Treatment of prostate cancer

Abstract

The present disclosure relates to methods of treating metastatic castration-resistant prostate cancer (mCRPC) in a subject, comprising administering to the subject (a) darolutamide, and (b) Compound 1, or a pharmaceutically acceptable salt thereof, including those methods wherein the mCRPC in the subject has been determined to be resistant to one or more androgen receptor signaling inhibitors (ARSI), including, for example, abiraterone acetate.

Description

WSGR Ref. 47134-782.601TREATMENT OF PROSTATE CANCERCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 753,809 filed on February 4, 2025, U.S. Provisional Application No. 63 / 807,016 filed on May 16, 2025, and U.S. Provisional Application No. 63 / 915,452 filed on November 11, 2025; which are hereby incorporated by reference in their entirety.JOINT RESEARCH AGREEMENT

[0002] Certain embodiments disclosed herein were made under a joint research agreement, as defined in 35 U.S.C. § 100(h), between Bayer Consumer Care AG and ORIC Pharmaceuticals, Inc., that was in effect on or before the effective filing date of such disclosed embodiments, and the disclosed embodiments were made as a result of activities undertaken within the scope of the joint research agreement.BACKGROUND OF THE INVENTION

[0003] Prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC), is the most common cancer among men in the United States, with about one in nine men diagnosed in their lifetime. Despite high incidence rates, mortality rates continue to remain low due to screening methods that allow for early intervention and new effective treatments. However, even with low mortality rates, prostate cancer remains one of the leading causes of death among men.

[0004] The range of new therapeutic agents has significantly improved the treatment landscape of both castration-sensitive (localized and metastatic) and castration-resistant prostate cancer. Despite prolonged clinical responses, improved survival and quality of life, systemic treatments eventually fail in nearly all patients as indicated by rising prostate-specific antigen (PSA) levels and / or radiographic disease progression. After progression on these systemic therapies, chemotherapy is the remaining option providing modest improvements in overall survival at the expense of significant morbidity.

[0005] A consequence of the use of androgen receptor signaling inhibitors (ARSIs), such as CYP17 inhibitor abiraterone acetate, and androgen receptor (AR) inhibitors such as apalutamide, darolutamide, and enzalutamide, has been the expansion of tumor heterogeneity highlighted by the clinical emergence of diverse phenotypic states to bypass ARSIs, including cells with heightened plasticity and divergent differentiation. Increased plasticity is a highly reproducible feature of prostate cancer tumors following ARSI therapy. Thus, there is a need to develop new therapeutic regimens to overcome or circumvent the emergence of epigenetic plasticity throughout prostate cancer treatment.SUMMARY OF THE INVENTION

[0006] Provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b)WSGR Ref. 47134-782.601Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0007] Also provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant to one or more first androgen receptor signaling inhibitors (ARSI), comprising administeringto the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0008] Further provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant to a CYP17 inhibitor, comprising administering to the subject (a) darolutamide at a dose of600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0009] Also provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant to abiraterone acetate, comprising administering to the subject (a) darolutamide at a dose ofWSGR Ref. 47134-782.601600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0010] Further provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, wherein the subject has received prior administration of one or more CYP17 inhibitors, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0011] Also provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of one or more CYP17 inhibitors, and (ii) is androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at adose of 600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.INCORPORATION BY REFERENCE

[0012] 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.WSGR Ref. 47134-782.601BRIEF DESCRIPTION OF THE FIGURES

[0013] FIG. 1 depicts the best percent changes in PSA (from baseline), as of December 10, 2024, for the human subjects enrolled in the clinical study described in Example 1.

[0014] FIG. 2 shows ctDNA reductions observed for Compound 1 in combination with darolutamide in post-abiraterone mCRPC patients, as of October 20, 2025.DETAILED DESCRIPTION OF THE INVENTION

[0015] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0016] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0017] “Administering” when used in conjunction with a therapeutic, including androgen receptor inhibitors and embryonic ectoderm development (EED) inhibitors, means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a subject (e. g. , a human) whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a subject (e.g., a human) by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.

[0018] The terms “androgen receptor signaling inhibitor,” “ARSI,” “androgen receptor pathway inhibitors”, and “ARPI,” as used herein, mean an agent that when administered to a subject having prostate cancer affect androgen signaling pathways in one or more cells comprising the prostate cancer. Androgen receptor signaling inhibitors include, but are not limited to, agents that inhibit androgen biosynthesis or modulate the function of the androgen receptor, including by inhibiting the function of the androgen receptor, by for example, binding to the receptor and interfering with the binding of androgen(s)WSGR Ref. 47134-782.601to the androgen receptors. Examples of agents that inhibit androgen biosynthesis are known to those of ordinary skill in the art and include, but are not limited to, agents that inhibit enzymes responsible for androgen biosynthesis, such as 17 a-hydroxylase / C17,20-lyase (CYP17). Examples of CYP17 inhibitors are known to those of ordinary skill in the art and include abiraterone and abiraterone prodrugs, including abiraterone acetate.

[0019] The term “androgen receptor inhibitor,” or “AR inhibitor,” as used herein, means an agent that bind to and modulate the function of androgen receptors and include, but are not limited to, agents that inhibit the binding of androgen(s) to androgen receptors, and agents that inhibit nuclear translocation of androgen receptors and their interaction with DNA. Examples of androgen receptor inhibitors are known to those having skill in the art and include, but are not limited to, apalutamide, darolutamide, and enzalutamide.

[0020] Darolutamide is an androgen receptor inhibitor having CAS Registry Number: 1297538-32-9 and the chemical structure:Darolutamide may be used according to the methods disclosed herein in the form of tablets for oral use comprising 300 mg of darolutamide and one or more excipients. The preparation of darolutamide and pharmaceutical compositions comprising darolutamide are known to those having ordinary skill in the art and are further described in United States Patent Nos.8,975,254; 9,657,003; 10,010,530; 10,383,853; 10,711,013; 10,835,515; 11,046,713; and 11,168,058, each of which is incorporated by reference herein for that purpose.

[0021] The terms “determine,” “determined,” and “determining,” and the like, as used herein mean that it has been established that a pre-condition in a subject exists, or a condition precedent with respect to a subject has been satisfied, prior to the administration to the subject of androgen receptor inhibitors and embryonic ectoderm development (EED) inhibitors.

[0022] The term “pharmaceutically acceptable”, as used herein, means a carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0023] The term “pharmaceutical composition” means a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[0024] The terms “progressing,” “relapsed,” “refractory, ” “resistant,” and the like as used herein refer to prostate cancer in a subj ect that appears to grow again after a period or remission, and / or being no longer responsive to the treatment that is currently being administered to the subject or that had beenWSGR Ref. 47134-782.601administered to the subject (e.g., prior treatment of a prostate cancer in a subject with a CYP17 inhibitor such as abiraterone). A determination of whether a cancer, or one or more cells comprising a cancer, in a subject is progressing, has relapsed, or has become refractory or resistant to a specific treatment modality, such as a CYP17 inhibitor such as abiraterone acetate, can be made by methods to known to those of ordinary skill in the art. For example, responsiveness, or non-responsiveness, as the case may be, of a cancer in a subject, or one or more cells comprising the cancer in a subject, can be assessed by measuring a subject’s clinical symptoms, conducting a biopsy of one or more relevant tissue types, reduction in the size and / or number of tumor lesions, duration of response, or progression-free survival. Further, prostate cancer in a subject can be determined to be resistant to a prior line of therapy by reference to the criteria set forth in the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria (see, for example, Scher et al. J. Clinical Oncology, 2016, vol. 34, number 12, pp. 1402-1418 and included appendices), including, but not limited to, (a) rising levels of prostate-specific antigen (PSA) defined as a minimum of 2 rising values obtained a minimum of one week apart with the latest result being at least 2.0 ng / mL (or l.Ong / mLifPSArise is the only indication of progression), (b) confirmation of 2 new bone lesions while being administered the last systemic therapy, (c) soft tissue progression per RECIST 1.1, and (d) radiographic progression.

[0025] As used herein, the term “PSA” means prostate-specific antigen. The term “PSA50,” as used herein, means a reduction in PSA in a subject of 50% or more measured from a baseline. The term “PSA90,” as used herein, means a reduction in PSA in a subject of 90% or more measured from a baseline. In the present disclosure, it is contemplated that a baseline used to measure PSA reductions in a subject is the PSA level measured in the subject prior to the administration to the subject of (a) darolutamide, and (b) Compound 1, or a pharmaceutically acceptable salt thereof.

[0026] As used herein, the term “QD” means that the compound, drug, or therapeutic referred to herein is administered to a subject once per day.

[0027] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a subject.

[0028] A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing orWSGR Ref. 47134-782.601displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0029] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition.

[0030] Provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b)Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0031] Also provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant to one or more first androgen receptor signaling inhibitors (ARSI), comprising administeringto the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to aboutWSGR Ref. 47134-782.601800 mg QD. In some embodiments, the one or more first androgen receptor signaling inhibitors (ARSI) is selected from one or more first CYP17 inhibitors and one or more first androgen receptor inhibitors. In some embodiments, the one or more first androgen receptor signaling inhibitors (ARSI) is selected from one or more first CYP17 inhibitors. In other embodiments, the one or more first CYP17 inhibitor is abiraterone acetate. In further embodiments, the one or more first androgen receptor signaling inhibitors (ARSI) is selected from one or more androgen receptor inhibitors. In some embodiments, the one or more first androgen receptor inhibitors is selected from apalutamide, darolutamide, and enzalutamide. In one embodiment, the one or more first androgen receptor inhibitor is apalutamide. In one embodiment, the one or more first androgen receptor inhibitor is darolutamide. In one embodiment, the one or more first androgen receptor inhibitor is enzalutamide.

[0032] Also provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant to a CYP17 inhibitor, comprising administering to the subject (a) darolutamide at a dose of <600 mg BID, and (b) Compound 1, <(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD. In one embodiment, the CYP17 inhibitor is abiraterone acetate.

[0033] Also provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant to abiraterone acetate, comprising administering to the subject (a) darolutamide at a dose of <600 mg BID, and (b) Compound 1, <(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0034] Further provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, wherein the subject has received prior administration of one or more CYP17 inhibitors, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,WSGR Ref. 47134-782.601(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0035] Further provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of one or more CYP17 inhibitors, and (ii) is androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at adose of 600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0036] Further provided herein are methods of treating metastatic castration -resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of abiraterone acetate, and (ii) is androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at a dose of600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of about 400 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 400 mg QD.

[0037] Further provided herein are methods of treating metastatic castration -resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of abiraterone acetate, and (ii) is androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at a dose ofWSGR Ref. 47134-782.601600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 500 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 500 mg QD.

[0038] Further provided herein are methods of treating metastatic castration -resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of abiraterone acetate, and (ii) is androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at a dose of600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of about 600 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 600 mg QD.

[0039] Further provided herein are methods of treating metastatic castration -resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of abiraterone acetate, and (ii) is androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at a dose of600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of about 700 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 700 mg QD.

[0040] Further provided herein are methods of treating metastatic castration -resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of abiraterone acetate, and (ii) isWSGR Ref. 47134-782.601androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at a dose of <<600 mg BID, and (b) Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of about 800 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 800 mg QD.

[0041] Further provided herein are methods of treating metastatic castration -resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of one or more CYP17 inhibitors, and (ii) is androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at a <dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD, and wherein the subject has not received prior administration for prostate cancer of a PRC2 inhibitor (EED inhibitor or EZH2 inhibitor), cytotoxic chemotherapy, radioligand therapy, poly [ADP-ribose] polymerase (PARP) inhibitor monotherapy, or other systemic anti cancer treatment. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 400 mg QD, about 500 mg QD, about 600 mg QD, about 700 mg QD, or about 800 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 400 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 500 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 600 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 700 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 800 mg QD.

[0042] Further provided herein are methods of treating metastatic castration -resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of one or more CYP17 inhibitors, and (ii) is androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at aWSGR Ref. 47134-782.601dose of 600 mg BID, and (b) Compound 1, <" (Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD, and wherein the subject has not received prior administration of a PRC2 inhibitor (EED inhibitor or EZH2 inhibitor). In some embodiments, the subject has not received prior administration of an EED inhibitor. In some embodiments, the subject has not received prior administration of an EZH2 inhibitor. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 400 mg QD, about 500 mg QD, about 600 mg QD, about 700 mg QD, or about 800 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 400 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 500 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 600 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 700 mg QD. In some embodiments, the subject is administered the free base form of Compound 1 at a dose of about 800 mg QD.

[0043] In some embodiments of the methods disclosed herein, the subject has received one or more prior chemotherapeutic treatments prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments of the methods disclosed herein, the subject has received up to one prior chemotherapeutic treatment prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0045] Also provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b)Compound< (Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD, and wherein the subject is CYP17 inhibitor-naive prior toWSGR Ref. 47134-782.601the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0046] Also provided herein are methods of treating metastatic castration-resistant prostate cancer in a subject, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b)Compound(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD, and wherein the subject is androgen receptor inhibitor naive prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0047] Also disclosed herein are any of the methods disclosed herein, wherein the subject has not been administered abiraterone acetate or an androgen receptor inhibitor selected from apalutamide, darolutamide, or enzalutamide prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0048] Also disclosed herein are any of the methods of treating prostate cancer disclosed herein, wherein the subject has not been administered abiraterone acetate or apalutamide prior to the administration to the subject of apalutamide and Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been administered abiraterone acetate or darolutamide prior to the administration to the subject of apalutamide and Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not been administered abiraterone acetate or enzalutamide prior to the administration to the subject of apalutamide and Compound 1, or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments of the methods disclosed herein, the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject sequentially or simultaneously. In other embodiments, the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject sequentially. In some embodiments, the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject on the same day. In some embodiments, the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject within a 24-hour period. In another embodiment, the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject within a 12-hour period, or a 10-hour period, or an 8-hour period, or a 6-hour period, or a 4-hour period, or a 2-hour period, or within an hour of each of other.WSGR Ref. 47134-782.601

[0050] In some embodiments, the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject simultaneously.

[0051] In some embodiments of the methods disclosed herein, the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject with food or without food. In some embodiments, the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject with food. In other embodiments, the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject without food.

[0052] In some embodiments of the methods disclosed herein, the subject has been administered one or more prior androgen deprivation therapies prior to the administration to the subject the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof. Examples of androgen deprivation therapies include, but are not limited to, LHRH agonists (e.g., leuprolide, leuprolide mesylate, goserelin, histrelin, and triptorelin) LHRH antagonists (e.g., degarelix and relugolix), and anti -androgens (e.g., bicalutamide, flutamide, and nilutamide).

[0053] In some embodiments of the methods disclosed herein, the subject has been administered a gonadotropin-releasing hormone (GnRH) analog prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments of the methods disclosed herein, the subject receives a gonadotropinreleasing hormone (GnRH) analog concurrently with the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof. In an embodiment, the GnRH analog is selected from leuprolide, leuprolide mesylate, goserelin, histrelin, triptorelin, degarelix, and relugolix. In an embodiment, the GnRH analog is leuprolide. In an embodiment, the GnRH analog is goserelin. In an embodiment, the GnRH analog is histrelin. In an embodiment, the GnRH analog is triptorelin. In an embodiment, the GnRH analog is degarelix. In an embodiment, the GnRH analog is relugolix.

[0055] In some embodiments of the methods disclosed herein, the subject had a bilateral orchiectomy prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments of the methods disclosed herein, the subject is not administered a compound that is a substrate of CYP3A4, CYP2C19, CYP2C8, CYP2C9, UGT, P-gp, BCRP, or OATP1B1 during the time period in which the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject.

[0057] In some embodiments of the methods disclosed herein, the subject is not administered a compound that is a substrate of CYP3A4, CYP2C9, UGT, P-gp, BCRP, or OATP1B1 during the time period in which the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject.

[0058] In some embodiments of the methods disclosed herein, the subject is not administered a compound that is (a) a CYP2C8 inhibitor, (b) a CYP3A4 inducer, or (c) a substrate of CYP3A4,WSGR Ref. 47134-782.601CYP2C9, or CYP2C19 during the time period in which the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject.

[0059] In some embodiments of the methods disclosed herein, subject is not administered a compound that is (a) a CYP3 A4 inducer, (b) a PG-p inhibitor, (c) a CYP3A4 inhibitor, (d) a BCRP substrate, (e) an OATP1B1 substrate, or (f) a OATP1B3 substrate during the time period in which the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject.

[0060] In some embodiments of the methods disclosed herein, the subject has not been administered one or more prior androgen deprivation therapies prior to the administration to the subject the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments of the methods disclosed herein, the subject has received administration of one or more of (i) abiraterone acetate; (ii) chemotherapy; (iii) lutetium Lu 177 vipivotide tetraxetan; (iv) cabozantinib; (v) atezolizumab; and (vi) bicalutamide prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0062] In other embodiments of the methods disclosed herein, the subject having mCRPC cancer that may benefit from the administration to the subject of darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof may include one or more of the following criteria: (a) the subject has undergone bilateral orchiectomy or be willing to continue GnRH analogue or antagonist to maintain castrate levels of testosterone; (b) the subject has progressed after at least one line of ARSI (abiraterone acetate, enzalutamide, apalutamide, darolutamide) and must not have received more than 2 chemotherapy regimens in the mCRPC setting; (c) a subject exhibiting evidence of progressive disease by PCWG3 criteria, including rising PSA, defined as a minimum of 2 rising values obtained a minimum of one week apart with the latest result being at least 2.0 ng / mL (or 1.0 ng / mL if PSA rise is the only indication of progression), or confirmation of 2 new bone lesions on last systemic therapy, or soft tissue progression per RECIST 1.1; (d) subject having measurable and / or evaluable disease by RECIST 1.1; (e) an ECOG performance status of 0 or 1; and (f) adequate organ function.

[0063] In other embodiments of the methods disclosed herein, the subject having mCRPC cancer that may benefit from the administration to the subject of darolutamide and Compound 1, or a pharmaceutically acceptable salt thereof, may include one or more of the following criteria: (a) documented evidence of histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features (neuroendocrine differentiation and other histologic components are permitted if adenocarcinoma is the primary histology); (b) surgically or medically castrated, with serum testosterone < 50 ng / dL or < 1.73 nmol / L at screening; (c) for subjects that have not undergone bilateral orchiectomy must initiate treatment with GnRH agonist or antagonist >4 weeks prior to treatment and continue throughout the duration of the treatment period; (d) may have received prior administration of abiraterone acetate; (e) evidence of disease progression including, but not limited to, one or more of (i) PSA progression, defined as a minimum of two rising PSA levels with an interval of >1 week between each determination within the last 12 months, wherein the PSA value may be >1 ng / mL if confirmed rise inWSGR Ref. 47134-782.601PSA is the only indication of progression per PCWG3 criteria, (ii) soft tissue disease progression as defined by RECIST 1.1, and (iii) bone disease progression defined by PCWG3 with 2 or more new metastatic bone lesions on a whole-body radionuclide bone scan, (f) metastatic disease in soft tissue documented on CT / MRI scan, or in bone documented on a radionuclide bone scan, including measurable soft tissue disease (per RECIST vl.l), (g) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and (h) adequate organ function.

[0064] In some embodiments of the methods disclosed herein, the subject is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 400 mg QD. In some embodiments of the methods disclosed herein, the subject is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 500 mg QD. In some embodiments of the methods disclosed herein, the subject is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 600 mg QD. In some embodiments of the methods disclosed herein, the subject is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 700 mg QD. In some embodiments of the methods disclosed herein, the subject is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 800 mg QD.

[0065] In some embodiments of the methods disclosed herein, wherein the subject exhibits a reduction in PSA of at least 50% following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments of the methods disclosed herein, the subject exhibits a reduction in PSA of at least 90% following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments of the methods disclosed herein, the reduction of PSA in the subject is maintained for at least 12 weeks following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments of the methods disclosed herein, the reduction of PSA in the subject is maintained for at least 38 weeks following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments of the methods disclosed herein, the reduction of PSA in the subject is maintained for at least 1 year (e.g., at least 18 months, at least 2 years, or at least 3 years) following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments of the methods disclosed herein, the subject exhibits a reduction in circulating tumor DNA (ctDNA) of at least 50% (e.g., at least 75%, at least 80%, at least 85%, or at least 90%) following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, optionally wherein the subject has a tumor comprising one or more of mutated AR, amplified AR, or wildtype AR, or one or more mutations in p53, SPOP, PI3K, orWSGR Ref. 47134-782.601BRCA. The ctDNA can be measured by a commercially available assay, for example PredicineCARE® or FoundationOne® Liquid CDx.

[0071] In some embodiments of the methods disclosed herein, the subject exhibits a reduction in circulating tumor DNA (ctDNA) of at least 95% (e.g., at least 96%, at least 97%, at least 98%, at least 99%) following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, optionally wherein the subject has a tumor comprising one or more of mutated AR, amplified AR, or wildtype AR, or one or more mutations in p53, SPOP, PI3K, or BRCA. The ctDNA can be measured by a commercially available assay, for example PredicineCARE® or FoundationOne® Liquid CDx.

[0072] In some embodiments of the methods disclosed herein, the subject exhibits a reduction in circulating tumor DNA (ctDNA) of at least 99.5% following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, optionally wherein the subject has a tumor comprising one or more of mutated AR, amplified AR, or wildtype AR, or one or more mutations in p53, SPOP, PI3K, or BRCA. The ctDNA can be measured by a commercially available assay, for example PredicineCARE® or FoundationOne® Liquid CDx.

[0073] In some embodiments of the methods disclosed herein, the subject exhibits radiographic Progression Free Survival (rPFS) for at least one month following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject exhibits radiographic Progression Free Survival (rPFS) for at least one month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 12 months, or at least 13 months, or at least 14 months, or at least 15 months, or at least 16 months, or at least 17 months, or at least 18 months, or at least 19 months, or at least 20 months, or at least 21 months, or at least 22 months, or at least 23 months, or at least 24 months following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof. As used herein, the term radiographic Progression Free Survival (rPFS) means the time starting from the date the subject is first administered darolutamide and Compound 1, or a pharmaceutically acceptable thereof, and ending on the date of the first to occur of (a) evidence of radiographic progression of disease, such as disease progression in soft tissue per RECIST 1.1 or in bone per PCWG3 criteria, and (b) the death of the subject.

[0074] In some embodiments of the methods disclosed herein, the subject exhibits overall survival of at least one month following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject exhibits overall survival of at least one month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 12 months, or at least 13 months, or at least 14 months, or at least 15 months, or at least 16 months, or at least 17 months, or at least 18 months, or at least 19 months, or at least 20 months, or at least 21 months, or at least 22 months, or at least 23 months, or at least 24 months followingWSGR Ref. 47134-782.601administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof. As used herein, the term overall survival means the time starting from the date the subject is first administered darolutamide and Compound 1, or a pharmaceutically acceptable thereof, and ending on the date of death of the subject.

[0075] Compound 1, or pharmaceutically acceptable salts thereof, may be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, those described in United States Patent No. 11,091,495, or may be prepared using other reagents and conventional methods well known to those skilled in the art. The contents of United States Patent No.11,091,495 are hereby incorporated by reference for that purpose.

[0076] In some embodiments are provided methods of treatment of prostate cancer in a subject, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. The desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. It is specifically contemplated herein that references to Compound 1, also refer in the alternative to pharmaceutically acceptable salts of compounds of Compound 1.

[0077] If Compound 1, or a pharmaceutically acceptable salt thereof, is a solid, it is understood by those skilled in the art that the compounds or salts thereof may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.

[0078] In one aspect, the compositions described herein comprise Compound 1, or a pharmaceutically acceptable salt thereof, are used for the treatment of prostate cancer in subjects. Such compositions may be prepared in pharmaceutically acceptable dosage forms for administration to subjects. Pharmaceutically acceptable dosage forms include, for example, liquids, suspensions, powders for reconstitution, tablets, pills, sachets, or capsules of hard or soft gelatin (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Compound 1, or a pharmaceutically acceptable salt thereof, may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable. Pharmaceutical compositions of the invention comprise a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an inert, pharmaceutically acceptable carrier or diluent.

[0079] The pharmaceutical carriers employed may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like.Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like. Similarly, the compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate orWSGRRef. 47134-782.601glyceryl distearate alone or with a wax, ethyl cellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties. For example, a bioavailability enhancer, such asLabrasol, Gelucire or the like, or formulator, such as CMC (carboxy-methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added. Gelucire, a semi-solid vehicle that protects active ingredients from light, moisture, and oxidation, may be added, e.g., when preparing a capsule formulation.

[0080] If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations. The inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.

[0081] To obtain a stable water-soluble dose form, Compound 1, or a pharmaceutically acceptable salt thereof, may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the compound, or a pharmaceutically acceptable salt thereof, may be dissolved in a suitable co-solvent or combinations of co-solvents.Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume. In an exemplary embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.

[0082] Proper formulation is dependent upon the route of administration selected. For injection, Compound 1, or a pharmaceutically acceptable salt thereof, may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0083] For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl -cellulose, sodiumWSGR Ref. 47134-782.601carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0084] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.

[0085] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0086] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0087] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0088] Additionally, the pharmaceutically acceptable formulations of Compound 1, or a pharmaceutically acceptable salt thereof, that may be used to practice the methods disclosed herein may contain Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of from about 0.5 w / w % to about 95 w / w %, or from about 1 w / w % to about 95 w / w %, or from about 1 w / w % to about 75 w / w %, or from about 5 w / w % to about 75 w / w %, or from about 10 w / w % to about 75 w / w %, or from about 10 w / w % to about 50 w / w %.

[0089] Furthermore, the pharmaceutically acceptable formulations of Compound 1, or a pharmaceutically acceptable salt thereof, that may be used to practice the methods disclosed herein may contain Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 mg to about 500 mg, or from about 100 mg to about 500 mg.

[0090] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof in 28-day cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof in multiple 28-dayWSGR Ref. 47134-782.601cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof for at least one 28 -day cycle. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof on each day of each 28-day cycle.

[0091] In some instances, the methods described herein comprise administering the compositions and formulations comprising the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, to the subject or subject in need thereof in multiple cycles repeated on a regular schedule with periods of rest in between each cycle. For example, in some instances, treatment given for one week followed by three weeks of rest is one treatment cycle. The length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycle ranges from three to four weeks. In some embodiments, the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, or four weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.Kits and articles of manufacture

[0092] Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one or more methods and compositions described herein. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[0093] A kit typically includes labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[0094] In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[0095] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack orWSGR Ref. 47134-782.601dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0096] Disclosed herein is a kit for use in treating mCRPC in a subject comprising (a) darolutamide, and(b) Compound< (Compound 1), or a pharmaceutically acceptable salt thereof, and a package insert comprising instructions for administering the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, to the subject having mCRPC.Numbered Embodiments

[0097] Embodiment 1. A method of treating metastatic castration-resistant prostate cancer in a subject, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0098] Embodiment 2. A method of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant to one or more first androgen receptor signaling inhibitors (ARSI), comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,WSGR Ref. 47134-782.601(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0099] Embodiment 3. The method of embodiment 2, wherein the one or more first androgen receptor signaling inhibitors (ARSI) is selected from one or more first CYP17 inhibitors and one or more first androgen receptor inhibitors.

[0100] Embodiment 4. The method of embodiment 3, wherein the one or more first androgen receptor signaling inhibitors (ARSI) is selected from one or more first CYP17 inhibitors.

[0101] Embodiment 5. The method of embodiment 4, wherein the one or more first CYP17 inhibitor is abiraterone acetate.

[0102] Embodiment 6. The method of embodiment 2, wherein the one or more first androgen receptor signaling inhibitors (ARSI) is selected from one or more androgen receptor inhibitors.

[0103] Embodiment 7. The method of embodiment 6, wherein the one or more first androgen receptor inhibitors is selected from apalutamide, darolutamide, and enzalutamide.

[0104] Embodiment 8. A method of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant to at least one CYP17 inhibitor, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0105] Embodiment 9. The method of embodiment 8, wherein the CYP17 inhibitor is abiraterone acetate.

[0106] Embodiment 10. A method of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to beWSGR Ref. 47134-782.601resistant to abiraterone acetate, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0107] Embodiment 11. A method of treating metastatic castration-resistant prostate cancer in a subject, wherein the subject has received prior administration of one or more CYP17 inhibitors, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

[0108] Embodiment 12. A method of treating metastatic castration-resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of one or more CYP17 inhibitors, and (ii) is androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.WSGR Ref. 47134-782.601

[0109] Embodiment 13. The method of any one of embodiments 1 to 12, wherein the subject has received one or more prior chemotherapeutic treatments prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0110] Embodiment 14. The method of any one of embodiments 1 to 12, wherein the subject has received up to one prior chemotherapeutic treatments prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.[OOlllJEmbodiment 15. The method of embodiment 1, wherein the subject is CYP17 inhibitor -naive prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0112] Embodiment 16. The method of embodiment 1, wherein the subject is androgen receptor inhibitor naive prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0113] Embodiment 17. The method of any one of embodiments 1 to 16, wherein the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject sequentially or simultaneously.

[0114] Embodiment 18. The method of embodiment 17, wherein the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject sequentially.

[0115] Embodiment 19. The method of any one of embodiments 1 to 18, wherein the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject on the same day.

[0116] Embodiment 20. The method of any one of embodiments 1 to 19, wherein the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject within a 24-hour period.

[0117] Embodiment 21. The method of embodiment 17, wherein the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject simultaneously.

[0118] Embodiment 22. The method of any one of embodiments 1 to 21, wherein the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject with food or without food.

[0119] Embodiment 23. The method of embodiment 22, wherein the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject with food.

[0120] Embodiment 24. The method of embodiment 22, wherein the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject without food.

[0121] Embodiment 25. The method of any one of embodiments 1 to 24, wherein the subject has been administered one or more prior androgen deprivation therapies prior to the administration to the subject the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.WSGR Ref. 47134-782.601

[0122] Embodiment 26. The method of any one of embodiments 1 to 25, wherein the subject has been administered a gonadotropin-releasing hormone (GnRH) analog prior to the administration to the subj ect of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0123] Embodiment 27. The method of any one of embodiments 1 to 26, wherein the subject receives a gonadotropin-releasing hormone (GnRH) analog concurrently with the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0124] Embodiment 28. The method of any one of embodiments 1 to 27, wherein the subject had a bilateral orchiectomy prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0125] Embodiment 29. The method of any one of embodiments 1 to 28, wherein the subject is not administered a compound that is a substrate of CYP3A4, CYP2C19, CYP2C8, CYP2C9, UGT, P-gp, BCRP, or OATP1B1 during the time period in which the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject.

[0126] Embodiment 30. The method of any one of embodiments 1 to 29, wherein the subject is not administered a compound that is a substrate of CYP3A4, CYP2C9, UGT, P-gp, BCRP, or OATP1B1 during the time period in which the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject.

[0127] Embodiment 31. The method of any one of embodiments 1 to 30, wherein the subject is not administered a compound that is (a) a CYP2C8 inhibitor, (b) a CYP3A4 inducer, or (c) a substrate of CYP3A4, CYP2C9, or CYP2C19 during the time period in which the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject.

[0128] Embodiment 32. The method of any one of embodiments 1 to 31, wherein the subject is not administered a compound that is (a) a CYP3A4 inducer, (b) a PG-p inhibitor, (c) a CYP3A4 inhibitor, (d) a BCRP substrate, (e) an OATP1B1 substrate, or (f) a OATP1B3 substrate during the time period in which the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof, are administered to the subject.

[0129] Embodiment 33. The method of embodiment 1, wherein the subject has not been administered one or more prior androgen deprivation therapies prior to the administration to the subject the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0130] Embodiment 34. The method of embodiment 1, wherein the subject has received administration of one or more of (i) abiraterone acetate; (ii) chemotherapy; (iii) lutetium Lu 177 vipivotide tetraxetan; (iv) cabozantinib; (v) atezolizumab; and (vi) bicalutamide prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0131] Embodiment 35. The method of any one of embodiments 1 to 34, wherein the subject is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 600 mg QD.

[0132] Embodiment 36. The method of any one of embodiments 1 to 34, wherein the subject is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 800 mg QD.WSGR Ref. 47134-782.601

[0133] Embodiment 37. The method of any one of embodiments 1 to 36, wherein the subject exhibits a reduction in PSA of at least 50% following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0134] Embodiment 38. The method of any one of embodiments 1 to 36, wherein the subject exhibits a reduction in PSA of at least 90% following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0135] Embodiment 39. The method of embodiment 37 or 38, wherein the reduction of PSA in the subject is maintained for at least 12 weeks following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0136] Embodiment 40. The method of embodiment 37 or 38, wherein the reduction of PSA in the subject is maintained for at least 38 weeks following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0137] Embodiment 41. The method of embodiment 37 or 38, wherein the reduction of PSA in the subject is maintained for at least 1 year following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0138] Embodiment 42. The method of any one of embodiments 1 to 41, wherein the subject exhibits a reduction in circulating tumor DNA (ctDNA) of at least 50% following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0139] Embodiment 43. The method of embodiment 42, wherein the subject exhibits a reduction in circulating tumor DNA (ctDNA) of at least 95% following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

[0140] Embodiment 44. The method of embodiment 43, wherein the subject exhibits a reduction in circulating tumor DNA (ctDNA) of at least 99.5% following administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.ExamplesExample 1: Clinical evaluation of darolutamide and Compound 1 in human subjects having metastatic castration- resistant prostate cancer (mCRPC)

[0141] A clinical study was conducted in subjects having metastatic castration-resistant prostate cancer (mCRPC), wherein the subjects were administered (a) darolutamide at a dose of 600 mg BID, and (b) the free base form of Compound 1 at a dose of 600 mg QD or 800 mg QD, in 28-day cycles.

[0142] Entry criteria for subjects enrolled in the study were as follows:• Aged >18 years at the time of signing the informed consent.• Patients with metastatic prostate cancer.• Must have undergone bilateral orchiectomy or be willing to continue GnRH analogue or antagonist to maintain castrate levels of testosterone throughout the duration of the study.WSGR Ref. 47134-782.601• Prior Therapies: Must have received only 1 prior line of abiraterone acetate, apalutamide, darolutamide, or enzalutamide in any setting; may have also received up to 1 prior line of chemotherapy.• Evidence of progressive disease by PCWG3 criteria for study entry.a. rising PSA, defined as a minimum of 2 rising values obtained a minimum of one week apart with the latest result being at least 2.0 ng / mL (or 1.0 ng / mL if PSA rise is the only indication of progression), orb. confirmation of 2 new bone lesions on last systemic therapy, orc. soft tissue progression per RECIST 1.1.• Measurable and / or evaluable disease (i.e., presence of bone lesions on a bone scan and / or at least one measurable lesion per RECIST 1.1.• Agreement and ability to undergo on-study punch skin biopsies, as follows:a. one pretreatment biopsy prior to enrollment on this study andb. one post treatment biopsy after 3-4 weeks on study treatment or at End of Treatment (EOT) whichever occurs first.• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.• Adequate organ function as defined by the following criteria:a. ANC >1500 cells / mm3(1.5 x 103cells / mm3)b. Platelets >100,000 / pL (100 x 109 / L)c. Hemoglobin >9.0 g / dL (90 g / L)d. AST (SGOT) or ALT (SGPT) <2.5 x ULN, <5.0 x ULN for patients with liver metastases. e. Bilirubin <1.5 x ULN; patients with a known history of Gilbert’s syndrome and / or isolated elevations of indirect bilirubin are eligible.f. Estimated glomerular filtration rate >60 mL / min.g. QTcF <470 msec.• Able to swallow oral medication without chewing or crushing

[0143] Exclusion criteria for study subjects included:• Patients with pure small-cell carcinoma (SCC) of prostate• Current participation in another clinical study of an investigational agent, vaccine, or device; concomitant participation in observational studies is acceptable after sponsor approval.• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured per investigator judgement and / or not requiring active treatment with systemic therapy.• History or presence of CNS metastases, unless previously treated and stable.• History of seizures or any condition or medication that may predispose to seizures.• Any other anticancer therapy within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug.WSGR Ref. 47134-782.601• Radiotherapy within 2 weeks prior to first dose of study drug (palliative radiation or stereotactic radiosurgery within 7 days prior to first dose of study drug); patients must have recovered from all radiotherapy-related toxicities.• Major surgery within 21 days prior to first dose of study drug or incomplete recovery from adverse effects resulting from such procedure.• History of class III or IV congestive heart failure or severe non-ischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months of first dose of study drug.• Known human immunodeficiency virus (HIV) infection, unless patient is healthy and has a low risk of AIDS-related outcomes• Active symptomatic Hepatitis B or C infection; patients with well controlled disease are eligible.• Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, short gut syndrome, etc.) or other malabsorption syndromes that would reasonably impact drug absorption per investigator judgement• Any other condition or circumstance (e.g. , clinical, psychological, familial, sociological, inability to swallow oral study drug) that, in the opinion of the investigator, may interfere with protocol compliance or contraindicates participation in the study.

[0144] Four subjects enrolled in the study were administered darolutamide at a dose of 600 mg BID and the free base form of Compound 1 at a dose of 600 mg QD. Each subject had received one or more prior therapies prior to enrollment in the study. The prior therapies received by each subject were as follows: (a) subject 1: abiraterone; chemotherapy; and lutetium Lu 177 vipivotide tetraxetan (b) subject 2: abiraterone; cabozantinib plus atezolizumab; (c) subject 3: abiraterone; bicalutamide; and olaparib; and (d) subject 4: abiraterone; chemotherapy.

[0145] On- treatment prostate-specific antigen (PSA) levels and change from baseline were measured in each subject. As of the data cut-off of December 10, 2024: (a) one subject experienced rising PSA levels during the first cycle of treatment (cycle = 28 days); and (b) 3 subjects experienced PSA reductions, one of which was aPSA50 response, and one of which was a PSA90 response. In addition, the daily regimen was generally well tolerated with subjects experiencing primarily Grade 1 and Grade 2 treatment-related adverse events that were consistent with subjects receiving PRC2 and AR inhibitors. There were no subjects that discontinued due to safety. The best percent changes in PSA (from baseline) for each subject administered the free base form of Compound 1 at a dose of 600 mg QD, as of December 10, 2024, are shown in FIG. 1.

[0146] An additional 7 subjects previously treated with abiraterone acetate were enrolled in the study (for a total of 11 subjects) and were administered darolutamide at a dose of 600 mg BID and the free base of Compound 1 at a dose of 400 mg QD, 600 mg QD, or 800 mg QD. The percentage of subjects in each dosing group that, as of May 9, 2025, achieved confirmed and unconfirmed PSA50s and PSA90s are set forth in Table 1 (where uPSA50 = unconfirmed PSA50; cPSA50 = confirmed PSA50; uPSA90 =WSGR Ref. 47134-782.601unconfirmed PSA 90; and cPSA90 = confirmed PSA90). Note that in Table 1, subjects that achieved an unconfirmed or confirmed PSA90 in a dosing group are also included in the total number of subjects that achieved an unconfirmed or confirmed PSA50 in that dosing group.Table 1Additional activity analysis

[0147] As of October 20, 2025, PSA responses and reductions in ctDNA were observed across all dose levels of Compound 1 at comparable rates in combination with darolutamide. ctDNA data can also serve as a useful biomarker to predict the duration of treatment benefit and survival in prostate cancer, as established in independent studies across lines of treatment and treatment paradigms.PSA activity, ongoing >1 year• About 64% (7 / 11) of patients achieved a PSA50 response; confirmed PSA50 response rate of 46% (5 / H).• About 18% (2 / 11) of patients achieved a PSA90 response; confirmed PSA90 response rate of 18% (2 / 11).ctDNA activity, measured by PredicineCARE® assay:• ctDNA responses were observed across a breadth of AR mutations and other tumor alterations, including mutated AR, amplified AR, or wildtype AR, or one or more mutations in p53, SPOP, PI3K, or BRCA.• About 80% (8 / 10) of patients demonstrated a relative change >50% in ctDNA reduction, see FIG.2.Preliminary safety analysis

[0148] As of October 20, 2025, Compound 1 in combination with darolutamide continues to be well tolerated. The combination regimen demonstrated a safety profile compatible with long term dosing, with a vast majority of adverse events (AEs) Grade 1 or 2 in severity and consistent with PRC2 and AR inhibition. Diarrhea was the most common treatment-related AE, with only one patient experiencing aWSGRRef. 47134-782.601Grade 3 event. There were no Grade 4 or Grade 5 treatment-related AEs attributed to Compound 1 with darolutamide. The combination of Compound 1 + AR inhibitor (darolutamide) compares favorably to an earlier PRC2 inhibitor (mevrometostat) + AR inhibitor (enzalutamide) and to AR inhibitor (enzalutamide) monotherapy.

Claims

WSGR Ref. 47134-782.601CLAIMS WHAT IS CLAIMED is:

1. A method of treating metastatic castration-resistant prostate cancer in a subject, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

2. A method of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant to one or more first androgen receptor signaling inhibitors (ARSI), comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

3. The method of claim 2, wherein the one or more first androgen receptor signaling inhibitors (ARSI) is selected from one or more first CYP17 inhibitors and one or more first androgen receptor inhibitors.

4. The method of claim 3, wherein the one or more first androgen receptor signaling inhibitors (ARSI) is selected from one or more first CYP17 inhibitors.

5. The method of claim 4, wherein the one or more first CYP17 inhibitor is abiraterone acetate.

6. The method of claim 2, wherein the one or more first androgen receptor signaling inhibitors (ARSI) is selected from one or more androgen receptor inhibitors.

7. The method of claim 6, wherein the one or more first androgen receptor inhibitors is selected from apalutamide, darolutamide, and enzalutamide.

8. A method of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant toWSGR Ref. 47134-782.601at least one CYP17 inhibitor, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

9. The method of claim 8, wherein the CYP17 inhibitor is abiraterone acetate.

10. A method of treating metastatic castration-resistant prostate cancer in a subject, wherein the metastatic castration-resistant prostate cancer in the subject has been determined to be resistant to abiraterone acetate, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.A method of treating metastatic castration-resistant prostate cancer in a subject, wherein the subject has received prior administration of one or more CYP17 inhibitors, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.WSGR Ref. 47134-782.60112. A method of treating metastatic castration-resistant prostate cancer in a subject, wherein the subject (i) has received prior administration of one or more CYP17 inhibitors, and (ii) is androgen receptor inhibitor naive, comprising administering to the subject (a) darolutamide at a dose of 600 mg BID, and (b) Compound 1,(Compound 1), or a pharmaceutically acceptable salt thereof, at a dose of from about 400 mg QD to about 800 mg QD.

13. The method of any one of claims 1 to 12, wherein the subject has received one or more prior chemotherapeutic treatments prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

14. The method of any one of claims 1 to 12, wherein the subject has received up to one prior chemotherapeutic treatments prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

15. The method of claim 1, wherein the subject is CYP17 inhibitor-naive prior to the administration to the subject of the darolutamide and the Compound 1, or a pharmaceutically acceptable salt thereof.

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