70% w / w. In some embodiments, a total dose of the Niraparib in the drug implant is from about 1 mg to about 20 mg. In some embodiments, the drag implant releases at least about 1.0 pg / day of the Niraparib after implantation in a subject. In some embodiments, the drug implant releases at least about 8.0 pg / day of the Niraparib after the implantation in a subject. In some embodiments, the drug implant releases the Niraparib by zero order release. In some embodiments, the zero order release comprises at least about 1.0 pg / day of the Niraparib after implantation in a subject. In some embodiments, the zero order release comprises at least about 8.0 pg / day of the Niraparib after implantation in a subject. In some embodiments, the drug implant releases at least about 100.0 pg / day of the Niraparib on Day 1, Day 2, Day 3, Day 4, or Day 5 after the implantation. In some embodiments, the drug implant releases a dose of the Niraparib that is lower than 100.0 pg / day after Day 1, Day 2, Day 3, Day 4, or Day 5 after the implantation. In some embodiments, at least 10%, at least 15%, at least 20%, at least 25%, or at least 50% of the Niraparib remains in the biocompatible polymer matrix after 100 days of implantation. In some embodiments, at least 10%, at least 15%, at least 20%, at least 25%, or at least 50% of the Niraparib remains in the biocompatible polymer matrix after 180 days of implantation. In some embodiments, the Niraparib is in solid form. In some embodiments, the Niraparib is in a crystalline form, a semi-crystalline form, or an amorphous form. In some embodiments, the Niraparib is in a dissolved form. In some embodiments, the drug implant has a Shore A hardness of at least 20 durometer when loaded with Niraparib. In some embodiments, the biocompatible polymer matrix comprises silicone. In some embodiments, the silicone is an acetoxy-cured silicone or a platinum-cured silicone. In some embodiments, the biocompatible polymer matrix comprises thermoplastic polyurethane. In some embodiments, the biocompatible polymer matrix comprises polyethylene vinyl acetate). In some embodiments, at least 99% by weight of the biocompatible polymer matrix remains in a target tissue of a subject after implantation for at least 12 months, atleast 24 months, at least 36 months, at least 48 months, at least 60 months, or longer. In some embodiments, the drug implant is visible by ultrasound or MRI when disposed in a target tissue of a subject. In some embodiments, the drug implant inhibits modulation of the Niraparib within the drug implant. In some embodiments, the modulation comprises degradation. In some embodiments, the drug implant is elongate. In some embodiments, the drug implant is cylindrical. In some embodiments, the drug implant is tubular. In some embodiments, the drug implant is rod-shaped. In some embodiments, the drug implant is circular. In some embodiments, the drug implant comprises one or more rods. In some embodiments, the one or more rods are connected. In some embodiments, the drug implant comprises a disk. In some embodiments, a diameter of the drug implant is from about 0.1 mm to about 5.0 mm. In some embodiments, a length of the drug implant is from about 1 mm to about 30 mm. In some embodiments, a volume of the drug implant is from about 0.1 mm3to about 30 mm3. In some embodiments, at least 50% of an outer surface of the drug implant is configured to directly contact a target tissue. In some embodiments, the drug implant is configured to be implanted into a target tissue or a tissue near or adjacent to the target tissue. In some embodiments, the target tissue is prostate tissue, bladder tissue, ovarian tissue, fallopian tissue, liver tissue, bone tissue, breast tissue, pancreatic tissue, lung tissue, gastric tissue, kidney tissue, gall bladder tissue, colon tissue, or a combination thereof. In some embodiments, the target tissue is prostate tissue. In some embodiments, the drug implant is configured to be delivered to the target tissue or the tissue near or adjacent to the target tissue using a lumen of a needle or a catheter. In some embodiments, the drug implant lacks at least one of a sheath, a scaffold, a retention member for retaining the drug implant within a target tissue, or a combination thereof. In some embodiments, the drug implant further comprises a coating. In some embodiments, the coating partially covers the drug implant. In some embodiments, the coating substantially covers the drug implant. In some embodiments, the coating contains comprises at least one additional therapeutic. In some embodiments, the at least one additional therapeutic comprises a cytotoxic therapeutic. In some embodiments, the at least one additional therapeutic comprises a hormonal therapeutic. In some embodiments, the at least one additional therapeutic comprises a biologic therapeutic. In some embodiments, the biocompatible polymer matrix comprises a non-biodegradable polymer. In some embodiments, the biocompatible polymer matrix comprises a biodegradable polymer. In some embodiments, the drug implant is not a nanoparticle. In some embodiments, the Niraparib is not encapsulated in a nanoparticle.

[0009] Described herein, in some aspects, is a method of treating a tumor in a subject, the method comprising implanting, into the tumor or into a tissue adjacent to the tumor of the subject, at leastone drug implant described herein. In some embodiments, the at least one drug implant continuously delivers the Niraparib to the subject for at least 6 months, at least 12 months, at least 24 months, at least 60 months, or longer. In some embodiments, a total dose of the Niraparib administered to the subject by the implanting is less than a total dose of the Niraparib when administered to a subject by oral administration. In some embodiments, a total dose of the Niraparib administered to the subject by the implanting is less than 200 mg over a period of 6 months. In some embodiments, the implanting results in a blood plasma concentration of the Niraparib that is less than a blood plasma concentration of the Niraparib obtained when the Niraparib is administered to a subject by oral administration. In some embodiments, the implanting occurs via transperineal administration. In some embodiments, the transperineal administration comprises using a template guided needle. In some embodiments, the implanting locally delivers the Niraparib to the tumor. In some embodiments, the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof. In some embodiments, the method further comprises, after the implanting, administering to the subject at least one additional therapy to treat the tumor. In some embodiments, the method further comprises, after the implanting, recommending that the subject receive at least one additional therapy to treat the tumor. In some embodiments, the at least one additional therapy comprises radiation, chemotherapy, biologic therapy, immunologic therapy, hormonal therapy, or a combination thereof. In some embodiments, the at least one additional therapy comprises radiation. In some embodiments, the at least one additional therapy is more efficacious for treating the tumor after the implanting than after oral administration of the Niraparib. In some embodiments, an amount of the at least one additional therapy needed to effectively treat the tumor is lower after the implanting, as compared to an amount of the at least one additional therapy needed to effectively treat the tumor in the absence of the Niraparib. In some embodiments, the method results in decreased toxicity to the subject as compared to when the subject receives the at least one additional therapy without the Niraparib. In some embodiments, the toxicity comprises weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity, or a combination thereof of the subject. In some embodiments, the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.

[0010] Described herein, in some aspects, is a method of manufacturing a drug implant of any one of the preceding, the method comprising: mixing an amount of polymer with an amount of the Niraparib to generate a mixture; and molding or extruding the mixture of (a) to create the drugimplant. In some embodiments, the polymer comprises uncured polymer. In some embodiments, the method comprises molding the mixture. In some embodiments, the method further comprises curing the drug implant for a period of time. In some embodiments, the amount of the Niraparib is from 10% w / w to 80% w / w of the uncured polymer. In some embodiments, the polymer comprises silicone, thermoplastic polyurethane, poly (ethylene vinyl acetate), or a combination thereof. In some embodiments, the curing further comprises heating the mixture at a temperature from about 100 °C to about 175 °C for about 3 to about 8 minutes. In some embodiments, the mixture further comprises a solvent. In some embodiments, the solvent is selected from the group consisting of: pentane, dichloromethane, tetrahydrofuran, heptane, toluene, and hexane. In some embodiments, the mixture is molded by a transfer molding process or by extrusion through a tube. In some embodiments, the molding comprises extruding the mixture using a ram extruder or a twin screw extruder. In some embodiments, the molding comprises injection molding. In some embodiments, the method further comprises performing an analysis on the drug implant. In some embodiments, the analysis is selected from the group consisting of: differential scanning calorimetry (DSC), deployment of the drug implant in surrogate tissue, elution testing, rheology, high pressure liquid chromatography (HPLC), simulated in vivo stability assay, and dynamic mechanical analysis (DMA).

[0011] Described herein, in some aspects, is a kit comprising: a sterilized package comprising a drug implant described herein; and instructions for implanting the drug implant into a target tissue of a subject.

[0012] Described herein, in some aspects, are drug implants comprising: a biocompatible polymer matrix; and Olaparib dispersed in the biocompatible polymer matrix. In some embodiments, the Olaparib is present in the drug implant at an amount from about 10% w / w to about 80% w / w. In some embodiments, the Olaparib is present in the drug implant at an amount of about 10% w / w. In some embodiments, the Olaparib is present in the drug implant at an amount of about 30% w / w. In some embodiments, the Olaparib is present in the drug implant at an amount of about 50% w / w. In some embodiments, the Olaparib is present in the drug implant at an amount of about 70% w / w. In some embodiments, a total dose of the Olaparib in the drug implant is from about 1 mg to about 20 mg. In some embodiments, the drug implant releases at least about 1.0 pg / day of the Olaparib after implantation in a subject. In some embodiments, the drug implant releases at least about 8.0 pg / day of the Olaparib after the implantation in a subject. In some embodiments, the drug implant releases the Olaparib by zero order release. In some embodiments, the zero order release comprises at least about 1.0 pg / day of the Olaparib after implantation in a subject. In some embodiments, the zero order release comprises at least about 8.0 pg / day of the Olaparib after implantation in a subject. Insome embodiments, the drug implant releases at least about 100.0 pg / day of the Olaparib on Day 1, Day 2, Day 3, Day 4, or Day 5 after the implantation. In some embodiments, the drug implant releases a dose of the Olaparib that is lower than 100.0 pg / day after Day 1, Day 2, Day 3, Day 4, or Day 5 after the implantation. In some embodiments, at least 10%, at least 15%, at least 20%, at least 25%, or at least 50% of the Olaparib remains in the biocompatible polymer matrix after 100 days of implantation. In some embodiments, at least 10%, at least 15%, at least 20%. at least 25%, or at least 50% of the Olaparib remains in the biocompatible polymer matrix after 180 days of implantation. In some embodiments, the Olaparib is in solid form. In some embodiments, the Olaparib is in a crystalline form, a semi-crystalline form, or an amorphous form. In some embodiments, the Olaparib is in a dissolved form. In some embodiments, the drug implant has a Shore A hardness of at least 20 durometer when loaded with Olaparib. In some embodiments, the biocompatible polymer matrix comprises silicone. In some embodiments, the silicone is an acetoxy-cured silicone or a platinum-cured silicone. In some embodiments, the biocompatible polymer matrix comprises thermoplastic polyurethane. In some embodiments, the biocompatible polymer matrix comprises polyethylene vinyl acetate). In some embodiments, at least 99% by weight of the biocompatible polymer matrix remains in a target tissue of a subject after implantation for at least 12 months, at least 24 months, at least 36 months, at least 48 months, at least 60 months, or longer. In some embodiments, the drug implant is visible by ultrasound or MRI when disposed in a target tissue of a subject. In some embodiments, the drug implant inhibits modulation of the Olaparib within the drug implant. In some embodiments, the modulation comprises degradation. In some embodiments, the drug implant is elongate. In some embodiments, the drug implant is cylindrical. In some embodiments, the drug implant is tubular. In some embodiments, the drug implant is rod-shaped. In some embodiments, the drug implant is circular. In some embodiments, the drug implant comprises one or more rods. In some embodiments, the one or more rods are connected. In some embodiments, the drug implant comprises a disk. In some embodiments, a diameter of the drug implant is from about 0.1 mm to about 5.0 mm. In some embodiments, a length of the drug implant is from about 1 mm to about 30 mm. In some embodiments, a volume of the drug implant is from about 0.1 mm3to about 30 mm3. In some embodiments, at least 50% of an outer surface of the drug implant is configured to directly contact a target tissue. In some embodiments, the drug implant is configured to be implanted into a target tissue or a tissue near or adjacent to the target tissue. In some embodiments, the target tissue is prostate tissue, bladder tissue, ovarian tissue, fallopian tissue, liver tissue, bone tissue, breast tissue, pancreatic tissue, lung tissue, gastric tissue, kidney tissue, gall bladder tissue, colon tissue, or a combination thereof. In some embodiments, the target tissue is prostate tissue. In someembodiments, the drug implant is configured to be delivered to the target tissue or the tissue near or adjacent to the target tissue using a lumen of a needle or a catheter. In some embodiments, the drug implant lacks at least one of a sheath, a scaffold, a retention member for retaining the drug implant within a target tissue, or a combination thereof. In some embodiments, the drug implant further comprises a coating. In some embodiments, the coating partially covers the drug implant. In some embodiments, the coating substantially covers the drug implant. In some embodiments, the coating contains comprises at least one additional therapeutic. In some embodiments, the at least one additional therapeutic comprises a cytotoxic therapeutic. In some embodiments, the at least one additional therapeutic comprises a hormonal therapeutic. In some embodiments, the at least one additional therapeutic comprises a biologic therapeutic. In some embodiments, the biocompatible polymer matrix comprises a non-biodegradable polymer. In some embodiments, the biocompatible polymer matrix comprises a biodegradable polymer. In some embodiments, the drug implant is not a nanoparticle. In some embodiments, the Olaparib is not encapsulated in a nanoparticle.

[0013] Described herein, in some aspects, is a method of treating a tumor in a subject, the method comprising implanting, into the tumor or into a tissue adjacent to the tumor of the subject, at least one drug implant described herein. In some embodiments, the at least one drug implant continuously delivers the Olaparib to the subject for at least 6 months, at least 12 months, at least 24 months, at least 60 months, or longer. In some embodiments, a total dose of the Olaparib administered to the subject by the implanting is less than a total dose of the Olaparib when administered to a subject by oral administration. In some embodiments, a total dose of the Olaparib administered to the subject by the implanting is less than 200 mg over a period of 6 months. In some embodiments, the implanting results in a blood plasma concentration of the Olaparib that is less than a blood plasma concentration of the Olaparib obtained when the Olaparib is administered to a subject by oral administration. In some embodiments, the implanting occurs via transperineal administration. In some embodiments, the transperineal administration comprises using a template guided needle. In some embodiments, the implanting locally delivers the Olaparib to the tumor. In some embodiments, the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof. In some embodiments, the method further comprises, after the implanting, administering to the subject at least one additional therapy to treat the tumor. In some embodiments, the method further comprises, after the implanting, recommending that the subject receive at least one additional therapy to treat the tumor. In some embodiments, the at least one additional therapy comprises radiation,chemotherapy, biologic therapy, immunologic therapy, hormonal therapy, or a combination thereof. In some embodiments, the at least one additional therapy comprises radiation. In some embodiments, the at least one additional therapy is more efficacious for treating the tumor after the implanting than after oral administration of the Olaparib. In some embodiments, an amount of the at least one additional therapy needed to effectively treat the tumor is lower after the implanting, as compared to an amount of the at least one additional therapy needed to effectively treat the tumor in the absence of the Olaparib. In some embodiments, the method results in decreased toxicity to the subject as compared to when the subject receives the at least one additional therapy without the Olaparib. In some embodiments, the toxicity comprises weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity, or a combination thereof of the subject. In some embodiments, the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12. RAD51. FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.

[0014] Described herein, in some aspects, is a method of manufacturing a drug implant of any one of the preceding, the method comprising: mixing an amount of polymer with an amount of the Olaparib to generate a mixture; and molding or extruding the mixture of (a) to create the drug implant. In some embodiments, the polymer comprises uncured polymer. In some embodiments, the method comprises molding the mixture. In some embodiments, the method further comprises curing the drug implant for a period of time. In some embodiments, the amount of the Olaparib is from 10% w / w to 80% w / w of the uncured polymer. In some embodiments, the polymer comprises silicone, thermoplastic polyurethane, poly(ethylene vinyl acetate), or a combination thereof. In some embodiments, the curing further comprises heating the mixture at a temperature from about 100 °C to about 175 °C for about 3 to about 8 minutes. In some embodiments, the mixture further comprises a solvent. In some embodiments, the solvent is selected from the group consisting of: pentane, dichloromethane, tetrahydrofuran, heptane, toluene, and hexane. In some embodiments, the mixture is molded by a transfer molding process or by extrusion through a tube. In some embodiments, the molding comprises extruding the mixture using a ram extruder or a twin screw extruder. In some embodiments, the molding comprises injection molding. In some embodiments, the method further comprises performing an analysis on the drug implant. In some embodiments, the analysis is selected from the group consisting of: differential scanning calorimetry (DSC), deployment of the drug implant in surrogate tissue, elution testing, rheology, high pressure liquid chromatography (HPLC), simulated in vivo stability assay, and dynamic mechanical analysis (DMA).

[0015] Described herein, in some aspects, is a kit comprising: a sterilized package comprising a drug implant described herein; and instructions for implanting the drug implant into a target tissue of a subject.INCORPORATION BY REFERENCE

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0018] Fig. 1A and Fig. IB illustrate examples of different drug implant configurations containing a PARP inhibitor (e.g. Pamiparib, Olaparib, or Niraparib). Fig. 1A illustrates an example of a drug implant containing a PARP inhibitor dispersed throughout a polymer matrix. Fig. IB illustrates an example of a drug implant containing a PARP inhibitor dispersed throughout a polymer matrix, coated with a control release layer. The addition of the control release layer may alter how the drug (e.g., Pamiparib, Olaparib, or Niraparib) is eluted from the drug implant.

[0019] Fig.2 illustrates assessment of cancer cell line models for testing the therapeutic efficacy of a drug implant described herein. Cancer cell lines were genetically engineered to harbor homologous recombination deficiency (HRD) of breast cancer gene 1 (BRCA1) or BRCA2 mutations. Functional HRD deficiency of BRCA1 or BRCA2 mutation was indicated by the loss of Rad51 foci induction by carboplatin in the engineered cell lines as compared to wild type cancer cell lines.

[0020] Figs. 3A-3C illustrate establishment and assessment of a prostate cancer cell model (PC3, clone 1E10) comprising BRCA2 deficiency, which is the most commonly identified homologous recombinant (HR) deficiency in men. The cells were engineered with CRISPR / Cas to introduce the BRCA2 mutation. Fig. 3A illustrates BRCA2 protein in wild type (WT) cells versus CRISPR / Cas engineered PC3 prostate cancer clones. Fig.3B illustrates increased sensitivity to carboplatin in 1E10 clone versus WT cells. Fig.3C illustrates 1E10 clone showing increased sensitivity to combined Niraparib and radiation therapy (XRT).

[0021] Fig.4 illustrates hematoxylin and eosin (H& E) staining of prostate cancer patient-derived xenograft (PDX)-BRCA2 implanted with placebo, 30%, 50%, or 70% Niraparib implant. Blowup (right) of tissue adjacent to implant shown, dashed box (left). (*) indicates implant site. Bar equal to 1000 pm.

[0022] Figs. 5A-5C illustrate an example of a computerized tomography (CT) scan and irradiation protocol. Fig. 5A and Fig. 5B illustrate coronal and semi-transparent 3D view respectively through a live mouse with tumor in virtual in vivo CT slices. Fig. 5C illustrates schematic of mouse tumor irradiation using image guided techniques on SARRP Xstrahl research platform.

[0023] Figs. 6A-6C illustrate an example of placement of a drug implant described herein. Fig.6A illustrates location of implantation in rat prostate lobes. Fig.6B illustrates a five millimeter implant into a rat prostate. Fig. 6C illustrates surgical implantation of a drug implant described herein into a dog prostate by laparotomy. Two 18 gauge needles were used to insert two 15 mm x 1 mm implant in both prostate lobes from a ventro-cranial approach with transrectal ultrasound confirmation of implant placement.

[0024] Fig.7A and Fig.7B illustrate elution of Olaparib from a drug implant of the disclosure. Fig.7A illustrates average daily elution over 50 days from a drug implant comprising 10%, 30%, 50%, or 70% of Olaparib. Fig.7B illustrates cumulative elution from a drug implant comprising 10%, 30%, 50%, or 70% of Olaparib.

[0025] Fig.8 lists various example formulations of Pamiparib implants.

[0026] Figs. 9 A and 9B illustrate cumulative and daily drug release of Pamiparib implants.

[0027] Fig. 10 compares cumulative elution from drug implants comprising Pamiparib with drug implants comprising Talazoparib.DETAILED DESCRIPTION OF THE DISCLOSURE

[0028] To address the current drawbacks relating to treatment with PARP inhibitors, described herein are drug implants containing Pamiparib, Olaparib, or Niraparib and methods for increasing the therapeutic efficacy of Pamiparib, Olaparib, or Niraparib and reducing adverse side effects associated with systemic administration of Pamiparib, Olaparib, or Niraparib. In some aspects, provided herein are drug implants comprising a biocompatible polymer matrix and Pamiparib, Olaparib, or Niraparib dispersed in the biocompatible polymer matrix. In some embodiments, the Pamiparib, Olaparib, or Niraparib is present in the drug implant at an amount from about 10% w / w to about 80% w / w. In some embodiments, the Pamiparib, Olaparib, or Niraparib is in dissolvedform, solid form, crystalline form, a semi-crystalline form an amorphous form, a dissolved form, or a combination thereof.

[0029] In some embodiments, the drug implant comprises a biocompatible polymer matrix. In some embodiments, the polymer matrix comprises a polymer described herein. In some embodiments, the polymer comprises a biodegradable polymer. In some embodiments, the polymer consists of the biodegradable polymer. In some embodiments, the polymer comprises a non-biodegradable polymer. In some embodiments, the polymer consists of the non-biodegradable polymer. In some embodiments, the polymer comprises a bio-degradable polymer, a non-biodegradable polymer, or a combination thereof.

[0030] In some embodiments, the polymer comprises a non-biodegradable polymer described herein. In some embodiments, the drug implant comprises a non-biodegradable polymer comprising silicone. In some embodiments, the drug implant comprises a non-biodegradable polymer comprising polyurethane. In some embodiments, the drug implant comprises a non-biodegradable polymer comprising polyethylene vinyl acetate). In some embodiments, the drug implant comprises Pamiparib. Fig. 1A illustrates a drug implant design, where the PARP inhibitor (e.g., Pamiparib, Olaparib, or Niraparib) is dispersed within the drug implant (e.g., without a coating). Such configuration may lead to an initial burst of elution of the PARP inhibitor (e.g., Pamiparib, Olaparib. or Niraparib) followed by a steady (but decreased) rate of elution of the PARP inhibitor (e.g., Pamiparib, Olaparib, or Niraparib) after the administration of the drug implant to the subject. The steady elution of the PARP inhibitor (e.g., Pamiparib, Olaparib, or Niraparib) can last for months or years after administration of the drug implant. Fig. IB illustrates another example of a drug implant design, where the drug implant comprises a control release coating layer. The coating can lead to controlled release of the PARP inhibitor (e.g., Pamiparib, Olaparib, or Niraparib).

[0031] In some embodiments, the drug implant delivers the Pamiparib, Olaparib, or Niraparib locally to a target tissue or a tissue near or adjacent to the target tissue. In some embodiments, the target tissue comprises prostate tissue, bladder tissue, ovarian tissue, fallopian tissue, liver tissue, bone tissue, breast tissue, pancreatic tissue, lung tissue, gastric tissue, kidney tissue, gall bladder tissue, colon tissue, or a combination thereof. In some embodiments, the local delivery of the Pamiparib, Olaparib, or Niraparib increases or potentiates therapeutic efficacy of a therapy such as radiation, chemotherapy, biologic therapy, immunologic therapy, hormonal therapy, or a combination thereof. In some embodiments, the local delivery of the Pamiparib, Olaparib, or Niraparib increases or potentiates therapeutic efficacy of radiation therapy. In some embodiments, the local delivery of the Pamiparib, Olaparib, or Niraparib decreases toxicity to a subject receivingthe drug implant. In some embodiments, the decrease of toxicity stems from the subject needing a decreased dose of the Pamiparib, Olaparib, or Niraparib, or a decreased dose of an additional therapy, such as radiation therapy. In some embodiments, the compositions and methods provided herein reduce (e.g., reduce occurrence of, reduce severity of, etc.) or eliminate adverse side effects associated with systemic administration. Adverse side effects associated with systemic administration of Pamiparib, Olaparib. or Niraparib, any of which can be reduced or eliminated by the compositions and methods provided herein, include, without limitation, thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, fatigue, constipation, vomiting, abdominal pain / distension, mucositis / stomatitis, diarrhea, dyspepsia, dry mouth, decreased appetite, urinary tract infection, AST / ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, and hypertension. In some embodiments, the local delivery of the Pamiparib, Olaparib, or Niraparib increases therapeutic efficacy for treating a disease or disorder in a subject. In some embodiments, the disease or disorder is associated with a tumor. In some embodiments, the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.

[0032] Described herein, in some aspects, is a method for treating a disease or disorder associated with a tumor in a subject. In some embodiments, the method comprises implanting, into the tumor or into a tissue adjacent to the tumor of the subject, at least one drag implant described herein. In some embodiments, the method comprises continuously delivering the Pamiparib, Olaparib, or Niraparib in the subject by the drug implant for at least 6 months, at least 12 months, at least 24 months, at least 60 months, or longer. In some embodiments, the use of the drug implant described herein results in a decreased total dose of the Pamiparib, Olaparib, or Niraparib needed in the subject for achieving the same therapeutic efficacy compared to an oral dose of the Pamiparib needed in the subject. In some embodiments, the total dose of the Pamiparib, Olaparib, or Niraparib administered to the subject by the implanting is less than 200 mg over a period of 6 months. In some embodiments, the method comprises implanting the drug implant into the subject by transperineal administration. In some embodiments, the method comprises implanting the drug implant into a target tissue or a tissue near or adjacent to the target tissue. In some embodiments, the target tissue comprises prostate tissue, bladder tissue, ovarian tissue, fallopian tissue, liver tissue, bone tissue, breast tissue, pancreatic tissue, lung tissue, gastric tissue, kidney tissue, gall bladder tissue, colon tissue, or a combination thereof. In some embodiments, the method increases or potentiates therapeutic efficacy of an additional therapy, such as radiation therapy. In some embodiments, themethod decreases toxicity to a subject receiving the drug implant. In some embodiments, the decrease of toxicity stems from the subject needing a decreased dose of the Pamiparib, Olaparib, or Niraparib or a decreased dose of an additional therapy, such as radiation therapy. Non-limiting example of the toxicity can include weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity or a combination thereof. In some embodiments, the method increases therapeutic efficacy for treating a disease or disorder in a subject. In some embodiments, the disease or disorder is associated with a tumor. In some embodiments, the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.

[0033] Provided herein are drug implants that are capable of delivering a therapeutically effective amount of Pamiparib, Olaparib, or Niraparib directly to a target tissue. Further provided herein are drug implants that, when implanted into a target tissue, result in a high concentration of Pamiparib, Olaparib, or Niraparib within the target tissue, and a low concentration of Pamiparib, Olaparib, or Niraparib in the systemic circulation (e.g., in the blood plasma). In some cases, the ability of the drug implants provided herein to deliver a therapeutically effective amount of Pamiparib, Olaparib, or Niraparib directly to the target tissue, while achieving low concentrations of Pamiparib, Olaparib, or Niraparib in the systemic circulation, may reduce or eliminate side effects or toxicity of Pamiparib, Olaparib, or Niraparib treatment that would otherwise occur from systemic administration. In addition, delivery of Pamiparib, Olaparib, or Niraparib directly to the target tissue by way of the drug implants described herein, ensures that the target tissue receives a therapeutically effective amount of Pamiparib, Olaparib, or Niraparib. In further aspects, the drug implants provided herein are capable of being loaded with a large amount of Pamiparib such that the drug implant is capable of sustained release of Pamiparib, Olaparib, or Niraparib to the target tissue for extended periods of time. In some aspects, Pamiparib, Olaparib, or Niraparib may be dispersed within a polymer matrix of the implant which may provide particular advantages (e.g., faster elution times, higher drug loading within the implant, etc.). In particular aspects, the drug implants provided herein may contain Pamiparib, Olaparib, or Niraparib at high concentrations such that a therapeutically effective amount of Pamiparib, Olaparib, or Niraparib can be administered directly to prostate tissue for long periods of time (e.g., 6 months or greater) while maintaining low systemic concentrations of Pamiparib, Olaparib, or Niraparib.

[0034] In various aspects, the drug implants disclosed herein may comprise a polymer matrix and Pamiparib, Olaparib, or Niraparib. In particular cases, Pamiparib, Olaparib, or Niraparib may be dispersed within the polymer matrix. In some cases, the polymer matrix comprises a non-biodegradable polymer. In some cases, the polymer matrix comprises a biodegradable polymer. The drug implants may be implanted into a target tissue, and may release a quantity of Pamiparib, Olaparib, or Niraparib over time. The drug implants containing Pamiparib, Olaparib, or Niraparib may be effective to treat a disease or a symptom thereof. In some cases, the disease is cancer or a tumor.

[0035] Further provided herein are methods of treating a disease by delivering a drug implant (e.g., containing Pamiparib, Olaparib, or Niraparib) of the disclosure to a target tissue of a subject in need thereof in order to deliver a therapeutically effective amount of Pamiparib, Olaparib, or Niraparib for extended periods of time. Additionally, methods of manufacturing drug implants and kits including drug implants are provided.Drug Implants

[0036] Provided herein are drug implants (also referred to herein as “implants”) suitable for delivering Pamiparib, Olaparib, or Niraparib to a target tissue. In some aspects of the disclosure, the implant comprises a polymer matrix and Pamiparib, Olaparib, or Niraparib dispersed therein.Generally, the implant comprises a biocompatible polymer. In some cases, the implant comprises a non-biodegradable polymer. In some cases, the implant comprises a biodegradable polymer. In some cases, the polymer matrix comprises a combination of a biodegradable polymer and a non-biodegradable polymer. Generally, the drug implants described herein are large (e.g., millimetersized) polymer implants that are surgically implanted into a subject. The implants provided herein are configured to remain within a tissue for a period of time. In some cases, the implants are configured to dissolve over a period of time, such as when a biodegradable polymer material is used. In other cases, the implants are configured to remain indefinitely within a target tissue, such as when a non-biodegradable polymer material is used. The drug implants described herein are not and / or do not comprise microparticles, nanoparticles, or the like. The drug implants described herein do not include Pamiparib, Olaparib, or Niraparib encapsulated within a microparticle, nanoparticle, or other similar particles.

[0037] In some embodiments, the drug implant is suitable for treating a disease or disorder associated with a tumor. In some embodiments, the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof.

[0038] The polymer matrix may comprise any polymer material. Generally, the polymer material is biocompatible. The term “biocompatible” as used herein refers to a property of a material that allowsfor prolonged contact with a tissue in a subject without causing toxicity or significant damage. In some cases, a “biocompatible” polymer material is in accordance with the guidelines set forth by the International Organization for Standardization (ISO) 10993-1:2018.

[0039] In some aspects, the polymer material may be “non-biodegradable” or “substantially non-biodegradable”. The terms “non-biodegradable” or “substantially non-biodegradable”, when used in reference to an implant of the disclosure, generally refer to an implant that is incapable or substantially incapable of being decomposed (e.g., by microorganisms, by enzymes (e.g., esterases), by oxidation) over the intended life of the implant. For example, a substantially non-biodegradable implant of the disclosure may have at least 99% by weight of the polymer material remaining two years after implanting the device into a target tissue. In some embodiments, at least 99% by weight of the biocompatible, non-biodegradable polymer matrix remains in a target tissue of a subject after implantation for at least 12 months, at least 24 months, at least 36 months, at least 48 months, at least 60 months, or longer.

[0040] In some cases, a “non-biodegradable” implant or polymer may be in accordance with the guidelines set forth by the Standard Guide for Assessment of Absorbable Polymeric Implants (ASTM F2902-16) by ASTM International. In some embodiments, the drug implant comprises biodegradable polymer. In some embodiments, the drug implant is at least partially biodegradable.

[0041] In certain aspects of the disclosure, the polymer matrix may comprise polysiloxane (silicone). The silicone may be any biocompatible silicone. The silicone may be any biocompatible, non-biodegradable silicone. In some cases, the silicone may be a medical grade silicone. In some cases, the silicone may be hydrophobic. In some cases, the silicone may be a United States Pharmacopeia (USP) Class V or USP Class VI certified silicone. In various aspects, the silicone may be an acetoxy-cure silicone. In some cases, the silicone may be a Silbione® silicone adhesive as manufactured by Elkem (e.g., Silbione® Biomedical ADH1 M200; accessible atsilicones.elkem.com / EN / our_offer / Product / 90061907 / _ / SILBIONE-BIO-ADH1-M200 as of September 1, 2020). In some cases, the silicone may be a platinum-cure silicone. In various aspects, the silicone may be any liquid silicone rubber (LSR). In some cases, the silicone may be a Silbione® Liquid Silicone Rubber (LSR) as manufactured by Elkem. In some cases, the Silbione® LSR may be one or more of Silbione® LSR 4301, Silbione® LSR 4305, Silbione® LSR 4310, Silbione® LSR 4325, Silbione® LSR 4330, Silbione® LSR 4340, Silbione® LSR 4350, Silbione® LSR 60. Silbione® LSR 4360, Silbione® LSR 4370, Silbione® LSR 4745, Silbione® LSR 4755, Silbione® LSR 4765, Silbione® LSR 4125, Silbione® LSR 4130, Silbione® LSR 4140, Silbione® LSR M301, Silbione® LSR M305, Silbione® LSR M310, Silbione® LSR M325, Silbione® LSR M330, Silbione® LSRM340, Silbione® LSR M350, Silbione® LSR M360, Silbione® LSR M365, Silbione® LSR M370, Silbione® LSR M125, Silbione® LSR M130, Silbione® LSR M140. In various aspects, the silicone may be Silbione® LSR D370. In some cases, the silicone may be a silicone manufactured by NuSil™. In various aspects, the silicone may be DDL 4870 as manufactured by NuSil™. In some cases, the silicone may be one or more of the following silicones as manufactured by NuSil™:MED-4801, MED-4805, MED-4810, MED-5820, MED-5830. MED-5840. MED-5850. MED-5860. MED-5870, MED-4880, MED50-5338, MED-5440, MED-4842, and MED 1-4855.

[0042] In other various aspects, the polymer material may be a thermoplastic polyurethane. In some embodiments, the thermoplastic polyurethane is biocompatible and non-biodegradable. In some cases, the polyurethane may be one or more of the following polyurethanes manufactured by Lubrizol: PY-PT72AE, PY-PT87AE, PY-PT87AS, PY-PT83AL, and PY-PT43DE20.

[0043] In other various aspects, the polymer material may be poly (ethylene vinyl acetate) (PEVA). In some embodiments, the polyethylene vinyl acetate) (PEVA) is biocompatible and non-biodegradable. In some cases, the PEVA may be one or more PEVAs manufactured by Celanese (e.g., under the brand name ATEVA® or VitalDose®). The vinyl acetate content of the PEVA may be from 9% to 40%. In particular embodiments, the vinyl acetate content is 10%. In other particular embodiments, the vinyl acetate content is 28%. In yet other particular embodiments, the vinyl acetate content is 40%.

[0044] The Shore A hardness scale measures the hardness of rubbers. A higher number on the scale refers to a firmer material, whereas a lower number on the scale refers to a softer material.Generally, the polymer material in the drug implant has a Shore A hardness of at least 30-durometer. For example, the polymer material may have a Shore A hardness of at least 30-durometer, at least 40-durometer, at least 50-durometer, at least 60-durometer, or at least 70-durometer. In one aspect, the uncured polymer material may have a Shore A hardness of 30-durometer, and the cured polymer material may have a Shore A hardness of 70-durometer.

[0045] The implant may further comprise a therapeutically active agent (e.g., Pamiparib, Olaparib, or Niraparib). In some cases, Pamiparib, Olaparib, or Niraparib is dispersed or distributed within the polymer matrix. In some cases, the Pamiparib, Olaparib, or Niraparib is dispersed or distributed throughout the polymer matrix. In some cases, Pamiparib, Olaparib, or Niraparib is uniformly or homogeneously dispersed or distributed within the polymer matrix. In other cases, Pamiparib, Olaparib, or Niraparib is heterogeneously dispersed or distributed within the polymer matrix. In other cases, Pamiparib, Olaparib, or Niraparib is dispersed or distributed within the polymer matrix in a gradient. In particular aspects, Pamiparib, Olaparib, or Niraparib is dispersed or distributedwithin the polymer matrix at the time of manufacture of the implant (e.g., Pamiparib, Olaparib, or Niraparib is mixed with the polymer material prior to curing of the polymer material, as disclosed herein). In some cases, dispersing Pamiparib, Olaparib. or Niraparib within the polymer matrix may be advantageous over other drug implants (e.g., those in which the drug is encapsulated in a capsule, or in the lumen of a tube). For example, dispersing Pamiparib, Olaparib, or Niraparib within the polymer matrix may allow for higher loading of Pamiparib, Olaparib. or Niraparib in the implant, faster elution rates, and the like. In some cases, the Pamiparib, Olaparib, or Niraparib is not encapsulated in a microparticle, a nanoparticle, or other similar particle.

[0046] In various aspects of the disclosure, the implant may comprise Pamiparib, Olaparib, or Niraparib in an amount from about 0.5% w / w to about 80% w / w. For example, the implant may comprise Pamiparib in an amount of about 0.5% w / w, about 1% w / w, about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, about 75% w / w, or about 80% w / w. In various aspects, the implant may comprise Pamiparib, Olaparib, or Niraparib in an amount of at least about 0.5% w / w, at least about 1% w / w, at least about 5% w / w, at least about 10% w / w, at least about 15% w / w, at least about 20% w / w, at least about 25% w / w, at least about 30% w / w, at least about 35% w / w, at least about 40% w / w, at least about 45% w / w, at least about 50% w / w, at least about 55% w / w, at least about 60% w / w, at least about 65% w / w, at least about 70% w / w, at least about 75% w / w, or at least about 80% w / w. In particular aspects, Pamiparib, Olaparib, or Niraparib is present in the implant in an amount of about 0.5% w / w, about 1% w / w, about 5% w / w, 10% w / w, about 30% w / w, about 45% w / w, or about 60% w / w. In some cases, the disclosure provides drug implants loaded with high concentrations of Pamiparib, Olaparib, or Niraparib (e.g., about 60% w / w or greater). In some cases, the implant may contain Pamiparib, Olaparib, or Niraparib in an amount of at least about 30% w / w. In some cases, the implant may contain Pamiparib, Olaparib, or Niraparib in an amount of at least about 45% w / w.

[0047] In various aspects of the disclosure, the implant may comprise Pamiparib, Olaparib, or Niraparib in an amount from about 5% volume / volume (v / v) to about 60% v / v. For example, the implant may comprise Pamiparib, Olaparib, or Niraparib in an amount of about 5% v / v, about 10% v / v, about 15% v / v, about 20% v / v, about 25% v / v, about 30% v / v, about 35% v / v, about 40% v / v, about 45% v / v. about 50% v / v, about 55% v / v, or about 60% v / v. In various aspects, the implant may comprise a therapeutically active agent (e.g., Pamiparib, Olaparib, or Niraparib) in an amount of at least about 5% v / v, at least about 10% v / v, at least about 15% v / v, at least about 20% v / v, at least about 25% v / v. at least about 30% v / v, at least about 35% v / v, at least about 40% v / v, at leastabout 45% v / v, at least about 50% v / v, at least about 55% v / v, or at least about 60% v / v. In particular aspects, Pamiparib, Olaparib, or Niraparib is present in the implant in an amount of at least about 30% v / v.

[0048] In various aspects, an implant of the disclosure may include Pamiparib, Olaparib, or Niraparib in a total amount of at least about 1 mg, for example, from about 1 mg to about 20 mg. In some cases, the total amount of Pamiparib, Olaparib, or Niraparib in the implant may be from about 8 mg to about 20 mg. For example, the implant may include Pamiparib, Olaparib, or Niraparib in a total amount of about 1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 20.0 mg.

[0049] In various aspects of the disclosure, the polymer material may be cured with the Pamiparib, Olaparib, or Niraparib present therein. Without wishing to be bound by theory, curing refers to a chemical process that results in the hardening of a polymer material by cross-linking polymer chains. Any method may be used to cure a polymer of the disclosure, including the use of electron beams, heating, and / or the addition of additives. In various aspects of the disclosure, Pamiparib may be mixed with an uncured polymer material prior to curing. In some aspects, the polymer matrix may be at least 95% cured, at least 96% cured, at least 97% cured, at least 98% cured, at least 99% cured, at least 99.9% cured, or 100% cured.

[0050] Generally, the polymer material has a molding or curing temperature that is lower than the melting temperature of Pamiparib, Olaparib, or Niraparib, e.g., to prevent melting and / or degradation of the drug. In some cases, the polymer material may have a molding or curing temperature that islower than 195 °C, lower than 190 °C, lower than 185 °C, lower than 180 °C, lower than 175 °C, lower than 170 °C, lower than 165 °C, lower than 160 °C, lower than 155 °C, or lower than 150 °C.

[0051] In some cases, the polymer is a thermo-melt or thermoplastic that becomes moldable at elevated temperature and hardens upon cooling (e.g., polyurethane). In some cases, the polymer is a thermoset that is irreversibly hardened by curing (e.g., silicone) which may be promoted by addition of a catalyst and / or heat. In some cases, the polymer material may be cured at room temperature (e.g., about 25 °C). In some cases, the polymer requires exposure to air to cure.

[0052] In various aspects of the disclosure, Pamiparib, Olaparib, or Niraparib may be present in the implant in solid form. In some cases, solid Pamiparib may be dissolved upon contact with biological fluids (e.g., after implantation into a tissue), and may diffuse out of the implant and into the target tissue. In some cases, Pamiparib, Olaparib, or Niraparib is present in the implant in a dissolved form, in crystalline form, in a semi-crystalline form, or in an amorphous form. In general, the particle size of Pamiparib, Olaparib, or Niraparib within the implant may be important for drug content uniformity within the implant. Without wishing to be bound by theory, a small particle size may ensure a uniform distribution within the formulation and between implants upon molding of the formulation. In some cases, the Pamiparib, Olaparib, or Niraparib present in the implant may have a median particle size (e.g.. D50 particle size) of less than about 10 pm. In some cases, the Pamiparib, Olaparib, or Niraparib present in the implant may have a D90 particle size of less than about 15 pm.

[0053] Generally, an implant of the disclosure has mechanical properties such that the implant can be successfully deployed into a target tissue. For example, an implant of the disclosure may be sufficiently stiff such that it can be deployed into a target tissue successfully, but not too stiff that it breaks during deployment. It should be understood that the mechanical properties of devices described herein may vary depending on the polymer material used, and may be determined empirically. In some aspects, the implant containing the Pamiparib, Olaparib, or Niraparib may have a Shore A hardness of at least 30 durometer.

[0054] In various aspects, the implant may have a three-dimensional shape. The three-dimensional shape may be any suitable shape. In some cases, the implant may be cylindrical or substantially cylindrical. In some cases, the implant may be tubular or substantially tubular. In some cases, the implant may be elongate (e.g., may have a length greater than a width). In some cases, the implant may be not hollow. In some cases, the implant may be a rod, rod-shaped, or rod-like. In some embodiments, the implant may be circular. In some embodiments, the implant may comprise one or more rods. In some embodiments, the one or more rods are connected. In some embodiments, the implant may be a disk.

[0055] In various aspects, the implant may have a diameter. In some cases, a diameter of the implant may be from about 0.1 mm to about 5.0 mm. In some cases, a diameter of the implant may be from about 0.7 mm to about 5.0 mm. In some cases, a diameter of the implant may be from about 0.9 mm to about 1.1 mm. In some cases, a diameter of the implant may be at least about 0.1 mm, for example, at least about 0.1 mm, at least about 0.2 mm, at least about 0.3 mm, at least about 0.4 mm, at least about 0.5 mm, at least about 0.6 mm, at least about 0.7 mm, at least about 0.8 mm, at least about 0.9 mm, at least about 1.0 mm, at least about 1.1 mm, at least about 1.2 mm, at least about 1.3 mm, at least about 1.4 mm, or at least about 1.5 mm. In some cases, a diameter of the implant may be less than about 1 mm, for example, less than about 1 mm, less than about 0.9 mm, less than about 0.8 mm, less than about 0.7 mm, less than about 0.6 mm, less than about 0.5 mm, less than about 0.4 mm, less than about 0.3 mm, less than about 0.2 mm, or less than about 0.1 mm. In some cases, a diameter of the implant may be at least about 0.1 mm. In some cases, a diameter of the implant may be at least about 0.8 mm. In some cases, a diameter of the implant may be about 1 mm. In some cases, a diameter of the implant may be about 2 mm. In some cases, a diameter of the implant may be about 3 mm. In some cases, a diameter of the implant may be about 4 mm. In some cases, a diameter of the implant may be about 5 mm.

[0056] In various aspects, the implant may have a length. In some cases, a length of the implant may be from about 1 mm to about 30 mm. In some cases, a length of the implant may be from about 5 mm to about 25 mm. In some cases, a length of the implant may be from about 10 mm to about 20 mm. In some cases, a length of the implant may be from about 12 mm to about 18 mm. In some cases, a length of the implant may be at least about 1 mm, at least about 2 mm, at least about 3 mm, at least about 4 mm, at least about 5 mm, at least about 6 mm, at least about 7 mm, at least about 8 mm, at least about 9 mm, at least about 10 mm, at least about 11 mm, at least about 12 mm, at least about 13 mm, at least about 14 mm, at least about 15 mm, at least about 16 mm, at least about 17 mm, at least about 18 mm, at least about 19 mm, at least about 20 mm, at least about 21 mm, at least about 22 mm, at least about 23 mm, at least about 24 mm, at least about 25 mm, at least about 26 mm, at least about 27 mm, at least about 28 mm, at least about 29 mm, or at least about 30 mm. In some cases, a length of the implant is at least about 1 mm. In some cases, a length of the implant is at least about 3 mm. In some cases, a length of the implant is about 15 mm. In some cases, a length of the implant may be less than about 30 mm, for example, less than about 30 mm, less than about 29 mm, less than about 28 mm, less than about 27 mm, less than about 26 mm, less than about 25 mm, less than about 24 mm, less than about 23 mm, less than about 22 mm, less than about 21 mm, less than about 20 mm, less than about 19 mm, less than about 18 mm, less than about 17 mm, lessthan about 16 mm, less than about 15 mm, less than about 14 mm, less than about 13 mm, less than about 12 mm, less than about 11 mm, less than about 10 mm, less than about 9 mm, less than about 8 mm, less than about 7 mm, less than about 6 mm, less than about 5 mm, less than about 4 mm, less than about 3 mm, less than about 2 mm, or less than about 1 mm.

[0057] In various aspects, the implant may have a volume. In some cases, the volume of the implant may be from about 0.1 mm3to about 30 mm3. For example, the volume of the implant may be about 0.1 mm3, about 0.5 mm3, about 1 mm3, about 5 mm3, about 10 mm3, about 15 mm3, about 20 mm3, about 25 mm3, or about 30 mm3. In some cases, the volume of the implant may be about 10 mm3.

[0058] In various aspects, the implant may lack a coating, covering, or a sheath. In some embodiments, the implant lacks at least one of a sheath, a scaffold, a retention member for retaining the drug implant within a target tissue, or a combination thereof. For example, in some cases, a portion of the outer surface of the implant may not be coated or covered such that the outer surface of the uncoated or uncovered portion of the implant is directly exposed to or directly contacts the biological environment (e.g., a target tissue, a biological fluid) after implantation. In some examples, the entire outer surface or substantially the entire outer surface of the implant is uncovered or uncoated such that the entire outer surface or substantially the entire outer surface of the implant is directly exposed to or directly contacts a biological environment after implantation. In other cases, less than the entire outer surface of the implant is directly exposed to or directly contacts a biological environment after implantation. For example, in some cases, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the outer surface of the implant is directly exposed to or directly contacts a biological environment after implantation. In some cases, at least about 50% of the outer surface of the implant is directly exposed to or directly contacts a biological environment after implantation. In some cases, the implant may lack a sheath, a scaffold, a retention member, a retention frame, or any other additional means for retaining the implant within the target tissue. In some cases, the implant may consist essentially of the polymer matrix and the therapeutically active agent (e.g., Pamiparib, Olaparib. or Niraparib) dispersed therein.

[0059] In some cases, the implant may comprise a coating. In some cases, the coating may cover the implant. In some cases, the coating may partially cover the implant. In some cases, the coating maysubstantially cover the implant. In some cases, the implant may comprise a core made of a first polymer material, and a coating of a second polymer material. In a non-limiting example, an implant of the disclosure may include a non-silicone core, surrounded by a silicone coating. In some cases, an implant of the disclosure does not comprise a metal. In some embodiments, the coating modulates the release of the Pamiparib, Olaparib, or Niraparib. For example, the coating allows the drug implant to release the Pamiparib by zero order release.

[0060] In some embodiments, the coating comprises at least one additional therapeutic. For example, the at least one additional therapeutic can be dispersed in the coating to be eluted after insertion of the drug implant into the subject. In some embodiments, the at least one additional therapeutic comprises a cytotoxic therapeutic. In some embodiments, the at least one additional therapeutic comprises a hormonal therapeutic. In some embodiments, the at least one additional therapeutic comprises a biologic therapeutic.

[0061] In various aspects, the implant may prevent modulation of the Pamiparib, Olaparib, or Niraparib contained therein when the implant is implanted into a subject. Modulation can include, but is not limited to, degradation, chemical modification, and the like. For example, the biological environment of a tissue may include degradants that are capable of degrading the drug (e.g., esterases, amidases). In some cases, the implant may protect the therapeutically active agent from degradation by preventing the degradant from penetrating the implant. In various aspects, in vitro stability testing may be performed to determine the protective effect of the implant on the therapeutically active agent contained therein. In such cases, the therapeutically active agent may be capable of diffusing out of the implant while maintaining in vivo stability within the implant. In various aspects, the ability of a degradant to degrade a therapeutically active agent within the implant may be determined by a simulated in vivo stability assay. In a non-limiting example, an implant of the disclosure comprising a therapeutically active agent may be incubated in a solution comprising a degradant (known to degrade the therapeutically active agent). After a period of incubation, the therapeutically active agent may be extracted from the implant and degradation peaks may be measured (e.g., by high-performance liquid chromatography (HPLC)).

[0062] In various aspects of the disclosure, an implant of the disclosure may be configured to be delivered directly to a target tissue of a subject. In some cases, the target tissue may be prostate tissue. In some cases, an implant of the disclosure may be configured to be delivered to a tissue adjacent to or nearby a target tissue. In some cases, the therapeutically active agent may diffuse out of the implant in a controlled manner and act directly on the target tissue.

[0063] In various aspects, an implant of the disclosure may be configured to remain within the target tissue for a period of time. In some cases, an implant of the disclosure may be configured to remain within the target tissue indefinitely (e.g.. is never removed). In some cases, two or more implants of the disclosure may be implanted into the target tissue. For example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more than 20 implants may be implanted in the target tissue. In some cases, the two or more implants may be implanted in different sites of the target tissue (e.g., to deliver drug to different sites of the target tissue). In some cases, the two or more implants may be implanted in close proximity to one another within the target tissue. In some cases, one or more initial implants may be implanted, and additional implants may be later implanted after the drug has been exhausted from the initial implants. For example, one or more additional implants may be implanted after a drug has stopped, or substantially stopped, eluting from one or more initial implants. In some cases, an implant of the disclosure may be visible by ultrasound when disposed within the target tissue of the subject. In some cases, an implant of the disclosure may be visible by MRI when disposed within the target tissue of the subject. In such cases, the position of the implant may be monitored non-invasively. In some cases, the implant may be sterilized prior to implantation into a subject. In some cases, the implant is sterilized via gamma sterilization.

[0064] In various aspects, an implant of the disclosure may be capable of delivering a sustained release of Pamiparib, Olaparib, or Niraparib for a period of time. For example, an implant of the disclosure may be capable of sustained release of the Pamiparib, Olaparib, or Niraparib. “Sustained release” as used herein refers to the capability of the implant to release an amount of drug for an extended period of time after implantation into a target tissue. In some cases, an implant of the disclosure may be capable of delivering an amount of drug to a target tissue for at least 6 months, at least 9 months, at least 12 months, at least 18 months, or at least 24 months. In particular cases, an implant of the disclosure may be capable of delivering at least 0.5 pg / day of Pamiparib, Olaparib, or Niraparib for at least 6 months after implantation into a target tissue (e.g., prostate tissue or tissue adjacent or near the prostate). In some cases, an implant of the disclosure may be capable of delivering at least 0.1 pg / day of Pamiparib, Olaparib, or Niraparib (e.g., to a target tissue) for up to 24 months after implantation into a target tissue (e.g., prostate tissue or tissue adjacent or near the prostate).

[0065] Methods for Manufacturing Drug Implants

[0066] Further provided herein are methods for manufacturing the implants described herein. A nonlimiting example of a method for manufacturing a drug implant of the disclosure may be as provided in Examples 1-4.

[0067] In some aspects, the methods may involve mixing an amount of polymer material with an amount of Pamiparib, Olaparib, or Niraparib to form a mixture. In some cases, the polymer is a thermoset and the Pamiparib, Olaparib, or Niraparib is mixed into the uncured polymer material. In some cases, the polymer is a thermoplastic and the Pamiparib, Olaparib, or Niraparib is mixed into a solution or melt of the polymer material. The methods may further involve molding the mixture to create a molded structure. The molded structure may be formed by molding the mixture in a mold (e.g., transfer molding process), by extruding the mixture (e.g., through a tube), or by any other process. In the case of a thermoset, the methods may further involve allowing the molded mixture to cure for a period of time with or without elevated temperature. In some cases, the polymer material may be any biocompatible silicone provided herein. In an exemplary aspect, the silicone may be Silbione® ADH1 M200. In another exemplary aspect, the silicone may be a platinum-cure silicone, e.g., Silbione® D370. In the case of a thermoplastic, the mixture may be molded as described at elevated temperature and cooled to solidify the polymer. In some cases, the thermoplastic may be any biocompatible polyurethane provided herein. In some cases, the molding includes extruding the mixture using a ram extruder or a twin screw extruder. In some cases, the molding includes injection molding.

[0068] In some aspects, the mixture may further comprise a solvent. Non-limiting examples of solvents that may be used include pentane, heptane, toluene, dichloromethane, tetrahydrofuran, and hexane. A solvent may be used to, e.g., reduce the viscosity of the liquid polymer. In some aspects, the mixture may be molded by a transfer molding process or by extrusion (e.g., through a tube).

[0069] The therapeutically active agent (e.g., Pamiparib, Olaparib, or Niraparib) may be provided in the mixture in an amount such that a total amount of active agent in the implant may be from about 0.5% w / w to about 80% w / w, for example, about 0.5% w / w, about 1% w / w, about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, about 75% w / w, or about 80% w / w. In some cases, the total amount of active agent (e.g., Pamiparib, Olaparib, or Niraparib) in the implant may be at least about 0.5% w / w, at least about 1% w / w, at least about 5% w / w, at least about 10% w / w, at least about 15% w / w, at least about 20% w / w, at least about 25% w / w, at least about 30% w / w, at least about 35% w / w, at least about 40% w / w, at least about 45% w / w, at least about 50% w / w, at least about 55% w / w, at least about 60% w / w, at least about 65% w / w, at least about 70% w / w, at least about 75% w / w, or at least about 80% w / w. Pamiparib, Olaparib, or Niraparib may be provided in the mixture in an amount such that atotal amount of Pamiparib, Olaparib, or Niraparib in the implant may be from about 1 mg to about 10 mg.

[0070] In some aspects, the thermomolding comprises heating and molding of the mixture (e.g., transfer molding, extrusion, or another process) at about 100 °C to about 175 °C, for example, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, or about 175 °C. The molding temperature generally depends on the polymer material selected. Generally, the molding temperature of the polymer material is selected such that it is lower than the melting temperature of the therapeutically active agent. For a thermoplastic, the mixture is heated for sufficient time to achieve a moldable state prior to molding. In some cases, the mixture is heated from about 3 minutes to about 8 minutes, for example, for about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, or about 8 minutes. In some cases, the melting temperature of Pamiparib, Olaparib, or Niraparib may be greater than the molding temperature of the silicone.

[0071] In some aspects, the mixture may further comprise a solvent. Non-limiting examples of solvents that may be used include pentane, heptane, toluene, dichloromethane, tetrahydrofuran, and hexane. A solvent may be used to, e.g., reduce the viscosity of the liquid polymer. In some aspects, the mixture may be molded by a transfer molding process or by extrusion (e.g., through a tube).

[0072] After manufacturing the implant as provided herein, the methods may further comprise performing one or more analyses on the implant. In some cases, the one or more analyses may be differential scanning calorimetry (DSC) (e.g., to determine the rate of curing of the implants and / or to evaluate properties of the drug). In some cases, the one or more analyses may be deployment of the implant into surrogate tissue. In some cases, the one or more analyses may be elution testing (e.g., to assess the rate of elution of drug from the implant). In some cases, the one or more analyses may be in vivo stability testing (e.g., to assess the ability of degradants to penetrate the implant). In some cases, the one or more analyses may be viscometry. In some cases, the one or more analyses may be the use of a rheometer (e.g., to assess the viscosity and curing profile for the formulation). In some cases, the one or more analyses may be high pressure liquid chromatography (e.g., to confirm content uniformity and assess impurities in the drug formulation and the molded implant). In some cases, the one or more analyses may be dynamic mechanical analysis (DMA) (e.g., to assess the mechanical properties of the implant to ensure it can be deployed correctly). In some cases, the one or more analyses may be high pressure liquid chromatography (HPLC).Methods of Treatment

[0073] Disclosed herein are methods of treating a disease (or a symptom thereof) in a subject. The terms “treating”, “treatment”, or “treat” may be used interchangeably herein and refer to providing atherapeutic benefit to a subject in need thereof. For example, treating a disease or disorder includes ameliorating, abrogating, reducing, relieving, or curing the disease or disorder. Treating a disease or disorder also includes ameliorating, abrogating, reducing, relieving, or curing one or more symptoms associated with a disease or disorder. When used in reference to a tumor, treating includes diminishing or reducing the size of the tumor or tumor volume.

[0074] In various aspects, the subject may have been diagnosed with, may be suspected of having, or may be at risk of having the disease (or one or more symptoms thereof). In some cases, the methods comprise implanting an implant of the disclosure into a target tissue of a subject. An implant of the disclosure may be implanted into a target tissue by any method. In some cases, the implant may be implanted into a target tissue by a surgical method or a non-surgical method. In some cases, the implant may be implanted using standard surgical tools, for example, tools commonly used for biopsies or brachytherapy. In some cases, the implant may be implanted into a target tissue by use of, e.g., a needle, forceps, a catheter (e.g., with a lumen). For example, in one embodiment, the implant may be implanted into a target tissue by deployment from the lumen of a needle or a catheter. In some cases, the implant may be implanted into a target tissue using a cannula of a prostate biopsy needle. In some cases, the implant may be implanted into a target tissue using a Mick® needle. In some cases, deployment of the implant may be guided by ultrasound. In some cases, deployment of the implant may be guided by MRI. In some cases, the implant may be implanted by transperineal implantation (e.g., by use of a template guided needle). In some cases, the implant may be sterile and disposed within a packaging.

[0075] In a non-limiting example, a method of deploying an implant of the disclosure into a target tissue may involve disposing a distal end of an elongate tube into the target tissue (e.g., the prostate or tissue adjacent the prostate). In some cases, the elongate tube may be a needle having a lumen. The elongate tube may have a sharp end such that the distal end of the elongate tube can penetrate the target tissue. In some cases, the distal end of the elongate tube may be disposed through a first portion of a grid (e.g., a guide template) such that a first position of the elongate tube in the subject is determined. The grid may allow for proper placement of the implant into the target tissue. In some cases, a trocar is disposed within the lumen of the elongate tube. The methods may involve inserting the elongate tube (with or without a trocar disposed within a lumen of the elongate tube) into the target tissue. The methods may further involve, when using a trocar, removing the trocar from the lumen of the elongate tube, while maintaining the distal end of the elongate tube within the target tissue. The methods may further involve placing an implant of the disclosure within the lumen of the elongate tube. The implant may be pushed through the lumen of the elongate tube by a blunt-endedrod (e.g., a stylet) that is sized to fit within the lumen of the elongate tube. The stylet may be used to push the implant from a proximal end of the elongate tube to the distal end of the elongate tube. The methods may further involve, while maintaining the stylet in position, removing the elongate tube from the target tissue. As the elongate tube is removed from the target tissue, the stylet may push the implant out of the elongate tube and into the target tissue. The methods may further involve removing both the stylet and the elongate tube together from the target tissue.

[0076] In some aspects, the methods may involve implanting more than one implant into a target tissue of the subject. For example, the methods may involve implanting a first implant into a first portion of the target tissue, and a second implant into a second portion of the target tissue. In some cases, the first portion of the target tissue and the second portion of the target tissue may be different. In some cases, the first implant may comprise a first therapeutically active agent (e.g., Pamiparib, Olaparib, or Niraparib) and the second implant may comprise a second therapeutically active agent. In some cases, the first therapeutically active agent (e.g., Pamiparib, Olaparib, or Niraparib) and the second therapeutically active agent may be the same. In other cases, the first therapeutically active agent (e.g., Pamiparib, Olaparib, or Niraparib) and the second therapeutically active agent may be different. In some cases, a grid (e.g., a guide template) may be used to position the first implant within the first portion of the target tissue, and to position the second implant within the second portion of the target tissue. In some cases, the first implant and / or the second implant may be positioned with the use of ultrasound guidance. In some cases, the first implant and / or the second implant may be positioned with the use of MRI guidance.

[0077] In some aspects, the methods may further comprise implanting additional implants into the target tissue. For example, the methods may further comprise implanting a third implant into a third portion of the target tissue, implanting a fourth implant into a fourth portion of the target tissue, implanting a fifth implant into a fifth portion of the target tissue, implanting a sixth implant into a sixth portion of the target tissue, implanting a seventh implant into a seventh portion of the target tissue, implanting an eighth implant into an eighth portion of the target tissue, and so forth. The third, fourth, fifth, sixth, seventh, eighth, or more, therapeutically active agents may each be the same, different, or combinations thereof. In some cases, at least three implants are implanted into a target tissue. For example, at least three implants may be implanted into the prostate or tissue adjacent or near the prostate by transperineal administration. In some cases, the implant(s) may be implanted into a target tissue via a minimally invasive approach.

[0078] In some aspects, one or more implants may be implanted into a target tissue (e.g., prostate or tissue adjacent or near a prostate) prior to a surgical procedure to treat cancer (e.g., prostate cancer).For example, one or more implants may be implanted into a prostate or tissue adjacent or near a prostate prior to performing a prostatectomy (e.g., a week before, two weeks before, three weeks before, etc.). In such cases, the prostatectomy may remove the prostate or a portion thereof. In some cases, the prostatectomy may remove one or more of the implants from the subject. In other cases, one or more implants may be implanted into a target tissue (e.g., prostate or tissue adjacent or near a prostate), and may remain in the target tissue indefinitely. For example, the one or more implants may provide a therapeutically effective amount of Pamiparib, Olaparib, or Niraparib to the target tissue for a period of time such that the subject is in remission, in non-progression, or cured of the cancer.

[0079] In some embodiments, described herein is a method for treating a disease or disorder in a subject. In some embodiments, the disease or disorder is a tumor in the subject, In some embodiments, the method comprises comprising implanting, into the tumor or into a tissue adjacent to the tumor of the subject, at least one drug implant described herein. In some embodiments, the at least one drug implant continuously delivers the Pamiparib, Olaparib. or Niraparib to the subject for at least 6 months, at least 12 months, at least 24 months, at least 60 months, or longer. In some embodiments, a total dose of the Pamiparib, Olaparib, or Niraparib administered to the subject by the implanting is less than a total dose of the Pamiparib, Olaparib. or Niraparib when administered to a subject by oral administration. In some embodiments, a total dose of the Pamiparib, Olaparib, or Niraparib administered to the subject by the implanting is less than 200 mg over a period of 6 months. In some embodiments, the implanting results in a blood plasma concentration of the Pamiparib, Olaparib, or Niraparib that is less than a blood plasma concentration of the Pamiparib, Olaparib, or Niraparib obtained when the Pamiparib, Olaparib, or Niraparib is administered to a subject by oral administration. In some embodiments, the implanting occurs via transperineal administration (e.g., by using a template guided needle). In some embodiments, the implanting locally delivers the Pamiparib, Olaparib. or Niraparib to the tumor. In some embodiments, the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof. In some embodiments, the method further comprises, after the implanting, administering to the subject at least one additional therapy to treat the tumor. In some embodiments, the method further comprises, after the implanting, recommending that the subject receive at least one additional therapy to treat the tumor. In some embodiments, the at least one additional therapy comprises radiation, chemotherapy, biologic therapy, immunologic therapy, hormonal therapy, or a combination thereof. In some embodiments,the at least one additional therapy comprises radiation. In some embodiments, the at least one additional therapy is more efficacious for treating the tumor after the implanting than after oral administration of the Pamiparib, Olaparib. or Niraparib. In some embodiments, an amount of the at least one additional therapy needed to effectively treat the tumor is lower after the implanting, as compared to an amount of the at least one additional therapy needed to effectively treat the tumor in the absence of the Pamiparib, Olaparib, or Niraparib. In some embodiments, the method results in decreased toxicity to the subject as compared to when the subject receives the at least one additional therapy without the Pamiparib, Olaparib, or Niraparib. In some embodiments, the toxicity comprises weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity, or a combination thereof of the subject. In some embodiments, the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51. FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.

[0080] The term “subject”, as used herein, generally refers to a vertebrate, such as a mammal, e.g., a human. Mammals include, but are not limited to, murines, simians, humans, research animals, farm animals, sport animals, and pets. In some cases, the methods described herein may be used on tissues derived from a subject and the progeny of such tissues. The tissues may be obtained from a subject in vivo. In some cases, the tissues may be cultured in vitro.

[0081] In some aspects, the methods provided herein may be used to treat a subject in need thereof. In some cases, the subject may suffer from a disease. In some cases, the subject may be a human. In some cases, the human may be a patient at a hospital or a clinic. In some cases, the subject may be a non-human animal, for example, a non-human primate, a livestock animal, a domestic pet, or a laboratory animal. For example, a non-human animal can be an ape (e.g., a chimpanzee, a baboon, a gorilla, or an orangutan), an old world monkey (e.g., a rhesus monkey), a new world monkey, a dog, a cat, a bison, a camel, a cow, a deer, a pig, a donkey, a horse, a mule, a lama, a sheep, a goat, a buffalo, a reindeer, a yak, a mouse, a rat, a rabbit, or any other non-human animal.

[0082] In cases where the subject may be a human, the subject may be of any age. In some cases, the subject may be about 50 years or older. In some cases, the subject may be about 55 years or older. In some cases, the subject may be about 60 years or older. In some cases, the subject may be about 65 years or older. In some cases, the subject may be about 70 years or older. In some cases, the subject may be about 75 years or older. In some cases, the subject may be about 80 years or older. In some cases, the subject may be about 85 years or older. In some cases, the subject may be about 90 years or older. In some cases, the subject may be about 95 years or older. In some cases, the subject may be about 100 years or older. In some cases, the subject may be about 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or greater than 100 years old. In some cases, the subject may be about 1, 2, 3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or greater than 20 years old. In some cases, the implants provided herein may be used for the prevention of cancer (e.g., in a subject from 20 years old to 50 years old). In some cases, the implants provided herein may be used for the treatment of cancer (e.g., in a subject from 20 years old to 85 years old).

[0083] In some cases, the methods provided herein may treat a disease in a subject. In some cases, the methods provided herein may alleviate or reduce a symptom of a disease. In some cases, the methods provided herein may result in a reduction in the severity of one or more symptoms associated with a disease. In some cases, the methods provided herein may slow, halt, or reverse the progression of one or more symptoms associated with a disease. In some cases, the methods provided herein may prevent the development of one or more symptoms associated with a disease. In some cases, the methods provided herein may slow, halt, or reverse the progression of a disease, as measured by the number and severity of symptoms experienced. In some cases, the methods provided herein may prevent the occurrence of cancer.

[0084] In some cases, the disease may be a proliferative disease or disorder. In some cases, the proliferative disease or disorder may be cancer. In some cases, the subject may have a tumor. In some embodiments, the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof. In some embodiments, the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof.

[0085] In some cases, the methods may reduce the size of a tumor. In some cases, the methods may reduce the size of a tumor by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or by about 100%.

[0086] In some aspects, the proliferative disease or disorder may be a proliferative disease or disorder of the prostate. In one non-limiting example, the proliferative disease or disorder of theprostate may be prostate cancer. Prostate cancer can be adenocarcinoma, sarcoma, neuroendocrine tumors, small cell carcinoma, transitional cell carcinoma, or squamous cell carcinoma.

[0087] The methods may be employed to deliver a therapeutically effective amount of Pamiparib, Olaparib, or Niraparib to a target tissue. In some cases, the methods may involve delivering a drag implant to a target tissue (or a tissue adjacent to the target tissue) of the subject. Any tissue may be suitable for delivery of a drug implant of the disclosure. In exemplary cases, the target tissue may be the prostate, tissue adjacent to the prostate, or both. Non-limiting examples of target tissue includes breast, pancreas, bladder, brain, skin, kidney, lung, liver, tongue, esophagus, stomach, intestine, gallbladder, heart, pituitary gland, pineal gland, thyroid gland, parathyroid gland, adrenal gland, eye, bone, fallopian tubes, uterus, ovary, sinuses, inner ear (eustachian tube), testes, and neck.

[0088] In various aspects of the disclosure, the methods provide for implanting a drug implant of the disclosure into the target tissue (or an adjacent tissue) of a subject, wherein the implant delivers a therapeutically effective amount of Pamiparib, Olaparib, or Niraparib to the target tissue. As used herein, a “therapeutically effective amount” when used in reference to a drug or therapeutically active agent refers to an amount of drag or therapeutically active agent that is capable of eliciting a therapeutic response in a subject. In various aspects of the disclosure, the implant may deliver a therapeutically effective amount of drag to a tissue of the subject from 6 months to 60 months or longer. In some cases, the implant may deliver a therapeutically effective amount of drug to a tissue of the subject for 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 36 months, 48 months, 60 months, or longer. In some cases, the implant may deliver a therapeutically effective amount of drag to a tissue of the subject for at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 36 months, at least 48 months, at least 60 months, or longer.

[0089] In various aspects of the disclosure, a therapeutically effective amount of drug may be at least about 0.1 pg / day. In some cases, a therapeutically effective amount of drag may be at least about 0.1 pg / day, about 0.2 pg / day, about 0.3 pg / day, about 0.4 pg / day, about 0.5 pg / day, about 0.6 pg / day, about 0.7 pg / day, about 0.8 pg / day, about 0.9 pg / day, about 1 pg / day, about 2 pg / day, about 3 pg / day, about 4 pg / day, about 5 pg / day, about 6 pg / day, about 7 pg / day, about 8 pg / day, about 9 pg / day. about 10 pg / day, about 15 pg / day, about 20 pg / day, about 25 pg / day, about 30 pg / day.about 35 pg / day, about 40 pg / day, about 45 pg / day, about 50 pg / day, about 55 pg / day, about 60 pg / day, about 65 pg / day, about 70 pg / day, about 75 pg / day, about 80 pg / day, about 85 pg / day, about 90 pg / day. about 95 pg / day, about 100 pg / day, about 110 pg / day, about 120 pg / day, about 130 pg / day, about 140 pg / day, about 150 pg / day, about 160 pg / day, about 170 pg / day, about 180 pg / day, about 190 pg / day, about 200 pg / day, about 210 pg / day, about 220 pg / day, about 230 pg / day. about 240 pg / day, about 250 pg / day, about 260 pg / day. about 270 pg / day, about 280 pg / day, about 290 pg / day, about 300 pg / day, about 310 pg / day, about 320 pg / day, about 330 pg / day, about 340 pg / day, about 350 pg / day, about 360 pg / day, about 370 pg / day, about 380 pg / day, about 390 pg / day, about 400 pg / day, about 410 pg / day, about 420 pg / day, about 430 pg / day, about 440 pg / day, about 450 pg / day, about 460 pg / day, about 470 pg / day, about 480 pg / day, about 490 pg / day, about 500 pg / day, about 510 pg / day, about 520 pg / day, about 530 pg / day, about 540 pg / day, about 550 pg / day, about 560 pg / day, about 570 pg / day, about 580 pg / day, about 590 pg / day, about 600 pg / day, about 610 pg / day, about 620 pg / day, about 630 pg / day. about 640 pg / day, about 650 pg / day, about 660 pg / day, about 670 pg / day, about 680 pg / day, about 690 pg / day, about 700 pg / day, about 710 pg / day, about 720 pg / day, about 730 pg / day, about 740 pg / day, about 750 pg / day, about 760 pg / day, about 770 pg / day, about 780 pg / day. about 790 pg / day, about 800 pg / day, about 810 pg / day. about 820 pg / day, about 830 pg / day, about 840 pg / day, about 850 pg / day, about 860 pg / day, about 870 pg / day, about 880 pg / day, about 890 pg / day, about 900 pg / day, about 910 pg / day, about 920 pg / day, about 930 pg / day, about 940 pg / day, about 950 pg / day, about 960 pg / day, about 970 pg / day, about 980 pg / day, about 990 pg / day, about 1000 pg / day or greater. It should be understood that a therapeutically effective amount of drug may vary based on the drug and / or the disease to be treated, and may be determined empirically.

[0090] In various aspects of the disclosure, the implant may be configured to remain within the target tissue for a period of time. In some cases, the implant may be configured to remain within the target tissue for long periods of time (e.g., months to years) or indefinitely (e.g., may never be removed). For example, after the implant has delivered all of the therapeutically active agent contained therein to the subject, the implant (devoid of the therapeutically active agent) may remain within the target tissue. In some cases, if additional treatment is needed, one or more additional implants may be delivered to the target tissue (without removing the initial implant). In some cases, the implant may be composed of a non-biodegradable and / or non-resorbable polymer material such that the polymer material remains substantially intact within the target tissue for long periods of time or indefinitely.

[0091] Advantageously, the implants of the disclosure are capable of delivering a therapeutically effective amount of Pamiparib, Olaparib, or Niraparib to the prostate tissue, or tissue adjacent or near the prostate, for extended periods of time (e.g., at least 6 months). Additionally, the implants of the disclosure are capable of delivering a high concentration of Pamiparib, Olaparib, or Niraparib locally to the prostate, while maintaining low systemic concentrations of Pamiparib, Olaparib, or Niraparib. In some cases, the implants of the disclosure may reduce or prevent toxicity due to high systemic concentrations of Pamiparib, Olaparib, or Niraparib. In some cases, the implants of the disclosure may reduce or prevent toxicity to a subject as compared to when the subject receives the at least one additional therapy without the Pamiparib, Olaparib, or Niraparib. In some embodiments, the toxicity includes weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity, or a combination thereof.

[0092] In various aspects, a total dose of Pamiparib, Olaparib, or Niraparib administered to the subject by an implant of the disclosure is less than a total dose of Pamiparib, Olaparib, or Niraparib when administered to a subject by systemic (e.g., oral) administration. Advantageously, the implants of the disclosure provide for administration of lower total doses of Pamiparib, Olaparib, or Niraparib relative to oral dosing regimens.

[0093] In various aspects, implanting a drug implant of the disclosure into the prostate or tissue adjacent or near the prostate results in a blood plasma concentration of Pamiparib, Olaparib, or Niraparib that is substantially less than a blood plasma concentration of Pamiparib, Olaparib, or Niraparib obtained when Pamiparib, Olaparib, or Niraparib is administered to a subject by systemic (e.g., oral) administration.Kits

[0094] Further provided herein are kits. In some aspects, a kit may comprise one or more implants as described herein. For example, a kit may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more than 20 implants. In some cases, the one or more implants may comprise a therapeutically active agent contained therein. In some cases, each of the one or more implants may comprise Pamiparib, Olaparib, or Niraparib. In other cases, each of the one or more implants may comprise one or more different therapeutically active agents.

[0095] In some aspects, a kit may comprise one or more surgical tools, such as a needle or forceps. In some aspects, a kit may be packaged in a sterilized package. In some cases, the sterilized package comprises a foil. In some aspects, a kit may further comprise instructions for implanting the implant into a tissue of a subject.

[0096] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0097] In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an”, and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes”, and “included”, is not limiting.

[0098] As used herein, ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 pL” means “about 5 pL” and also “5 pL.” Generally, the term “about” includes an amount that would be expected to be within experimental error, e.g., within 15%, 10%, or 5%.

[0099] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.EXAMPLESExample 1. Methods for making implants - platinum-cure silicone

[0100] Manufacture of the implant includes two main steps: formulation of the active pharmaceutical ingredient (API) (e.g., Pamiparib, Olaparib, or Niraparib) with an elastomer (e.g., medical-grade, platinum-cure silicone) to ensure uniform mixing of the API within the polymer matrix, and molding of the implants to ensure the product can be deployed to the organ as intended.Formulation

[0101] The implant formulation includes medical grade silicone as an excipient mixed with the API. A solvent is used for reducing the viscosity of the silicone, if needed, to incorporate the desired API loading.

[0102] The Pamiparib, Olaparib, or Niraparib formulation is made using a centrifugal mixer. The required amount of silicone Part A and Part B is added to the mixing cup with an equal weight of a solvent (that dissolves silicone; e.g., pentane) added. The silicone and solvent are speed-mixed until the viscosity of the silicone is reduced such that it flows. The API powder is then incorporated into the mixing cup and speed-mixed until a visibly smooth mixture is obtained with no dry API spots. The solvent is then removed (with or without vacuum) leaving a paste of silicone and API. Table 1 below shows an example for the formulation of Pamiparib, Olaparib, or Niraparib made to 10% load by weight.

[0103] This method may be used to formulate active pharmaceutical ingredient (e.g., Pamiparib, Olaparib, or Niraparib) with an elastomer (e.g., platinum-cure silicone) from as low as 10% load by weight, to above 70% load by weight.

[0104] Other methods to achieve the same mix uniformity that are solvent-less may be used, such as shear mixing. Other solvents (e.g., dichloromethane, tetrahydrofuran, hexane, pentane, heptane, toluene, and the like) that aid in reduction of viscosity and dissolve silicone may also be used for formulation.Table 1. Example Formulation CompositionComponent Weight Added (g)Elkem Silbione® LSR D370 Part A 0.9Elkem Silbione® LSR D370 Part B 0.9Solvent 1Pamiparib Olaparib, or Niraparib 0.2Milled PowderTable 2. Example Solvent Removal ConditionsSolvent Step Speed (RPM) Time (min) Vacuum (psi) Removal Cycle1 1 950 1.8 9.02 950 0.3 14.73 1450 1.8 3.92 1 1950 2.8 3.92 1950 2.8 3.93 1950 2.8 3.94 1950 2.8 3.93 1 800 2.8 0.142 2400 0.3 0.143 950 2.8 0.14Molding

[0105] Implant rods are made using a (e.g., aluminum) mold (e.g., via a transfer molding process) or by extruding the apalutamide formulation (e.g., through a tube). The molded rods are cured for a predetermined time (e.g., about 3 to 8 minutes) at a certain temperature (e.g., about 125°C to 175°C) based on the silicone supplier’s recommendations for curing. Post-curing, the mold is cooled, and the rods are de-molded for characterization.Example 2. Methods for making implants - acetoxy-cured silicone

[0106] In this example, the implant formulation includes a medical-grade silicone with an acetoxycure silicone with an alternative curing chemistry to platinum-cure to be used as an excipient mixed with the API.Formulation

[0107] The implant formulation includes medical grade silicone as an excipient mixed with the API. A solvent is used for reducing the viscosity of the silicone, if needed, to incorporate the desired API loading.

[0108] The Pamiparib, Olaparib, or Niraparib formulation is made using a centrifugal mixer. The required amount of silicone is added to the mixing cup with an equal weight of a solvent (that dissolves silicone; e.g., pentane) added. The silicone and solvent are speed-mixed until the viscosity of the silicone is reduced such that it flows. The API powder is then incorporated into the mixing cup and speed-mixed until a visibly smooth mixture is obtained with no dry API spots. The solvent is then removed (with or without vacuum) leaving a paste of silicone and API. A portion of the solvent (as high as 50% w / w) may be left in the mixture to slow the curing process and extend pot life as well as reduce viscosity to aid in molding or extrusion. Table 3 below shows an example for the formulation of Pamiparib, Olaparib, or Niraparib made to 10% load by weight.

[0109] This method may be used to formulate active pharmaceutical ingredient (e.g., Pamiparib, Olaparib, or Niraparib) with an elastomer (e.g., acetoxy-cured silicone) from as low as 10% load by weight, to above 70% load by weight.

[0110] Other methods to achieve the same mix uniformity that are solvent-less may be used, such as shear mixing. Other solvents (e.g., dichloromethane, tetrahydrofuran, hexane, pentane, heptane, toluene, and the like) that aid in reduction of viscosity and dissolve silicone may also be used for formulation.Table 3. Example Formulation CompositionComponent Weight Added (g)Elkem Silbione® ADH1 M200 1Solvent 1Pamiparib Olaparib, or Niraparib 0.1Milled PowderMolding

[0111] Implant rods are made by extruding the Pamiparib, Olaparib, or Niraparib formulation (e.g., through a tube). The molded rods are cured for a predetermined time (about 1-3 days) at an ambient temperature to ensure the silicone has cured. Post-curing, the rods are pulled out of the tubing and cut to length, and are characterized.Example 3. Methods for making implants - thermoplastic polyurethane solvent process

[0112] In this example, the implant formulation includes thermoplastic polyurethane as an excipient mixed with the API.Formulation

[0113] A solvent is used for dissolution of the polyurethane to allow compounding with the API to create a uniform dispersion at the desired loading. After compounding, the solvent is removed and the resulting polyurethane- API pellet is molded into implant rods by transfer molding or extrusion.

[0114] The polyurethane pellets are added to a mixing cup with solvent (e.g., dichloromethane) and incubated at 37°C with agitation for several hours until dissolution of the polyurethane is achieved. The ratio of polyurethane to solvent is selected to achieve full dissolution of the polyurethane and a solution of sufficiently low viscosity for mixing (e.g., about 20% solids content by weight). The API powder is then added to the solution and speed-mixed until a visibly smooth mixture is obtained with no dry API spots. Table 4 below shows an example for a formulation made with 30% API w / w. The solvent is then removed under vacuum leaving a large pellet consisting of polyurethane. API, and residual solvent that may be used for thermomolding. Table 5 below shows an example set of solvent removal conditions. Other solvents (e.g., tetrahydrofuran, dimethylformamide, dimethylacetamide, etc.) that dissolve polyurethane may also be used for formulation.Table 4. Example Formulation CompositionComponent Weight Added (g)Lubrizol Pathway PT-87 AS 1 gSolvent 6 gPamiparib Olaparib, or Niraparib 0.45 gMilled PowderTable 5. Example Solvent Removal ConditionsSolvent Step Speed (RPM) Time (min) Vacuum (psi) Removal Cycle1 1 950 1.8 9.02 950 0.3 14.73 1450 1.8 3.92 1 1950 2.8 3.92 1950 2.8 3.93 1950 2.8 3.94 1950 2.8 3.9 3 1 800 2.8 0.142 2400 0.3 0.143 950 2.8 0.14Molding

[0115] Implant rods are made using a (e.g., aluminum) mold (e.g., via a transfer molding process) or by extruding the Pamiparib, Olaparib, or Niraparib formulation (e.g., through a tube). The formulation is melted for several minutes (about 3 to 8 minutes) at a certain temperature (about 150° C to 200° C) before injection or extrusion. Post-curing, the mold is cooled, and the rods are demolded for characterization.Example 4. Methods for making implants - thermoplastic polyurethane and polyethylene vinyl acetate extrusion process

[0116] In this example, the implant formulation includes thermoplastic polyurethane or polyethylene vinyl acetate as an excipient mixed with the API.Formulation

[0117] Milled excipient powder (thermoplastic polyurethane or polyethylene vinyl acetate) is added to the mix cup along with the API (Pamiparib, Olaparib, or Niraparib). The cup is speed-mixed until powders are fully incorporated. Table 6 below shows typical measurements for a 2-gram powder mix at 50% API load by weight. Ratios are adjusted for different targeted loads.Table 6. Example Formulation Composition - 50% Pamiparib Olaparib, or Niraparib load by weightComponent Weight Added (g)Lubrizol Pathway PT-87 AE cryo milled 1 gPamiparib, Olaparib, or Niraparib 1 gMilled PowderMolding

[0118] Implant rods are made with an extrusion process using either ram or twin-screw extruder. An aliquot of the powder mix (0.5-10 g) is placed in the extruder cavity and heated to approximately 150 °C for 1-3 minutes. A plunger or rotating screws are activated to force the melted powder mix through the extrusion nozzle or die. As the extruded rope leaves the fixture, it is collected by hand or using a conveyor system. The nozzle or die diameter and the conveyor speed can be adjusted toobtain an implant of a certain diameter. After it has cooled for a few seconds, it can be cut to desired lengths for implant rods.

[0119] An alternative method uses a twin-screw extruder (e.g., ThermoFisher HAAKE MiniCTW) to melt and extrude the Pamiparib, Olaparib, or Niraparib polymer powder mix for larger batch sizes. The mix is introduced into the barrel of the extruder which is heated to 150-200 °C and the melted mix is pushed through a die to produce an extruded strand of desired diameter. A conveyor belt carries the extruded strand which is allowed to cool and then cut to desired lengths for implant rods.

[0120] This process can be completed with powder mixes containing a milled excipient and API powder, or even pellets from solvent mixes as described herein.Example 5. Characterization of Pamiparib, Olaparib, or Niraparib containing formulation and implants

[0121] Various analytical techniques are used for characterization of the formulation and molded implants. Differential Scanning Calorimetry (DSC) is used to e.g., determine the rate of curing of the implants and to evaluate properties of the drug. Elution testing is used to assess the rate of elution of drug from the implant. High Pressure Liquid Chromatography (HPLC) is used to e.g., confirm content uniformity and assess impurities in the drug formulation and molded rods.Example 6. Selection of optimal implant formulation for localized drug delivery to potentiate radiation therapy

[0122] The most effective PARPi seed implant for local delivery and define the maximal load is selected for stability and long-term release within a polymer scaffold and the optimal excipient to provide an early release burst. PARPi elution rate increases with the amount loaded, compound structure, and ratio of drug to polymer. Decreasing the percentage of polymer (w / w) increases implant fragility but increases burst and release plateau. Fig.7A illustrates average daily elution of Olaparib over 50 days from a drug implant comprising 10%, 30%, or 50% of Olaparib. Fig. 7B illustrates cumulative elution from a drug implant comprising 10%, 30%. or 50% of Olaparib.Increasing Olaparib to its maximum percentage (w / w) in a silicone scaffold resulted in increased daily and cumulative drug release in ongoing elution studies for 180 days, which are projected to elute PARPi for >1 year.

[0123] The release of PARPi (e.g., Olaparib) is modulated by varying the ratio of polymer and API blending and increased by co-formulating with excipients such as lactose. This increases both the amplitude of the initial burst, as well as the daily release rate, while maintaining a minimal 1-year delivery duration. In vitro: in vivo correlations are determined from the studies in Example 7. The optimal implant formulation is used for subsequent in vivo murine, rat, or canine studies.Experimental data and polymer (EVA and silicone) properties suggest that Olaparib can be a suitable candidate. The optimal implant formulation delivers the highest (e.g., supra-therapeutic) PARPi level with rapid prostate tissue distribution, which transitions to therapeutic levels maintained for at least 12 months. The therapeutic goal is to have daily elution of at least 10x over the IC50 of prostate tumors for the respective PARPi during the course of at least one year.

[0124] Sustained and long-term delivery of therapeutic levels of active drug is also assessed. For these experiments, a 1.5 cm silicone-based implant containing Olaparib (N=5) formulated with increasing percentage, up to 80%, is sterilized and incubated in eluting solution (PBS containing 1% SDS and later tissue culture media) at 37 °C. Initially daily then weekly, eluting solution is collected and replaced with fresh eluting solution and evaluated for PARPi release and stability by HPLC. Methods for Olaparib quantification are developed using an Agilent 1100 HPLC coupled to a Phenomenex Kinetex C18 column (100 x 4.6 mm, 5 um particle size). Column separation is achieved by isocratic elution with a mobile phase composed of 45% acetonitrile:55% water with a flow rate of 1 mL / minute. Injection volumes to elute the respective PARPi as a single peak with appropriate standard curves is established. Data analysis is conducted with Chemstation software. Elution properties are studied up to >12 months. EVA and TPU polymers are mixed with PARPi by tumbling and extruded into rods for evaluating release rates. Thus, the long- and short-term release of polymer-based formulations is qualitatively and quantitatively compared to preliminary studies with the goal to minimally release from >100 μg / d during burst and then 10-30 pg per day of Olaparib for >365 days to achieve these supratherapeutic levels (e.g., 11,200 pg of drug per 80% implant). If necessary, dip-coating implants with a higher durometer silicone is used to retard drug release to prolong exposure. PARPi and excipient compatibility and release profile are determined for Olaparib to identify implant designs that meet the dose and duration goals.

[0125] Optimal sterilization and radiation therapy inertness is determined for sterilizing the drug implant and co-formulated drug for in vivo testing (e.g., Example 7). Common forms of device and drug sterilization include gamma and electron beam irradiation, ethylene oxide incubation, and autoclaving. The preferred method is radiation sterilization as it has been shown that three of the four polymers are impervious to radiation therapy (~25 kGy) which far exceed therapeutic radiation therapy doses used in patients and proposed in Example 7. The proposed PARPi is inert to radiation therapy but is further tested for long term stability after radiation.

[0126] Drug implant and PARPi stability is tested. Lead drug implant with EVA, TPU, or silicone is mechanically tested to assess compression, tension, and relaxation. Additional testing to assess silicone cure is conducted, which includes differential scanning calorimetry (DSC) and rheology.Curing of silicone can be poisoned by contaminates (e.g., latex from gloves), as well as drugs that are being incorporated. Although firm and undetectable by touch, DSC and rheology can detect partially cured silicone. PARPi durability and stability is a significant concern and can be tested during elution studies of implants, monthly. At the conclusion of elution studies, all remaining PARPi and degradative products are recovered using an established solvent extraction method using tetrahydrofuran. Samples are evaluated by HPLC for retention time impurities, percent impurity is correlated with time for degradation pre- and post-radiation.

[0127] Sizing and physical structure of PARPi implants is examined for further in vivo and clinical testing. PARPi implant is placed within the prostate 6-8 weeks prior to radiation therapy to allow sufficient time for the PARPi to sensitize the tumor cells to radiation and then continue PARPi elution for at least 12 months and possibly 2 years. This is similar to current approved adjuvant hormonal therapy in radiation therapy in high-risk men which is given for 6 months to 2 years. 8-16 implants (1.5 cm in length by 0.95 mm in diameter) are accommodated for surgical insertion with an 18-gauge biopsy needle in a 30-minute procedure.

[0128] These implants deliver a rapid release of the PARPi to sensitize prostate cancer cells to radiation. Selection and blending of polymers (e.g., Silicone, EVA, and TPU) tailors the burst and continuous elution rate profiles. Excipients, such as lactose create a more porous structure for a rapid burst and quicker compound release which all together define the elution kinetics to provide sufficient drug release for one year. Other excipients, such as cellulose, or sucrose, are also assessed.Example 7. Evaluation of localized PARPi delivery to potentiate radiation therapy (XRT) and determine the relevance of HRD mutations using HRD-mutated mouse models

[0129] This example aims to develop a drug eluting implant that delivers an efficacious PARPi (e.g., Pamiparib, Olaparib, or Niraparib) dose selectively to the prostate of men with high risk localized prostate cancer to prevent progression and sensitize their tumors to radiation therapy. In this example, a scaled lead formulation is examined, bringing forward the most suitable PARPi implant to test its ability to potentiate XRT in three complementary settings by employing specific HRD prostate cancer mouse models. Each of the proposed models validates its own responsiveness to PARPi and radiation. The greatest radiation and PARPi sensitivity in BRCA1 or BRCA2 mutations, less effective to Ataxia-Telangiectasia Mutated (ATM) mutations and lesser still for Checkpoint kinase 2 (CHEK2), and ineffective for intact HR tumors are examined. The radiation dose for safety and effect size in each setting before comparing the effects of combined PARPi and XRT is established (Table 7). This example also examines the effect of PARPi on radiation therapy efficacy in HR-intact PC3 and DU145 prostate cancer cells. Significantly less response to the PARPidelivered via the PARPi eluting implant in the parental HR intact prostate cells and potentiation of XRT compared to HRD variants is expected. These examples serve as baseline efficacy and safety studies and as control for the additional examples provided herein.Table 7. Schemata of drug implant prototype down selectionCohorts (mouse #)Model Endpoint Sham PARPi XRT Combo Total PC3 / DU-145 Safety / dose - 3 9 - 12 A PC3 / DU-145 Efficacy 6 6 6 6 24+4 PC3 / DU-145- Safety / dose - 3 9 - 12 BRCA1PC3 / DU-145- Efficacy 6 6 6 6 24+4 B BRCA1PC3 / DU-145- Efficacy 6 6 6 6 24+4 BRCA2PC3 / DU-145-ATM Efficacy 6 6 6 6 24+4 J000077451 (WT) Safety / dose - 3 9 - 12 J000077451 (WT) Efficacy 6 6 6 6 24+4 C LHL-60 (BRCA2) Efficacy 6 6 6 6 24+4 TM00298 (BRCA2) Efficacy 6 6 6 6 24+4

[0130] The combined efficacy is determined in two established HR competent prostate cancer xenograft models, followed by assessing the impact of BRCA1 / 2 and ATM mutations on the ability of PARPi to potentiate radiation therapy. This is done with CRISPR engineered HR-mutated PC3 and DU145 prostate cancer cell line models.

[0131] BRCA1 and BRCA2 models were created and tested for functional BRCA loss (Fig. 2). Fig.2 illustrates assessment of cancer cell line models for testing the therapeutic efficacy of a drug implant described herein. Cancer cell lines were genetically engineered to harbor homologous recombination deficiency (HRD) of BRCA1 or BRCA2 mutations. Functional HRD deficiency of BRCA1 or BRCA2 mutations was indicated by the loss of Rad51 foci induction by carboplatin in the cancer cell lines as compared to wild type cancer cell lines (Fig.2).

[0132] The effects of PARPi on XRT in BRCA 1 / 2 and ATM mutated isogenic prostate cancer cells from parental PC3 and DU145 was assessed. To this end, a functionally deficient BRCA2 PC3 prostate cancer model (clone 1E10) was established. Such cancer models harbored comparable mutations as the most commonly identified HR deficiency in men (Fig.3A and Fig.3B). Fig. 3A illustrates BRCA2 protein in wild type (WT) cells versus CRISPR / Cas engineered PC3 prostate cancer clones. Fig.3B illustrates increased sensitivity to carboplatin in 1E10 clone versus WT cells. As expected, the functional loss of BRCA2 caused increased sensitivity to carboplatin (Fig.2).When cells were treated separately and in combination with Niraparib and XRT, the BRCA2 mutated cells exhibited greater cell death compared to parental WT cells (Fig. 3C). Fig.3C illustrates 1E10 clone showing increased sensitivity to combined Niraparib and radiation therapy (XRT).

[0133] Additional cells are engineered (e.g., through CRISPR / Cas engineering) for generating BRCA1 / 2 and ATM deficient PC3 and DU145 prostate cancer cells. The clones are selected through Sanger sequencing, Western blot, and verified functionally by assessing sensitivity to carboplatin and Rad51 foci induction (Fig.2). Once established, the cells are examined for increased sensitivity to XRT and PARPi (e.g., Pamiparib, Olaparib, or Niraparib) in mouse xenograft models.

[0134] The effect of PARPi on XRT in HRD mutated prostate cancer PDX models is assessed. Similar to cell line models, there are few established HRD prostate cancer PDX models. This example can more closely mimic clinical testing. The sensitivity to radiation and PARPi are tested in two BRCA2 mutated PDX models (JAX lab, (ID#TM00298, T3033frameshift; LHL-60) and compared to an HR-intact prostate cancer PDX model (ID#J000077451). The BRCA2 mutant models exhibits increased sensitivity to combined PARPi and XRT, whereas the effects in the HR-intact model are minimal.

[0135] The studies using the LHL-60 BRCA2 mutated prostate cancer PDX demonstrated the feasibility of placing a 3 mm x 1 mm implant within a PDX growing subcutaneously. Sham implants had negligible impact on tumor growth or histology. Radiating out from niraparib-silicone implants, necrotic and apoptotic cells were observed, increasing in distance with higher % Niraparib (w / w) formulations (Fig.4). Fig. 4 illustrates hematoxylin and eosin (H& E) staining of prostate cancer patient-derived xenograft (PDX)-BRCA2 implanted with placebo, 30%, 50% or 70% Niraparib implant. Blowup (right) of tissue adjacent to implant shown, dashed box (left). (*) indicates implant site. Bar equal to 1000 pm.

[0136] A safe XRT dose and its effect size are determined. Prior data suggests that these mice can tolerate 6 Gray unity (Gy) given once in 5 fractions. Three male NRG mice each are implanted with the respective cells (PC3 and DU145, see Fig.4 and Figs. 5A-5C). When tumors reach a size of 150-200 mm3, each mouse has one (3 mm x 1 mm) sham implant implanted into the center of their tumor. Mice are treated with 1, 3, or 5 fractions of 6 Gy radiation therapy to assess tolerability and the effect size. If mice exhibit >20% weight loss or distress, this is considered toxic, and the XRT dose is lowered. To be able to assess combination effects, an XRT dose resulting in a <20% effect on tumor growth is selected. Three mice are then implanted with a (3 mm x 1 mm) PARPi-containing implant to assess the feasibility and preliminary release properties in an assessment period of 30days. All mice undergo necropsy to evaluate pathology. The prostate and surrounding tissue is collected for formalin-fixed, paraffin-embedded (FFPE) and tissue histology analyzed for pathology. Major organs (e.g., heart, lung, liver, brain, or kidney) and prostate are harvested, and drug levels quantified by LC-MS / MS for the three initial mice with a PARPi implant to measure systemic exposure when implanted into the tumor. Once established, the efficacy studies proceed. For each, 28 four to six-week-old male NRG mice have 1×106cells (cell lines) or a ~2 × 2 mm3tumor piece (PDX), mixed 1:1 with Matrigel, implanted into the dorsal flank. When tumors reach -150-200 mm3, mice are randomized into four cohorts of six (four animals with outlier tumor volumes can be removed): Cohort 1 - Sham implant, Cohort 2 - PARPi implant, Cohort 3 - Sham implant, XRT only, and Cohort 4 - PARPi implant and radiation. Implants are placed in the middle of palpable tumors along the longest diameter. Treatment assignment is blinded to limit potential for bias during data acquisition or analysis. Image guided radiation treatment is initiated 3-7 days depending on PARPi penetrance as determined above and to assess the efficacy of the PARPi alone. XRT is given in 5 (or as determined in the safety study) daily doses of 6 Gy. The primary endpoint is a comparison of tumor growth during therapy and tumor burden at experimental termination. When 2 mice in any cohort reach the tumor volume endpoint (e.g., 2000 mm3) or require euthanasia due to distress, the study is ended, at which time tumors are harvested for subsequent analysis as described in mechanism characterization above. Translating preclinical XRT studies can be hindered by radiation dose administered in an imprecise or clinically irrelevant manner. To ensure the reliability and reproducibility, a standard operation procedure is formulated using the Xstrahl SARRP ('Surrey. UK), a system combining high-resolution CT imaging and accurate conformal beam therapy (Fig.5). Fig. 5A and Fig. 5B illustrate coronal and semi-transparent 3D view respectively through a live mouse with tumor in virtual in vivo CT slices. Fig. 5C illustrates schematic of mouse tumor irradiation using image guided techniques on SARRP Xstrahl research platform. The absolute dosimetry is independently verified. Image-guided techniques improve the translational potential of these studies. A preliminary 3-7-day time point for pretreatment prior to radiation has been deemed optimal to reflect tumor growth and the ability to measure difference based on initial data. Timing of radiation is changed if experimental data suggest that shorter or longer PARPi pre-treatments or multiple radiation therapy time points are needed.

[0137] At study conclusion, mice are euthanized, major organs, blood, and tumor collected, processed and drug concentrations quantified. Half of the tumors are processed for drug penetration and the other half for biomarker modulation (e.g., reduced RAD51 foci induction; Fig. 2); Ki67 down regulation; caspase cleavage and TUNEL staining). For PK quantification, drug is extractedfrom tissues by protein precipitation and quantified using validated LC-MS / MS method.Additionally, tumor is flash frozen and embedded in gelatin for sectioning and MALDI-mass spectrometry imaging (MSI). Tissue sections are imaged for drug distribution at 80 pM spatial resolution. Image acquisition and quantification is carried out using Multimaging QMSI software. MSI is overlaid with H& E-stained sections for anatomical referencing and correlated molecular biomarker IHC analysis. Together these results form a topographic representation of tumor drug distribution.

[0138] For the efficacy experiments, six mice per intervention (Sham, PARPi, Sham + XRT and PARPi + XRT) x 4 interventions = 24 male mice total x 8 efficacy experiments (n=192 mice) + 32 mice (4 mice / experiment dropout before randomization (aka outliers) x 8 experiments) = 224 mice is assessed. This can provide statistical power of 80% to show a minimum effect size of 2.7 (2.5 v. 1.3 SD: 0.45) assuming a Bonferroni corrected alpha level of 0.008 (0.05 / 6 null hypotheses tests of pair-wise comparison of interventions) based on a two-sample independent t-test of the log transformed maximum tumor volume using Stata v.16.1. Based on a previous experiment, the effect size of 2.7 is adequate when comparing combination treatments with PARPi to PARPi alone, and more than adequate to show statistically significant pairwise differences between PARPi alone (mean of 1.3) and control (mean of 10 with common SD: 0.45) resulting in an effect size of 16. Tumor volume is log-transformed. An independent two-sample independent t-test is used for pair-wise comparisons between interventions of log transformed tumor- volume. Two-sided p-values less than 0.008, a Bonferroni adjusted p-value to protect the family wise-error rate at alpha level of 0.05, is considered statistically significant. Longitudinal analysis is explored to assess whether tumor volume differs by intervention using linear mixed effects regression analysis for continuous outcomes. Trajectories of the therapeutic efficacy is flexibly modeled by testing whether including quadratic or cubic terms for time or random slopes for individual mice improve the model fit and include them if indicated by a significant (P<0.05) likelihood ratio test. Trajectories change over time or differ by cohort is estimated via a post-estimation test using a contrast and t-test. At the time tumor volume forms, the mice are randomized (1:1: 1:1) to one of the 4-cohorts. The number of mice required is estimated to be: N=224.

[0139] BRCA2 in the PC3 prostate cancer cell line model has been dysregulated and shown these cells were more sensitive to carboplatin and PARPi. Initial experiments further showed that these cell lines grew as xenografts rendering the PC3 studies feasible. Loss of BRCA function through CRISPR-Cas9 engineering can be established for BRCA1 and ATM in PC3 and DU145. An alternate CRISPR approach (dCAS9-CRISPR interference or CRISPRi) can be used. Tumorpenetrance and insertion modalities have been established in preliminary studies and implants are radiation therapy inert. Implanting the drug eluting seed can give a broader understanding of drug distribution from an implant across a tumor. The most potent formulation can be used to validate the mechanism of action, including mutation setting and distribution properties. Other formulations can be tested if drug distribution is poor, or release is too slow. This example can provide insights into drug distribution and XRT efficacy in a tumor. Another major goal of this example is to define whether PARPi can potentiate XRT and in which setting (e.g., HR proficient, BRCA1 / 2- and ATM-mutated, CHEK2 if feasible).

[0140] For assessing drug implant safety, toxicity, and PARPi tissue distribution, rats and canine prostates are implanted with a single drug-eluting (silicone, TPU or EVA) implant in each lobe (2 implants per animal). Drug implants have been shown to be safely placed (Figs. 6A-6C). Fig. 6A illustrates location of implantation in rat prostate lobes. Fig.6B illustrates a five millimeter implant into a rat prostate. Fig. 6C illustrates surgical implantation of a drug implant described herein into a dog prostate by laparotomy. Two 18 gauge needles were used to insert two 15 mm x 1 mm implant in both prostate lobes from a ventro-cranial approach with transrectal ultrasound confirmation of implant placement.

[0141] Rat and canine prostate models are used to determine safety, toxicity and PK / PD of the PARPi implants. The implant is expected to have a high initial burst, and then to deliver therapeutic PARPi levels for > 12 months.

[0142] Rat studies assess safety and drug biodistribution of PARPi-eluting implant formulations at short- and long-term intervals. The rat studies identify a lead formulation for use in IND-enabling canine GLP safety / toxicity and PK studies for clinical translation.

[0143] To do this and in consideration of animal welfare 3R principles, feasibility studies are performed in rats with the four lead formulations identified in Example 6. The rat model is conducted to reduce the number of experiments to be performed in a larger canine model to avoid unnecessary and costly usage of canines. Studies in this example profile the safety and PK profile for the four lead formulations identified in Example 6 by performing a 2- and 8-week study in rats to establish the in vivo elution and tissue distribution; (2) down- selection of the two most promising candidates from (1) for a longer term (i.e. up to 12-months) rat study with multiple timepoints to further establish the relationship between in vitro drug elution, duration of delivery, and distribution in major organs and prostate (long-term tolerance); and (3) selection of the lead seed implant based on the most favorable safety / toxicity and elution profiles and ratio of drug in the prostate to plasma. The implant selected in (3) is used in a canine study.

[0144] First, a 2- and 8-week study is performed in rats with 4 lead PARPi formulations to establish the in vivo delivery of PARPi to the prostate and its robustness and reproducibility. The selected time points characterize burst and slope profiles. An oral reference control cohort of the formulated PARPi is included. Data from the control cohort serves as a comparator to select a lead formulation for the canine study as described below.

[0145] Four cohorts of six male rats per cohort are used for two time points (up to 48 total): cohorts 1-4 comprising the 4 lead PARPi seed implants (24 rats for each time point). Two oral groups are treated with the selected PARPi (N=6 for each time point). For the reduced rat prostate size, downscaled 3 mm x 1 mm implant formulations are utilized. Implants are placed in each of the ventral prostrate lobes of sexually mature naive Sprague-Dawley rats (>6 months in age) via an open abdominal approach using an 18G needle to ascertain easy placement and assurance that implants stay in situ. The ventral prostate lobes measure -0.5-1 g, with -7 mm diameter and are easily accessed via an open laparotomy to fit an implant segment 3 mm in length (Fig. 7). N=60 rats are needed for this study.

[0146] Plasma is collected throughout the study (0, 1, 2, 3, 7, 14, 28, 42 and 56 days) and tissue samples from prostate and off-target organs are collected at necropsy and analyzed for PARPi levels. Additionally, histopathology are assessed from formalin fixed paraffin-embedded tissue sections to evaluate implant related tissue reactions and toxicities. An LC-MS / MS method is developed and qualified prior to use for sample analysis. Drug levels in plasma at different timepoints over 14 days and in the prostate (collected at necropsy) for the PARPi formulation implants is compared to that from orally administered PARPi. Implants (explants) are also recovered at necropsy for extraction and analysis of remaining drug amount via an existing HPLC method and back-estimation of the in vivo drug elution profile. At least one prostate section in each group is flash frozen and embedded in gelatin for sectioning and MALDI-mass spectrometry imaging (MSI; contracted through ImaBiotech). Tissue sections are imaged for drug distribution at 80 μM spatial resolution using a Bruker 7T FTICR-HR-MALDI MSI system. Image acquisition and quantification is carried out using Multimaging QMSI software. MSI is overlaid with H& E-stained sections for anatomical referencing and correlated molecular biomarker IHC analysis. Together these results form a topographic representation of prostate drug distribution and action.

[0147] The data collected is used to demonstrate feasibility of using the rat model for longer term studies by establishing that the PARPi seed implants: (i) are well tolerated by prostate tissue and are not toxic to surrounding tissue; (ii) show PARPi levels in vivo that compare favorably with those achieved by oral administration; and (iii) show an in vivo PARPi elution profile that anticipatesfavorable translation to canines. Two PARPi implant formulations that best meet these criteria are chosen for further long term rat study. Descriptive statistics are provided at each scheduled sampling time point for drug concentration and tissue response: number of rats, mean, SD, CV, geometric mean (where applicable), median, minimum, and maximum. For the PK analyses, the concentrationtime profiles is estimated for all evaluable rats can on the actual sampling times in all computations involving sampling times. The PK Analyses are performed using 6 cohorts including Cmax(maximum concentration), Tmax(Time at which Cmaxoccurred), ti / 2 (elimination half-life), AUCo-t (Area under the concentration-time curve) and AUCo-inf.

[0148] The two most promising PARPi formulations identified in the short-term study are evaluated in a long-term rat study. Two lead formulations of implants for 5 time points: at 2, 4, 6, 8 and 12 months are assessed. One oral cohort of the selected PARPi is added for verification at 2 months only, implant segments are surgically placed in the rats as described above. Plasma levels, prostate levels and distribution and off target PARPi tissue levels are obtained for each cohort at the respective time point at time of necropsy (2, 4, 6, 8 and 12 months; therefore, (6 rats / cohort x 6 cohorts) + 2 extra rats to safeguard for animal mortalities at the 8- and 12-month time points] x 2 formulations = 76 rats). The descriptive statistics are provided at each scheduled timepoint for drug concentration and tissue response: number of rats, mean, SD, CV, geometric mean (where applicable), median, minimum, and maximum. The plasma concentration-time profiles are estimated for all evaluable rats based on the actual sampling times. The PK analyses are performed by 6 cohorts for comparison including Cmax (maximum concentration), Tmax(Time at which Cmax occurred), ti / 2 (elimination half-life), AUCo-t (Area under the concentration-time curve) and AUCo-inf. The. At each necropsy timepoint, samples of prostate and major organs are collected and divided for PARPi quantitation and histopathology analysis. An N=76 rats are needed.

[0149] Statistical Analyses include: (i) tissue and plasma samples for determining PARPi levels; (ii) toxicity in other major organs; (iii) PARPi effects on proliferation in prostate tissue; (iv) drug distribution by MSI; and (v) measurement of residual drug in the implants. For (v), the implants are removed, and residual drug concentration are measured to determine which implant formulation is most likely to provide a projected 2-year in vivo release profile. Experimental data is compared to projected forecasting from in vitro elution extrapolations to establish an in vitro-in vivo correlation of PARPi delivery. Additionally, the drug impurity profile in explants is measured to verify the respective PARPi remains stable and active. Study cohort size (N=6) has been estimated.

[0150] Emerging preclinical and clinical studies in metastatic prostate cancer suggest that HRD-related prostate cancers are more aggressive and less hormone sensitive. Thus, the current adjuvanttherapy with bicalutamide and LHRH (ant)agonists may not adequately treat men with high-risk tumors and HRD mutations. As such, the potential role of localized therapy prior to radiation in patients with high-risk early-stage prostate cancer with germline HRD mutations is explored to leverage both the sensitivity of HRD related prostate cancer to PARPi and their ability to sensitize to radiation therapy. Optimized PARPi-eluting implant developed in Example 6 and down selected to the final lead implant and study its safety, local and systemic toxicity, and PARPi tissue distribution profile in a canine prostate model in preparation for IND enable GLP studies are examined. This model has been chosen based on the robustness to predict preclinical release rate across different studies and its translatability to clinical findings. They are implanted into the two lobes of the prostate of 3 male purpose-bred canine mongrel each for an 8- and 24-week study.

[0151] Canines are monitored continuously to assess the procedural implant safety, adverse effects while carrying the implant, impact on spermatogenesis, and drug biodistribution in the prostate and other major organs in an implant. This canine experiment, including implantation, housing, and care as well as subsequent tissue collection are carried out. The study is conducted under an IACUC approved protocol. To minimize the use of suboptimal implants, a full analysis of implants for short-and long-term placements is conducted in rats with full PK characterization and correlation of the biodistribution in the prostate with drugs levels remaining in the explanted implants. The extensive in vitro elution profiles and the long-term rat studies allows a two time point abbreviated study. 8-and 24-week timepoints gives sufficient data for extrapolation for time beyond one year. The 8-week time point mimics the time point when men are expected to receive radiation therapy after the neoadjuvant hormonal therapy, and the 24-week time coincides with the end of the hormonal therapy (hormonal may be given for 2 years but is not easily tolerable).

[0152] For transition to human clinical trials, implant dimensions are limited to 18-gauge needle / catheter delivery. Implants fit within a brachytherapy needle and are placeable using a transperineal approach. Dogs can undergo laparotomy under general anesthesia. A brachytherapy needle is inserted from the cranial toward the caudal end of the prostate and a single implant (1.5 cm 1 mm) is implanted into the glandular region of each prostatic lobe.

[0153] In addition to daily monitoring for changes in well-being, general activity, and body weight, animals have blood drawn weekly until week 8 and then monthly to assess clinical chemistry. At the conclusion of the study, gross and histopathology of organs, prostate, and prostate surrounding tissue is evaluated by a board-certified veterinary pathologist.

[0154] The drug implant delivery steady state is reached at 8 weeks which is verified in the rat studies. To this end, blood for plasma PK is collected at 2, 24, and 48 hours for PARPi levels andcompared to prostate and off-target tissue levels at necropsy by LC-MS and analyzed as described in this example. In addition to histopathology for all off target tissues, a more in-depth analysis of prostate to evaluate drug distribution across the prostate is done by mass spectrometry imaging. The prostate is sectioned into slices and drug distribution correlated with findings from histopathology to map histological changes to PARPi tissue levels.

[0155] All canines are continuously evaluated for safety analysis. The maximum grade for each type of adverse event is recorded for each canine, and frequency table is reviewed to determine patterns and relatedness. Secondary outcome analysis and exploratory analyses for tissue and PK analyses is prepared. Descriptive statistics (means, standard deviations, medians and IQR for continuous variables and frequencies and percentages for categorical variables) are presented. Three animals per cohort are the minimum to give use meaningful data without subjecting unnecessary canines to study procedures.

[0156] The preliminary proof of concept canine studies showed that comparable drug eluting bicalutamide implants did not elicit adverse effects. All implant materials used here are routinely used in vivo. Studies from this application provide insights into safety and the PK profile of a PARPi delivered locally versus systemically. While Olaparib is approved in prostate cancer, given the much higher potency, much emphasis can be placed to develop an implant with Olaparib. The PK studies in this example evaluate and validate the silicone: PARPi:excipient composition and the separation of studies per time points allow refining implants at each step. Whole gland therapy in patients is achieved by increasing the number of implants placed. Adding an excipient, such as lactose, can tailor the initial burst, whereas utilizing a “locally” more potent PARPi provides longer release. MSI of canine and rat study prostates help define the spacing and number of implants required to achieve therapeutic levels across the tumor and remaining prostate. This implant is inserted via an 18-gauge biopsy needle and visualized by ultrasound and MRI, the same gauge used for routine prostate screening and brachytherapy seed delivery, supporting the feasibility of multiple implants and its adoption in the clinic.Example 8: Formulating a Pamiparib Implant

[0157] Five different Pamiparib implants were formulated as shown in Fig. 8. A first implant was made with 30%w / w Pamiparib in a thermoplastic polyurethane (TPU) matrix using a vacuum compression molding process at 180 °C for 15 minutes. A second implant was made with 30%w / w Pamiparib in an ethylene-vinyl acetate (EVA) matrix using a vacuum compression molding process at 200 °C for 10 minutes. A third implant was made with 50%w / w Pamiparib in an EVA matrix using a vacuum compression molding process at 200 °C for 10 minutes. A fourth implant was madewith 30%w / w Pamiparib in a silicone matrix. A fifth implant was made with 10% w / w Pamiparib in a silicone matrix.Example 9: Elution of Pamiparib Implants

[0158] . Fig. 9 A illustrates cumulative elution from a drug implant comprising 30% or 50% Pamiparib in a vinyl acetate (VA) matrix over 60 days. Fig. 9B illustrates average daily elution of Pamiparib over 60 days from a drug implant comprising 30% or 50% Pamiparib in a vinyl acetate (VA) matrix. Increasing Pamiparib concentration results in increased daily and cumulative drug release. The in vitro model may include incubating the drug implant in 1% sodium dodecyl sulfate (SDS) in water at 37 °C for the specified time period with continuous agitation.Example 10: Comparison of Elution of Pamiparib and Talazoparib Implants

[0159] . Fig. 10 illustrates cumulative elution from drug implants comprising: 30% and 50% Pamiparib or Talazoparib in a vinyl acetate (VA) matrix over 100 days. Increasing both Talazoparib and Pamiparib concentration results in increased cumulative drug release. At the same concentrations, Talazoparib and Pamiparib had similar cumulative release profiles. The in vitro model may include incubating the drug implant in 1% sodium dodecyl sulfate (SDS) in water at 37 °C for the specified time period with continuous agitation.

[0160] While the foregoing disclosure has been described in some detail for purposes of clarity and understanding, it will be clear to one skilled in the art from a reading of this disclosure that various changes in form and detail can be made without departing from the true scope of the disclosure. For example, all the techniques and apparatus described above can be used in various combinations. All publications, patents, patent applications, and / or other documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, and / or other document were individually and separately indicated to be incorporated by reference for all purposes.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A drug implant comprising:(a) a biocompatible polymer matrix; and(b) Pamiparib dispersed in the biocompatible polymer matrix.

2. The drug implant of claim 1, wherein the Pamiparib is present in the drug implant at an amount from about 10% w / w to about 80% w / w.

3. The drug implant of claim 2, wherein the Pamiparib is present in the drug implant at an amount of about 10% w / w.

4. The drug implant of claim 2, wherein the Pamiparib is present in the drug implant at an amount of about 30% w / w.

5. The drug implant of claim 2, wherein the Pamiparib is present in the drug implant at an amount of about 50% w / w.

6. The drug implant of claim 2, wherein the Pamiparib is present in the drug implant at an amount of about 70% w / w.

7. The drug implant of any one of claims 1-6, wherein a total dose of the Pamiparib in the drug implant is from about 1 mg to about 20 mg.

8. The drug implant of any one of claims 1-9, wherein the drug implant releases the Pamiparib by zero order release.

9. The drug implant of any one of claims 1-8, wherein at least 10%, at least 15%, at least 20%, at least 25%, or at least 50% of the Pamiparib remains in the biocompatible polymer matrix after 100 days of implantation.

10. The drug implant of claim 9, wherein at least 10%, at least 15%, at least 20%, at least 25%, or at least 50% of the Pamiparib remains in the biocompatible polymer matrix after 180 days of implantation.

11. The drug implant of any one of claims 1-10, wherein the Pamiparib is in solid form.

12. The drug implant of any one of claims 1-10, wherein the Pamiparib is in a crystalline form, a semi-crystalline form, or an amorphous form.

13. The drug implant of any one of claims 1-10, wherein the Pamiparib is in a dissolved form.

14. The drug implant of any one of claims 1-13, wherein the drug implant has a Shore A hardness of at least 20 durometer when loaded with Pamiparib.

15. The drug implant of any one of claims 1-14, wherein the biocompatible polymer matrix comprises silicone.

16. The drug implant of claim 15, wherein the silicone is an acetoxy-cured silicone or a platinum-cured silicone.

17. The drug implant of any one of claims 1-14, wherein the biocompatible polymer matrix comprises thermoplastic polyurethane.

18. The drug implant of any one of claims 1-14, wherein the biocompatible polymer matrix comprises poly (ethylene vinyl acetate).

19. The drug implant of any one of claims 1-18, wherein at least 99% by weight of the biocompatible polymer matrix remains in a target tissue of a subject after implantation for at least 12 months, at least 24 months, at least 36 months, at least 48 months, at least 60 months, or longer.

20. The drug implant of any one of claims 1-19, wherein the drug implant is visible by ultrasound or MRI when disposed in a target tissue of a subject.

21. The drug implant any one of claims 1-20, wherein the drug implant inhibits modulation of the Pamiparib within the drug implant.

22. The drug implant of claim 21, wherein the modulation comprises degradation.

23. The drug implant of any one of claims 1-22, wherein the drug implant is elongate.

24. The drug implant of any one of claims 1-22, wherein the drug implant is cylindrical.

25. The drug implant of any one of claims 1-22, wherein the drug implant is tubular.

26. The drag implant of any one of claims 1-22, wherein the drag implant is rod-shaped.

27. The drag implant of any one of claims 1-22, wherein the drug implant is circular.

28. The drag implant of any one of claims 1-22, wherein the drug implant comprises one or more rods.

29. The drag implant of claim 28, wherein the one or more rods are connected.

30. The drag implant of any one of claims 1-22, wherein the drag implant comprises a disk.

31. The drag implant of any one of claims 1-30, wherein a diameter of the drag implant is from about 0.1 mm to about 5.0 mm.

32. The drag implant of any one of claims 1-30, wherein a length of the drug implant is from about 1 mm to about 30 mm.

33. The drag implant of any one of claims 1-32, wherein a volume of the drug implant is from about 0.1 mm3to about 30 mm3.

34. The drug implant of any one of claims 1-33, wherein at least 50% of an outer surface of the drug implant is configured to directly contact a target tissue.

35. The drug implant of any one of claims 1-34, wherein the drug implant is configured to be implanted into a target tissue or a tissue near or adjacent to the target tissue.

36. The drug implant of claim 35, wherein the target tissue is prostate tissue, bladder tissue, ovarian tissue, fallopian tissue, liver tissue, bone tissue, breast tissue, pancreatic tissue, lung tissue, gastric tissue, kidney tissue, gall bladder tissue, colon tissue, or a combination thereof.

37. The drug implant of claim 36, wherein the target tissue is prostate tissue.

38. The drug implant of any one of claims 35-37, wherein the drug implant is configured to be delivered to the target tissue or the tissue near or adjacent to the target tissue using a lumen of a needle or a catheter.

39. The drug implant of any one of claims 1-38, wherein the drug implant lacks at least one of a sheath, a scaffold, a retention member for retaining the drug implant within a target tissue, or a combination thereof.

40. The drug implant of any one of claims 1-39, wherein the drug implant further comprises a coating.

41. The drug implant of claim 40, wherein the coating partially covers the drug implant.

42. The drug implant of claim 40, wherein the coating substantially covers the drug implant.

43. The drug implant of claim 40, wherein the coating contains comprises at least one additional therapeutic.

44. The drug implant of claim 43, wherein the at least one additional therapeutic comprises a cytotoxic therapeutic, a hormonal therapeutic, a biologic therapeutic, or a combination thereof.

45. The drug implant of any one of claims 1-44, wherein the biocompatible polymer matrix comprises a non-biodegradable polymer.

46. The drug implant of any one of claims 1-45, wherein the biocompatible polymer matrix comprises a biodegradable polymer.

47. The drug implant of any one of claims 1-46, wherein the drag implant is not a nanoparticle.

48. The drag implant of any one of claims 1-46, wherein the Pamiparib is not encapsulated in a nanoparticle.

49. A method of treating a tumor in a subject, the method comprising implanting, into the tumor or into a tissue adjacent to the tumor of the subject, at least one drug implant of any one of claims 1-48.

50. The method of claim 49, wherein the at least one drag implant continuously delivers the Pamiparib to the subject for at least 6 months, at least 12 months, at least 24 months, at least 60 months, or longer.

51. The method of claim 49 or claim 50, wherein a total dose of the Pamiparib administered to the subject by the implanting is less than a total dose of the Pamiparib when administered to a subject by oral administration.

52. The method of any one of claims 49-51, wherein the implanting results in a blood plasma concentration of the Pamiparib that is less than a blood plasma concentration of the Pamiparib obtained when the Pamiparib is administered to a subject by oral administration.

53. The method of any one of claims 49-52, wherein the implanting occurs via transperineal administration.

54. The method of claim 53, wherein the transperineal administration comprises using a template guided needle.

55. The method of any one of claims 49-54, wherein the implanting locally delivers the Pamiparib to the tumor.

56. The method of any one of claims 49-55, wherein the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof.

57. The method of any one of claims 49-56. further comprising, after the implanting, administering to the subject at least one additional therapy to treat the tumor.

58. The method of any one of claims 49-56, further comprising, after the implanting, recommending that the subject receive at least one additional therapy to treat the tumor.

59. The method of claim 57 or claim 58, wherein the at least one additional therapy comprises radiation, chemotherapy, biologic therapy, immunologic therapy, hormonal therapy, or a combination thereof.

60. The method of claim 59, wherein the at least one additional therapy comprises radiation.

61. The method of any one of claims 57-60. wherein the at least one additional therapy is more efficacious for treating the tumor after the implanting than after oral administration of the Pamiparib.

62. The method of any one of claims 57-61, wherein an amount of the at least one additional therapy needed to effectively treat the tumor is lower after the implanting, as compared to an amount of the at least one additional therapy needed to effectively treat the tumor in the absence of the Pamiparib.

63. The method of any one of claims 57-62, wherein the method results in decreased toxicity to the subject as compared to when the subject receives the at least one additional therapy without the Pamiparib.

64. The method of claim 63, wherein the toxicity comprises weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity, or a combination thereof of the subject.

65. The method of any one of claims 59-64, wherein the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.

66. A method of manufacturing a drug implant of any one of claims 1-48, the method comprising:(a) mixing an amount of polymer with an amount of the Pamiparib to generate a mixture; and (b) molding or extruding the mixture of (a) to create the drug implant.

67. The method of claim 66, wherein the polymer comprises uncured polymer.

68. The method of claim 66, wherein (b) is molding the mixture of (a).

69. The method of claim 66, further comprising curing the drag implant for a period of time.

70. The method of claim 66, wherein the amount of the Pamiparib is from 10% w / w to 80% w / w of the uncured polymer.

71. The method of any one of claims 6-70, wherein the polymer comprises silicone, thermoplastic polyurethane, polyethylene vinyl acetate), or a combination thereof.

72. The method of claim 69, wherein the curing further comprises heating the mixture at a temperature from about 100 °C to about 175 °C for about 3 to about 8 minutes.

73. The method of any one of claims 66-72, wherein the mixture further comprises a solvent.

74. The method of claim 80, wherein the solvent is selected from the group consisting of: pentane, dichloromethane, tetrahydrofuran, heptane, toluene, and hexane.

75. The method of any one of claims 66-74, wherein the mixture is molded by a transfer molding process or by extrusion through a tube.

76. The method of any one of claims 66-75, wherein the molding comprises extruding the mixture using a ram extruder or a twin screw extruder.

77. The method of any one of claims 66-76, wherein the molding comprises injection molding.

78. The method of any one of claims 66-77, further comprising performing an analysis on the drag implant.

79. The method of claim 78, wherein the analysis is selected from the group consisting of: differential scanning calorimetry (DSC), deployment of the drug implant in surrogate tissue, elution testing, rheology, high pressure liquid chromatography (HPLC), simulated in vivo stability assay, and dynamic mechanical analysis (DMA).

80. A kit comprising:a sterilized package comprising a drug implant of any one of claims 1-48; and instructions for implanting the drug implant into a target tissue of a subject.

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