Vepdegestrant dosage regimen in CYP3a-inducer treatment in cancer

Abstract

The invention relates to a method for treating cancer comprising administering to a subject Compound A having a structure of: or a pharmaceutically acceptable salt thereof, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer, and particularly, a CYP3A4 inducer.

Description

[0001]Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 ADMINISTRATION OF CYP3A INDUCERS IN THE TREATMENT OF CANCER RELATED APPLICATIONS This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 532,161, filed August 11, 2023, and U.S. Provisional Application No.63 / 679,463, filed August 5, 2024, the contents of which are incorporated herein by reference in their entireties for all purposes. BACKGROUND OF THE INVENTION Certain bifunctional compounds can target specific cellular proteins for degradation via the ubiquitin-proteasome system. Examples of such proteolysis targeting chimeric compounds (i.e., “PROTAC®protein degraders”) that target the estrogen receptor (ER) for ubiquitination and subsequent degradation are disclosed in U.S. Pat. No. 10,647,698, which is incorporated herein by reference in its entirety. Such bifunctional molecules exhibit a range of pharmacological activities consistent with the degradation of the ER including, but not limited to, treatment or amelioration of a disease condition such as cancer (e.g., breast cancer, uterine cancer, ovarian cancer, prostate cancer, or endometrial cancer), or endometriosis. A bifunctional molecule of particular interest is (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione or (3S)-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1R,2S)- 1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthalenylphenyl]-4-piperidinyl]methyl]-1- piperazinyl]-2H-isoindol-2-yl]-2,6-piperidinedione (referred to herein as “Compound A”), which has the molecular formula of C45H49N5O4and the following structure: . Compound A is under development as a PROTAC®protein degrader that targets estrogen receptor (ER) for the potential treatment of breast cancer and has been shown to be a useful 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway. CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43. The CYP3A4 enzyme is particularly susceptible to enzyme inducers, and marked reductions in the plasma concentrations of CYP3A4 substrates may occur. CYP3A4 inducers are drugs that increase the activity of CYP3A4. Carbamazepine is a specific strong inducer of CYP3A4. Along with its safety profile, carbamazepine has often been utilized as a perpetrator drug for CYP3A4 induction drug interaction studies. (Andreasen AH, Brøsen K, Damkier P. A comparative pharmacokinetic study in healthy volunteers of the effect of carbamazepine and oxcarbazepine on cyp3a4. Epilepsia.2007 Mar;48(3):490-6; Bertilsson L, Tybring G, Widén J, et al. Carbamazepine treatment induces the CYP3A4 catalysed sulphoxidation of omeprazole but has no or less effect on hydroxylation via CYP2C19. Br J Clin Pharmacol.1997 Aug;44(2):186-9.) The simultaneous or nearly simultaneous (e.g., concomitant) presence of two drugs in a subject may alter the effects of one or the other, or both, drugs. Such alterations are termed drug- drug interactions. Concomitant administration of different drugs often leads to adverse effects since the metabolism and / or excretion of each drug may reduce or interfere with the metabolism and / or excretion of the other drug(s), thus increasing the effective concentrations of those drugs as compared to effective concentrations of those drugs when administered alone. Accordingly, methods of treatment that minimize drug-drug interactions in the treatment of cancer are needed. SUMMARY OF THE INVENTION The present disclosure provides, in part, methods for administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject, for treating cancer. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter. Provided herein is a method of treating cancer in a subject who has been administered a CYP3A inducer, the method comprising: a) discontinuing the administration of the CYP3A inducer to the subject; and b) administering an effective amount of Compound A: 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 or a pharmaceutically acceptable salt thereof, to the subject. Provided herein is a method of treating cancer in a subject who has been administered a CYP3A4 inducer, the method comprising: a) discontinuing the administration of the CYP3A4 inducer to the subject; and b) administering an effective amount of Compound A: or a pharmaceutically acceptable salt thereof, to the subject. In embodiments, the method of treating cancer in a subject who has been administered a CYP3A inducer or a CYP3A4 inducer, respectively, is further comprising step a’): a') waiting a first time period after step a) before performing step b). In embodiments of the method of treating cancer in a subject who has been administered a CYP3A inducer or a CYP3A4 inducer, respectively, the first time period after step a) is about 14 days plus 5 half-lives of the CYP3A inducer or the CYP3A4 inducer. In embodiments of the method of treating cancer in a subject who has been administered a CYP3A inducer or a CYP3A4 inducer, respectively, the first time period after step a) is about 3 to 5 half-lives of the CYP3A inducer or the CYP3A4 inducer. In embodiments of the method of treating cancer in a subject who has been administered a CYP3A inducer or a CYP3A4 inducer, respectively, the CYP3A inducer or CYP3A4 inducer is apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor, ivacaftor, mitotane, phenytoin, rifampin, or St. John’s wort, and is preferably, carbamazepine. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inducer or a CYP3A4 inducer, respectively, the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day orally to the subject. In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inducer or a CYP3A4 inducer, respectively, the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg. In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inducer or a CYP3A4 inducer, respectively, the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg. In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inducer or a CYP3A4 inducer, respectively, the subject is in a fed state. In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inducer or a CYP3A4 inducer, respectively, the cancer may be breast cancer; and the breast cancer may be metastatic or locally advanced; the breast cancer may be estrogen positive (ER+) breast cancer; and the estrogen receptor positive (ER+) breast cancer may be human epidermal growth factor receptor 2 negative (HER2-). In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inducer or a CYP3A4 inducer, respectively, the subject is human. Provided herein are methods for treating cancer comprising administering to a subject Compound A having a structure of: , or a pharmaceutically acceptable salt thereof, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 Provided herein are methods for treating cancer comprising administering to a subject Compound A having a structure of: , or a pharmaceutically acceptable salt thereof, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A4 inducer. Additionally provided herein are methods for treating cancer comprising administering to a subject Compound A having a structure of: , or a pharmaceutically acceptable salt thereof, wherein a physician is provided with instructions including a warning that the treatment is not to be administered with concomitant administration of a CYP3A inducer. Additionally provided herein are methods for treating cancer comprising administering to a subject Compound A having a structure of: 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 , or a pharmaceutically acceptable salt thereof, wherein a physician is provided with instructions including a warning that the treatment is not to be administered with concomitant administration of a CYP3A4 inducer. In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer or a CYP3A4 inducer, respectively, the CYP3A inducer or CYP3A4 inducer is apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor, ivacaftor, mitotane, phenytoin, rifampin, or St. John’s wort, and is preferably, carbamazepine. In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer or a CYP3A4 inducer, respectively, the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day (QD) orally to the subject. In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer or a CYP3A4 inducer, respectively, an effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg. In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer or a CYP3A4 inducer, respectively, an effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg. In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be 6 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 administered with concomitant administration of a CYP3A inducer or a CYP3A4 inducer, respectively, the subject is in a fed state. In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer or a CYP3A4 inducer, respectively, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer. In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer or a CYP3A4 inducer, respectively, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer. In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer or a CYP3A4 inducer, respectively, the cancer is breast cancer, lung cancer, or prostate cancer. In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer or a CYP3A4 inducer, respectively, the cancer is breast cancer; and the breast cancer may be metastatic or locally advanced; the breast cancer may be estrogen receptor positive (ER+) breast cancer; and the estrogen receptor positive (ER+) breast cancer may be human epidermal growth factor receptor 2 negative (HER2-). In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inducer or a CYP3A4 inducer, respectively, the subject is human. Provided herein is a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or label that includes a 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 warning that concomitant administration of the Compound A, or the pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inducer. Provided herein is a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or label that includes: a) avoiding concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inducer; b) discontinuing concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inducer; or c) contraindicating concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inducer. Provided herein is a kit comprising: (a) a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form; and (b) an instruction or label that includes a warning that concomitant administration of the Compound A, or the pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inducer. In any of the previous embodiments of the pharmaceutical product or the kit, the oral dosage form of the Compound A, or the pharmaceutically acceptable salt thereof, is a tablet or capsule; and is preferably a tablet. In any of the previous embodiments of the pharmaceutical product or the kit, the strong CYP3A inducer is apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor, ivacaftor, mitotane, phenytoin, rifampin, or St. John’s wort; and is preferably carbamazepine. In any of the previous embodiments of the pharmaceutical product or the kit, the strong CYP3A inducer is a strong CYP3A4 inducer. In any of the previous embodiments of the pharmaceutical product or the kit, the amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg. In any of the previous embodiments of the pharmaceutical product or the kit, the amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated into and form a part of the specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the disclosure. The drawings are only for the purpose of illustrating an embodiment of the disclosure and are not to be construed as limiting the disclosure. Further objects, features and advantages of the disclosure will become apparent from the following detailed description taken in conjunction with the accompanying figures showing illustrative embodiments of the disclosure, in which: FIG. 1 presents the study schema for the 2-period study to estimate the effect of multiple doses of the strong CYP3A4 inducer, carbamazepine, on the pharmacokinetics (PK) of Compound A 200 mg under the fed condition in healthy male participants, and healthy female participants of nonchildbearing potential. FIGs. 2A-B depict median plasma Compound A concentration-time profiles with and without carbamazepine. FIG.2A is linear scale and FIG.2B is semi-log scale. LLOQ (lower limit of quantification) = 2.50 ng / mL. FIG. 3A depicts individual and geometric mean plasma Compound A Cmaxwith and without carbamazepine. FIG. 3B depicts individual and geometric mean plasma Compound A AUCinf with and without carbamazepine. Circles represent individual values and stars represent geometric mean value for each treatment group. Box plot provides median and 25% / 75% quartiles with whiskers to the last point within 1.5 times interquartile range. FIGs. 4A-B depict median plasma Compound B concentration-time profiles with and without carbamazepine. FIG. 4A is linear scale and FIG. 4B is semi-log scale. LLOQ = 2.50 ng / mL. FIG. 5A depicts individual and geometric mean plasma Compound B AUClast with and without carbamazepine. FIG.5B depicts individual and geometric mean plasma Compound B Cmax with and without carbamazepine. Circles represent individual values and stars represent geometric mean value for each treatment group. Box plot provides median and 25% / 75% quartiles with whiskers to the last point within 1.5 times interquartile range. DETAILED DESCRIPTION OF THE INVENTION The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. Definitions Unless otherwise defined herein, scientific, and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art. The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. As used herein, the singular form “a,” “an,” and “the” include plural references unless indicated otherwise. For example, “a” substituent includes one or more substituents. As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of Compound A, a pharmaceutically acceptable salt thereof, or of a CYP3A inducer) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg. As used herein, terms, including, but not limited to, “agent”, “composition”, “compound”, “drug”, and “therapeutic agent” may be used interchangeably to refer to compounds included in the methods, uses, pharmaceutical products, and kits of the present invention, specifically Compound A and pharmaceutically acceptable salts thereof. Compound A, having the structure: and pharmaceutically acceptable salts thereof are disclosed in, e.g., International Publication No. WO 2018 / 102725 and U.S. Patent Nos. 10,647,698, 10,899,742 and 11,104,666; International Publication No. WO 2021 / 041348; U.S. Serial No. 17 / 472,847; U.S. Serial No. 17 / 548,842; and U.S. Serial No. 17 / 873,748. The contents of each of the foregoing references are incorporated herein by reference in their entireties for all purposes. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 Compound A is a Biopharmaceutics Classification System Class IV compound (low solubility / low permeability). Compound A may interconvert to its epimer, Compound B: . Without wishing to be bound by theory, preclinical data demonstrates that the exposure of Compound B is limited compared to Compound A (<26%). Evidence indicates that Compound B does not degrade the ER; however, Compound B shows similar antagonism of ER-dependent transcription compared to Compound A. Additional embodiments relate to the pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds described herein include the acid addition and base addition salts thereof. Another embodiment also relates to the pharmaceutically acceptable acid addition salts of the compounds described herein. Suitable acid addition salts are formed from acids which form non-toxic salts. Non-limiting examples of suitable acid addition salts, i.e., salts containing pharmacologically acceptable anions, include, but are not limited to, the acetate, acid citrate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, bitartrate, borate, camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methanesulfonate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, tosylate, trifluoroacetate and xinofoate salts. Additional embodiments relate to base addition salts of the compounds described herein. Suitable base addition salts are formed from bases which form non-toxic salts. Non-limiting examples of suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 The compounds described herein that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are those that form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1’-methylene-bis-(2-hydroxy-3- naphthoate)] salts. The compounds described herein that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the compounds described herein that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine- (meglumine), and the lower alkanolammonium, and other base salts of pharmaceutically acceptable organic amines. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds described herein are known to one of skill in the art. Administration and Dosing The terms “treat” and “treating” a cancer or a cancer-associated disease, as used herein, mean to administer an agent, composition, compound, drug, or therapeutic agent according to the present disclosure to a subject, participant or patient having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The terms “treatment” and “therapy,” as used herein, unless otherwise indicated, refer to the act of treating as “treating” is defined immediately above. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and / or prolonging survival of patients the cancer. Positive therapeutic effects in cancer may be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. (2009) 50:1S–10S). “Concomitant” as used to describe the administration of two drugs, means that the timing of the administration of the two drugs is simultaneous or nearly simultaneous. In other words, the two drugs are administered either at the same time or almost at the same time. In concomitant administration, the two drugs are present, e.g., being metabolized and / or excreted, in a subject at the same time. A “half-life” or a “terminal elimination half-life” of a drug is the time it takes for the amount of a drug’s active pharmaceutical ingredient in a subject to reduce by half. In other words, a drug's half-life is an estimation of the time it takes for the drug's initial concentration in the body of a subject to decrease by half. “Fed condition” or “fed state” as used to describe a subject herein, means that the subject has eaten less than 4 hours before a time point of interest, such as the time of administering Compound A. In embodiments, a subject in the fed state has not eaten for at most any of 4, 3, 2, 1, or 0.5 hours prior to administration of Compound A. As used herein, the terms, “subject”, “participant” and “patient,” are used interchangeably, to refer to a human. Human subjects may be of any gender. In an embodiment, a human is an adult human. An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, or in combination with one or more other agents, a detectable response of any duration of time (transient, medium, or long term), a desired outcome in or an objective or 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured). Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects / symptoms, consequences, or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not worsening) state of the disease, is considered a satisfactory outcome. The term “effective amount” also means an amount of an agent alone or in combination with one or more other agents, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor. In reference to the treatment of cancer, an effective amount refers to that amount that has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and / or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer. Therapeutic or pharmacological effectiveness of the doses and administration regimens also may be characterized as the ability to induce, enhance, maintain, or prolong disease control and / or overall survival in patients with these specific tumors, which may be measured as prolongation of the time before disease progression. As used herein, “ameliorate” refers to any reduction in the extent, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular disease. “Symptom” refers to any subjective evidence of disease or of a subject’s condition. Compound A is preferably dosed in the form of a free base. The daily dose or daily dosage of Compound A, or a pharmaceutically acceptable salt thereof, is the free base equivalent of Compound A. Dosage amounts provided herein refer to the dose of the free base form of Compound A, or are calculated as the free base equivalent of an administered Compound A salt form. For example, a dosage or amount of Compound A, such as about 100 mg or about 200 mg refers to the free base equivalent. Embodiments of the present invention provide a dose, dosage, and dosing regimen comprising administering to a subject an amount, or an effective amount of Compound A, or a pharmaceutically acceptable salt thereof. The amount, or the effective amount, may be a daily dose of about 100 mg or about 200 mg. In embodiments, a daily dose is about 200 mg. In embodiments, a daily dose is about 100 mg. In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once per day (QD). 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 The compounds disclosed herein may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth. In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered orally. Compound A, or a pharmaceutically acceptable salt thereof, may be present in a pharmaceutical composition, which includes a pharmaceutically acceptable excipient. A “pharmaceutically acceptable excipient” refers to a component that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and causes no significant adverse effects nor therapeutic effects to a subject. The term “excipient” is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The compounds of the methods or uses of the present invention may be formulated prior to administration. The formulation preferably will be adapted to the particular mode of administration. These compounds may be formulated with pharmaceutically acceptable excipients as known in the art and administered in a wide variety of dosage forms as known in the art. Dosage unit forms or pharmaceutical compositions suitable for oral administration include, but are not limited to tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous, and nonaqueous oral solutions and suspensions, packaged in containers adapted for subdivision into individual doses. Repetition of the administration or dosing regimens may be conducted as necessary to achieve the desired reduction or diminution of cancer cells. A “continuous dosing schedule,” as used herein, is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 28-day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule. In embodiments, the compounds of the present invention may be administered in a continuous dosing schedule. In embodiments, the compounds disclosed herein may be administered concurrently in a continuous dosing schedule. In embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily to comprise a complete cycle of 28-days. Repetition of 28-day treatment cycles is continued during treatment in accordance with the methods and uses of the present disclosure. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 Method of Treatment In one embodiment, the disclosure provides a method of administering Compound A, or a pharmaceutically acceptable salt thereof, in the treatment of cancer. The references to the methods of treatment of this description are to be interpreted as being also references to the compound(s), pharmaceutical compositions, and medicaments of the present invention for use in those methods. The term “locally advanced,” as used herein, as it relates to cancer, may or may not be treated with curative intent. For example, locally advanced breast cancer (LABC) is defined by the U.S. National Comprehensive Cancer Network as a subset of breast cancer characterized by the most advanced breast tumors in the absence of distant metastasis, wherein the tumors are more than 5 cm in size with regional lymphadenopathy; tumors of any size with direct extension to the chest wall or skin, or both (including ulcer or satellite nodules), regardless of regional lymphadenopathy; presence of regional lymphadenopathy (clinically fixed or matted axillary lymph nodes, or any of infraclavicular, supraclavicular, or internal mammary lymphadenopathy) regardless of tumor stage. (Garg et al. Curr Oncol. 2015 Oct; 22(5): e409–10; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Fort Washington, PA: NCCN; 2015. Ver.2.2015.) The term “metastatic breast cancer” refers to cancer that has spread from the breast to other parts of the body, such as the bones, liver, lungs, or brain. Metastatic breast cancer may also be referred to as stage IV breast cancer. Provided herein are methods of treating cancer as described in the Summary of the Invention section of this application. In some embodiments, discontinuing administration of a CYP3A inducer is to avoid an adverse drug interaction with Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, discontinuing administration of a CYP3A4 inducer is to avoid an adverse drug interaction with Compound A, or a pharmaceutically acceptable salt thereof. In embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer. In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer. In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the breast cancer is metastatic or locally advanced. In 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer. In embodiments, the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-). In embodiments, the subject is human. Pharmaceutical Products and Kits In embodiments, the invention provides pharmaceutical products comprising Compound A, or a pharmaceutically acceptable salt thereof, formulated for oral administration, wherein the that includes a warning that concomitant administration of the Compound A, or the pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inducer, Another aspect of the invention provides kits comprising a pharmaceutical product comprising Compound A, or a pharmaceutically acceptable salt thereof, formulated for oral administration. The kit may include an instruction or a label that includes a warning that concomitant administration of Compound A, or a pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inducer, such as a CYP3A4 inducer. The kit may include instructions for use in a diagnostic or therapeutic method. In another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains an 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 oral dosage form comprising Compound A, or a pharmaceutically acceptable salt thereof, in quantities sufficient to carry out the methods of the invention. Abbreviations AE is adverse event; AUCextrap% is the percent of AUCinf obtained by forward extrapolation; BID is twice a day; BMI is Body mass index; CBZ is carbamazepine or Carbamazepine; CI is confidence interval; Cmax maximum observed plasma concentration CV% is coefficient of variation; CYP is cytochrome P450; ECG is electrocardiogram; ER is estrogen receptor; ICD is informed consent document; MRCmaxis metabolite ratio PK is pharmacokinetic(s); QD is once per day or once daily; SAE is serious adverse event; SD is standard deviation; SOC is system organ class; SOP is standard operating procedure; t½ is terminal elimination half-life; TEAE is treatment emergent adverse events; TID is three times a day; ULN is upper limit of normal; and Vz / F is apparent volume of distribution after oral dose. EXAMPLES In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 A Clinical Study to Estimate the Effect of Multiple Doses of Carbamazepine on the Pharmacokinetics (PK) of Single Dose Compound A in Healthy Adult Participants Overview: Compound A was investigated in an interventional, Phase 1, open-label, fixed sequence, 2-period study to estimate the effect of multiple doses of carbamazepine on the PK of a single dose of 200 mg of Compound A under the fed condition in healthy adult males and females of nonchildbearing potential. Background: Nonclinical Pharmacokinetics and Metabolism The PK profile of Compound A in the nonclinical species (mouse, rat, dog, and monkey) was characterized by a low to moderate clearance (13.8% to 33.8% of hepatic blood flow), extensive tissue distribution (2.1 to 6.0 L / kg), short to moderate t½(2.1 to 8.2 hours), and moderate to good oral bioavailability (27% to 65%). A dose-dependent increase in Compound A exposure was observed when Compound A was administered as an oral solution in the mouse (10, 30, 100 mg / kg), rat (30, 100, 300 mg / kg), dog (15, 45, 90, 200, and 400 mg / kg), and monkey (1 and 3 mg / kg). A 3-fold increase in AUC and reduced inter-animal variability were observed in fed dogs; as such, the data indicated that the tablets should be administered with food in clinical trials. A CYP reaction phenotyping study was conducted using 2 orthogonal methods in human liver microsomes and recombinant CYP isoforms. This study indicated CYP3A4 as the principal isoform responsible for CYP metabolism of Compound A (accounting for 85%). Rationale: A CYP reaction phenotyping study indicated CYP3A4 as the principal isoform responsible for CYP metabolism of Compound A. Carbamazepine is a strong inducer of CYP3A4. Since Compound A is a substrate for CYP3A4, concomitant administration of multiple doses of carbamazepine along with Compound A may lead to decreased systemic exposure (i.e., reduce the exposure) of Compound A. The objective of this study is to estimate the effect of multiple doses of carbamazepine on the PK of Compound A. Carbamazepine is a specific strong inducer of CYP3A4. Along with its safety profile, carbamazepine has often been utilized as a perpetrator drug for CYP3A4 induction drug 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 interaction studies. Since Compound A is a substrate for CYP3A4, concomitant administration of multiple doses of carbamazepine along with Compound A may lead to decreased systemic exposure of Compound A. Using the in vitro-derived point estimate of Compound A fm,CYP3A4 (fraction of metabolized through CYP3A4) of 0.36, carbamazepine is predicted to decrease Compound A exposure by 54% (AUCR = 0.46). A sensitivity analysis of Compound A fm,CYP3A4 resulted in predicted decrease in Compound A exposure ranging from 37% (fm,CYP3A4 = 0.18, AUCR = 0.63) to 70% (fm,CYP3A4 = 0.72, AUCR = 0.30). The objective of this study was to evaluate the effect of a strong CYP3A4 inducer, carbamazepine at steady-state on a single dose of Compound A 200 mg. Purpose: This was a drug-drug interaction study to assess the effects of a single dose of Compound A after multiple dose administrations of carbamazepine. PK was evaluated for Compound A. Carbamazepine was utilized as a cytochrome P4503A4 (CYP3A4) inducer. Overall Study Design: This was a Phase 1, open-label, fixed-sequence, 2-period study to estimate the effect of multiple doses of the strong CYP3A4 inducer, carbamazepine, on the PK of Compound A 200 mg, in healthy male and female participants of nonchildbearing potential under the fed condition. The study consisted of 2 periods: Period 1 = single dose of Compound A 200 mg alone and Period 2 = carbamazepine dosing titrated from 200 mg QD (once a day) (Day 1 – Day 3) to 200 mg BID (Day 4 - Day 7) to the final dose of 200 mg TID (Day 8 – Day 19) for 19 days + single dose of Compound A 200 mg on Day 14. Following administration of Compound A in each period, participants underwent serial PK sampling up to144 hours post dose. The two single doses of Compound A were at least 20 days apart. Estimated Enrollment: A total of approximately 12 participants were planned to be enrolled in the study. Participants who withdrew could be replaced at the discretion of the sponsor. The study schema is presented in FIG.1. Study Arms and Duration: 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 The study consisted of 2 periods: Period 1 (7 days) = single dose of Compound A 200 mg administered on Day 1, and Period 2 (20 days) = carbamazepine dosing titrated from 200 mg QD (Day 1 to Day 3) to 200 mg BID (Day 4 to Day 7) to the final dose of 200 mg TID (Day 8 to Day 19) + single dose of Compound A 200 mg on Day 14. Following administration of Compound A in each period, participants underwent serial PK sampling for 144 hrs post-dose. Period 1 Day 1: Following an overnight fast of at least 10 hours and after the collection of the pre-dose Compound A PK sample, participants started the standard breakfast (approximately 700 calories with a fat content of approximately 35%) approximately 30 minutes prior to administration of Compound A 200 mg as two 100 mg tablets. Participants received study medication at approximately 0800 hours (plus or minus 2 hours). Investigator site personnel administered Compound A with ambient temperature water to a total volume of approximately 240 mL. Participants swallowed the study intervention whole without manipulated or chewed the study intervention prior to swallowing. No additional food was allowed for at least 4 hours post dose. Period 2 Days 1 – 19 (inclusive): Participants received carbamazepine at approximately 0800 hours (plus or minus 2 hours). Carbamazepine can be administered with or without food on all study days except on Study Day 14 when dosing with Compound A as described below. There was no water restriction for carbamazepine dosing except on Day 14 (with co-administration of Compound A; No additional water beside what was provided with the breakfast and study drug(s) allowed 1 hour before and after Compound A administration). Carbamazepine 200 mg QD was administered orally on Days 1, 2, and 3, and titrated up to 200 mg BID on Days 4, 5, 6 and 7. Carbamazepine was titrated up to and maintained at 200 mg TID stably in the rest of the Period 2 from Days 8 to 19. On Period 2 Day 1-19 except on Day 14, carbamazepine was administered with up to 100 ml of water. On Period 2 Day 14, following an overnight fast of at least 10 hours and after the collection of the pre-dose Compound A PK sample, participants started the standard breakfast (approximately 700 calories with a fat content of approximately 35%) consumed prior to the administration of carbamazepine 200 mg followed by Compound A 200 mg as two 100 mg tablets, at approximately 0800 hours (plus or minus 2 hours). The study drugs were administered within 5 minutes with approximately 240 mL of ambient temperature water. Participants swallowed the carbamazepine and Compound A tablets whole without manipulating or chewing the medications prior to swallowing. No additional food was allowed for at least 4 hours post dose of both drugs. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 Objectives and Endpoints: The objectives and endpoints of the clinical study are shown below in Table 1 and associated definitions of PK parameters are shown in Table 2. Table 1. Calculation of Pharmacokinetic Parameters: The following Compound A and Compound B PK parameters in Table 2 were calculated for each participant and treatment, as appropriate, and as data permitted, using non-compartmental 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 analysis of plasma concentration-time data. Samples below the lower limit of quantitation (LLOQ) were set to 0 for the PK analysis. Actual sample collection times were used for the PK analysis. Table 2. PK parameters were calculated using a Pfizer validated open non-compartmental analysis system (oNCA version 2.7.8)aIf data permittedbOnly reported for Compound A The following supporting data from the estimation of t1 / 2were also reported: the terminal phase rate constant (kel); the first, last, and number of time points used for the log-linear regression (kel,t(lo), kel,t(hi), and kel,t(n)); the goodness-of-fit statistic from the regression (r2); and the percent of 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 the area under the plasma concentration-time curve from time zero to infinite time, AUCinf, obtained by forward extrapolation (AUCextrap%). Unless otherwise noted, parameters marked “if data permitted” were reported only where a well-characterized terminal phase was observed. A well-characterized terminal phase is defined as one with at least 3 data points, r2^0.9, and AUCextrap%^20. Eligibility Ages Eligible for Study: 18 Years and older Sexes Eligible for Study: All Gender Based: No Gender Eligibility Criteria: Accepts Healthy Volunteers: Yes Study Population: Key inclusion and exclusion criteria are listed below: Inclusion Criteria: Participants must meet the following inclusion criteria to be eligible for enrollment into the study: 1. Male participants, and female participants of non-childbearing potential aged 18 years or older (or the minimum age of consent in accordance with local regulations) at screening who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. 2. BMI of 16-32 kg / m2; and a total body weight >45 kg (99.2 lb). 3. Capable of giving signed informed consent, which includes compliance with requirements and restrictions listed in the ICD and in this protocol. 4. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations and other study procedures. Exclusion Criteria: Participants with any of the following key characteristics / conditions will be excluded: 1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). • Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). • History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, HBcAb, or HCVAb. Hepatitis B vaccination is allowed. 2. Participants shown to carry or be positive for HLA-B*1502 and / or HLA-A*3101 (genotyping alleles / markers related with carbamazepine-associated SJS or TEN). 3. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation / behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study. 4. Use of prescription or non-prescription medications, including vitamins, herbal and dietary supplements, grapefruit / grapefruit containing products, and Seville orange / Seville orange containing products within 7 days prior to the first dose of study intervention with the exception of: • Moderate / strong CYP3A4 inducers which are prohibited within 14 days plus 5 half- lives prior to the first dose of study intervention. • Moderate / strong CYP3A4 inhibitors which are prohibited within 14 days plus 5 half- lives prior to the first dose of study intervention. 5. Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). 6. A positive urine drug test. A single repeat for positive drug screen may be allowed. 7. Screening supine BP ^140 mm Hg (systolic) or ^90 mm Hg (diastolic) for participants <60 years; and ^150 / 90 mm Hg for participants ^60 years old, following at least 5 minutes of supine rest. If systolic BP is ^140 or 150 mm Hg (based on age) or diastolic ^90 mm Hg, the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant’s eligibility. 8. Baseline standard 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results. 9. Participants with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat test, if deemed necessary: 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 • AST, ALT, or Total Bilirubin Level >1.05× ULN; 10. Renal impairment as defined by an eGFR <60 mL / min / 1.73m². Based upon participant age at screening, eGFR is calculated using the recommended CKD-EPI equations to determine eligibility and to provide a baseline to quantify any subsequent kidney safety events. 11. History of alcohol abuse or binge drinking and / or any other illicit drug use or dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine). 12. History of use of tobacco or nicotine-containing products in excess of the equivalent of 5 cigarettes / day or 2 chews of tobacco / day. 13. History of sensitivity to Compound A and carbamazepine or any of the formulation components of Compound A and carbamazepine (Tegretol®). 14. Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members. Primary Outcome Measures: x Maximum Observed Plasma Concentration (Cmax) of Compound A when administered alone [ Time Frame: Period 1 - Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 144 hour post-dose ] x Cmaxof Compound A when administered with carbamazepine [ Time Frame: Period 1 - Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 144 hour post-dose ] x Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Compound A when administered alone [ Time Frame: Period 1 -Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 144 hour post-dose ] x AUCinf of Compound A when administered with carbamazepine [ Time Frame: Period 1 - Day 1 pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 144 hour post-dose ] Secondary Outcome Measures: x Number of Participants with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Time the participant provides informed consent 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 through and including follow-up contact occurring 28 to 35 calendar days after the last administration of the study intervention. ] x Number of Participants with Clinical Laboratory Abnormalities [ Time Frame: Baseline up to Period 2 Day 20 ] x Number of Participants with ECG Abnormalities [ Time Frame: Baseline up to Period 2 Day 20 ] Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Baseline up to Period 2 Day 20 ] Number of Participants With Abnormalities in Physical Examinations [ Time Frame: Baseline up to Period 2 Day 20 ] Clinical Study Results: Study Participants 1. Disposition of Participants A total of 12 participants were screened and enrolled into the study. All enrolled participants were treated, 9 (75%) participants completed the study, 3 (25%) participants discontinued during the follow-up phase: x 2 (16.7%) participants discontinued due to AEs. x 1 (8.3%) participant discontinued due to withdrawal by participant. 2. Demographic and Other Baseline Characteristics The mean (standard deviation, SD) age of all participants was 42.0 (12.29) years. All participants were male, 9(75.0%) were White by race, and 10 (83.3%) were Non-Hispanic or Latino by ethnicity. The mean (SD) height of all participants was 176.3 (8.03) cm and the mean (SD) weight was 76.4 (7.84) kg of all participants. The reported mean BMI (SD) was 24.6 (2.06) kg / m2 among all participants (Table 3). Table 3. Demographic and Baseline Characteristics - Safety Analysis Set 27 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 Age is collected at screening. 3. Exposure In Period 1, the participants received Compound A as two 100 mg tablets on Day 1 with a washout period of at least 20 days. In Period 2, the participants received carbamazepine 200 mg QD orally on Days 1, 2, and 3, and titrated up to 200 mg BID on Days 4, 5, 6 and 7, and titrated up to and maintained at 200 mg TID stably in the rest of the Period 2 from Days 8 to 19. On Day 14, the carbamazepine 200 mg morning dose was administered orally first, immediately followed by Compound A 200 mg as two 100 mg tablets. Clinical Study Results: Evaluation Of Response To Study Intervention 1. Safety Adverse Events AEs described below were all TEAEs if not specifically identified. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 Brief Summary of Adverse Events Following the administration of Compound A alone (from Period 1, Day 1 up to just before the first dose of carbamazepine administered alone in Period 2, Day 1): x No severe AEs, SAEs, discontinuation, or dose reduction due to AEs were reported. x 9 AEs were reported in 6 (50%) participants, 2 AEs of which in 2 (16.7%) participants were assessed as treatment-related. Following the administration of carbamazepine alone (from first dose of carbamazepine administered alone in Period 2, Day 1 up to just before coadministration of Compound A with carbamazepine): x No severe AEs, SAEs, discontinuation, or dose reduction due to AEs were reported. x 55 AEs were reported in all 12 (100%) participants, none of the AEs were assessed as treatment-related. Following the administration of carbamazepine with Compound A (from coadministration of carbamazepine with Compound A in Period 2 Day 14 through the end of the study): x 2 (16.7%) participants reported severe SAEs, which were assessed as not related to Compound A. x 2 (16.7%) participants discontinued from study due to AEs, both were assessed not related to Compound A. x 20 AEs were reported in 9 (75%) participants, none of the AEs were assessed as treatment- related. 2. Pharmacokinetics Compound A Pharmacokinetics Median plasma Compound A concentration-time profiles with and without carbamazepine are presented in FIG.s 2A-B (linear and semi-log plots). Plasma PK parameters are defined in Table 2 and summarized in Table 4. Statistical comparisons of plasma exposures after a single dose of Compound A with and without multiple doses of carbamazepine are summarized in Table 5. Box plots of individual and geometric mean AUCinf and Cmax are presented by treatment in FIG.s 3A-B. The median Compound A concentration-time profile was lower when a single oral dose of Compound A was co-administered with multiple oral doses of carbamazepine than that observed when Compound A was administered alone. Median Tmax was 6.00 hours when Compound A was 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 administered alone and when administered with carbamazepine. Following attainment of Cmax, the mean t1 / 2was 50.07 hours when Compound A was administered alone and 45.39 hours when Compound A was co-administered with carbamazepine. The apparent oral clearance of Compound A was 8.043 L / hr when Compound A was administered alone and 12.39 L / hr when Compound A was co-administered with carbamazepine. Co-administration of carbamazepine (200 mg three times a day, TID, Tegretol) with a single 200 mg dose of Compound A decreased plasma Compound A AUCinf by 36% and Cmax by 20%. The test / reference ratios of the adjusted geometric means (90% CI) for Compound A AUCinf, AUClast, and Cmax were 64.05% (60.02%, 68.35%), 66.81% (62.75%, 71.14%), and 80.15% (74.00%, 86.81%), respectively, following Compound A administration with carbamazepine (Test) as compared to administration alone (Reference). Similar inter-participant variability for AUC and Cmaxwas observed when Compound A was administered alone compared to when Compound A was co-administered with carbamazepine. Geometric CV% of AUCinf, AUClast, and Cmaxwas 16%, 17%, and 22% when Compound A was administered alone and geometric CV% of AUCinf, AUClast, and Cmaxwas 21%, 20%, and 27%, respectively, following co-administration with carbamazepine. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 Compound B Pharmacokinetics Median plasma Compound B concentration-time profiles following Compound A administration alone and when Compound A was co-administered with carbamazepine are presented in FIGs 4A-B (linear and semi-log plots). Plasma PK parameters are defined in Table 2 and summarized in Table 6. Statistical comparisons of Compound B plasma exposures after a single dose of Compound A with and without multiple doses of carbamazepine are summarized in Table 7. Box plots of individual and geometric mean AUClast, and Cmaxare presented by treatment in FIGs 5A-B. The median Compound B concentration-time profile was lower when a single dose of Compound A was co-administered with multiple doses of carbamazepine than that observed when Compound A was administered alone. Median Tmax of Compound B was 24.0 hours when Compound A was administered alone and 12.0 hours when Compound A was co-administered with carbamazepine. The mean t / 2 of Compound B was 48.92 hours when Compound A was administered alone and 43.75 hours when Compound A was co-administered with carbamazepine. The AUCinf and t / 2 of Compound B could only be reported for 6 of 12 participants in Period 1 (Compound A alone) and 10 of the 12 participants in Period 2 (Compound A with carbamazepine) based on prespecified criteria (AUCextrap% ^20). The PK sampling duration was not sufficient for estimating AUCinfand t / 2 of Compound B. Therefore, AUCinfwas not used as the primary AUC metric for Compound B. AUClast(N=10) was selected as the primary AUC metric for Compound B. Compound B to Compound A AUClastratios were 0.2961 and 0.2692, and Cmaxratios were 0.1106 and 0.1034 following a dose of Compound A alone or with carbamazepine, respectively. Co-administration of carbamazepine (200 mg TID, Tegretol) with a single 200 mg dose of Compound A decreased plasma Compound B AUClastand Cmaxto a slightly larger extent than its epimer. The Compound B test / reference ratios of the adjusted geometric means (90% CI) for 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 AUClast, and Cmaxwere 60.43 (56.79%, 64.31%), and 74.90% (71.28%, 78.71%), respectively, following Compound A administration with carbamazepine (Test) as compared to administration alone (Reference). Similar inter-participant variability for AUC and Cmax of Compound B was observed when Compound A was administered alone compared to when Compound A was co-administered with carbamazepine. Geometric CV% of AUClast, and Cmax was 18%, and 18% when Compound A was administered alone and geometric CV% of AUClast, and Cmax was 22%, and 21%, respectively, following co-administration with carbamazepine. 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 Table 7. Statistical Summary of Natural Log Transformed Plasma Compound B PK Parameters (AUCinf, AUClastand Cmax) - PK Parameter Analysis Set 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 CONCLUSIONS Pharmacokinetics x Co-administration of carbamazepine (200 mg TID, Tegretol), a strong CYP3A4 inducer, with a single 200 mg dose of Compound A decreased plasma Compound A AUCinf by 36% and Cmax by 20% in healthy adult volunteers. The test / reference ratios of the adjusted geometric means (90% CI) for Compound A AUCinf and Cmax were 64.05% (60.02%, 68.35%) and 80.15% (74.00%, 86.81%), respectively, following Compound A administration with carbamazepine (Test) as compared to administration alone (Reference). Safety x Compound A was safe and well-tolerated in healthy adult participants. No new safety signals were identified. SAEs or AEs leading to discontinuations were not assessed to be related to Compound A. EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. The methods of the disclosure have been described herein by reference to certain preferred embodiments. However, as particular variations thereon will become apparent to those skilled in the art, based on the disclosure set forth herein, the disclosure is not to be considered as limited thereto. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification and claims, the singular forms also include the plural unless the context clearly dictates otherwise. It is to be understood that at least some of the descriptions of the disclosure have been simplified to focus on elements that are relevant for a clear understanding of the disclosure, while eliminating, for purposes of clarity, other elements that those of ordinary skill in the art will appreciate may also comprise a portion of the disclosure. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the disclosure, a description of such elements is not provided herein. 35 306865454 Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 Further, to the extent that a method does not rely on the particular order of steps set forth herein, the particular order of the steps recited in a claim should not be construed as a limitation on that claim. All patents, patent applications, references and publications cited herein are fully and completely incorporated by reference as if set forth in their entirety. Such documents are not admitted to be prior art to the present disclosure. 306865454

Claims

Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 CLAIMS We claim: A method of treating cancer in a subject who has been administered a CYP3A inducer, the method comprising: a) discontinuing the administration of the CYP3A inducer to the subject; and b) administering an effective amount of Compound A:or a pharmaceutically acceptable salt thereof, to the subject. The method of claim 1, further comprising step a’): a') waiting a first time period after step a) before performing step b). The method of claim 2, wherein the first time period is about 14 days plus 5 half-lives of the CYP3A inducer.

4. The method of claim 2, wherein the first time period is about 3 to 5 half-lives of the CYP3A inducer.

5. The method of any one of claims 1-4, wherein the CYP3A inducer is apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor, ivacaftor, mitotane, phenytoin, rifampin, or St. John’s wort.

6. The method of claim 5, wherein the CYP3A inducer is carbamazepine.

7. The method of any one of claims 1-6, wherein the CYP3A inducer is a CYP3A4 inducer. 306865454Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 8. The method of any one of claims 1-7, wherein the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day orally to the subject.

9. The method of any one of claims 1-8, wherein the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is a daily dose of about 200 mg.

10. The method of any one of claims 1-8, wherein the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is a daily dose of about 100 mg.

11. The method of any one of claims 1-10, wherein the subject is in a fed state.

12. The method of any one of claims 1-11, wherein the cancer is breast cancer.

13. The method of claim 12, wherein the breast cancer is metastatic or locally advanced.

14. The method of claim 12 or 13, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

15. The method of claim 14, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

16. The method of any one of claims 1-15, wherein the subject is human.

17. A pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or a label that includes a warning that concomitant administration of the Compound A, or the pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inducer. 306865454Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 18. A pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or a label that includes: a) avoiding concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inducer; b) discontinuing concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inducer; or c) contraindicating concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inducer.

19. A kit comprising: (a) a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form; and (b) an instruction or label that includes a warning that concomitant administration of the Compound A, or the pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inducer.

20. The pharmaceutical product or the kit of any one of claims 17-19, wherein the oral dosage form is a tablet or capsule.

21. The pharmaceutical product or the kit of claim 20, wherein the oral dosage form is a tablet.

22. The pharmaceutical product or the kit of any one of claims 17-21, wherein the strong CYP3A inducer is apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor, ivacaftor, mitotane, phenytoin, rifampin, or St. John’s wort.

23. The pharmaceutical product or the kit of claim 22, wherein the strong CYP3A inducer is carbamazepine.

24. The pharmaceutical product or the kit of any one of claims 17-23, wherein the strong CYP3A inducer is a strong CYP3A4 inducer.

25. The pharmaceutical product or the kit of any one of claims 17-24, wherein the amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg. 306865454Cooley Docket No. ARVN-059 / 001WO 331216-2844 Arvinas Docket No. ARVN0193WO2 26. The pharmaceutical product or the kit of any one of claims 17-24, wherein the amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg. 306865454

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