WO2024206147A1

WO2024206147A1 - Dosage regimens of estrogen receptor degraders

Info

Publication number: WO2024206147A1
Application number: PCT/US2024/021150
Authority: WO
Inventors: Richard Walter GEDRICH; Jessica Li Fong TEH; Ian Charles Anthony TAYLOR
Original assignee: Arvinas Operations Inc
Current assignee: Arvinas Operations Inc
Priority date: 2023-03-24
Filing date: 2024-03-22
Publication date: 2024-10-03
Anticipated expiration: 2025-09-24
Also published as: TW202440096A

Abstract

Disclosed herein are methods for treating cancer comprising administering to a subject a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor.

Description

Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 DOSAGE REGIMENS OF ESTROGEN RECEPTOR DEGRADERS Related Applications This application claims priority to, and the benefit of, U.S. Provisional Application No 63/454,608, filed March 24, 2023 and U.S. Provisional Application No.63/508,502 filed June 15, 2023, which are incorporated by reference in their entireties for all purposes. Background of the Invention Certain bifunctional compounds 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 International Publication No. WO 2018/102725, 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, 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” or “Cpd A”), which has the molecular formula of C₄₅H₄₉N₅O₄ and 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 Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway. There is a need for appropriate dosage regimens of Compound A as an oral therapy for treating cancers (e.g., breast cancer), to improve its benefit, including safety and efficacy, and convenience to patients while at the same time minimizing adverse events and risks to patients. Summary of the Invention The present disclosure provides, in part, dosage regimens for administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject in combination therapies, 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 are methods for treating cancer comprising administering to a subject a Compound A, having a structure of:

, or a pharmaceutically acceptable salt thereof, in combination with a phosphatidylinositol 3- kinase (PI-3 kinase or PI3K) inhibitor.

Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 In some embodiments, the present disclosure provides a compound having the structure:

, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer, the method comprising administering to a subject a daily dose of the compound in combination with a PI3K inhibitor. Provided herein also are methods for treating cancer comprising administering to a subject a daily dose of Compound A, having a structure of:

, or a pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor, wherein the daily dose of the compound is about 200 mg. In embodiments, the PI3K inhibitor is copanlisib, idelalisib, umbralisib, inavolisib, duvelisib, or alpelisib, or a pharmaceutically acceptable salt thereof. In embodiments, the PIK3 inhibitor is inavolisib, or a pharmaceutically acceptable salt thereof. In embodiments, the PIK3 inhibitor is alpelisib, or a pharmaceutically acceptable salt thereof. In embodiments, the PIK3 inhibitor is inavolisib. In embodiments, the PIK3 inhibitor is alpelisib. In embodiments, the compound may be administered daily in 28-day cycles in combination with the alpelisib. In embodiments, the daily dose of Compound A is administered once per day (QD). Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 In embodiments, the daily dose of Compound A is administered orally to the subject. In embodiments, the subject is in a fed state. 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. For example, the breast cancer may be metastatic or locally advanced. Alternatively, the breast cancer may be estrogen receptor positive (ER+) breast cancer (e.g., human epidermal growth factor receptor 2 negative (HER2-)). In embodiments, the subject is human. In some embodiments, the present disclosure provides combined preparations of (i) a compound having a structure of:

or a pharmaceutically acceptable salt thereof, and (ii) a PI3K inhibitor, for simultaneous, separate, or sequential use in a method of treating cancer. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 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. Brief Description of the Drawings FIGs.1A–1H are graphs showing quantification of the MCF7 and T47D live-cell imaging proliferation assays. FIGs.1A and 1C show relative cell growth kinetics over 120 hours by live cell imaging of MCF7 and T47D cells dosed with Compound A and/or alpelisib at their respective approximate GI₅₀ concentrations. Each plot is representative of three independent experiments. FIGs.1E and 1G show relative cell growth kinetics over 120 hours by live cell imaging of MCF7 and T47D cells dosed with Compound A and/or inavolisib at their respective approximate GI₅₀ concentrations. Each plot is representative of three independent experiments. FIGs.1B, 1D, 1F and 1H show differences in relative MCF7 and T47D cell growth compared to vehicle control at 120 hours of treatment. Graphs show the mean of three independent experiments. Error bars = standard error of the mean (SEM). *p<0.03, ***p=0.0002, ****p<0.0001 (one-way ANOVA test). FIGs.2A–2L are graphs showing viability and synergistic analysis of MCF7 cells at day-5 dosed with Compound A in combination with alpelisib or inavolisib in an 8x8 block matrix. FIGs.2A, 2B, 2G, and 2H show single agent curves of Compound A, alpelisib, and inavolisib, respectively. FIG.2C shows Compound A dose-response shift with the addition of alpelisib. FIG.2I shows Compound A dose-response shift with the addition of inavolisib. Drug synergies were evaluated using Combenefit software. BLISS (2D and 2J), Loewe (2E and 2K) and Highest Single Agent (2F and 2L) model output is shown (representative of three independent experiments). FIGs.3A and 3B are graphs showing in vivo efficacy studies of Compound A in combination with the PI3K inhibitors alpelisib (FIG.3A) and inavolisib (FIG.3B) using MCF7 orthotopic xenograft models. Mean tumor volumes are reported ± SEM. FIG.4A is a graph showing body weights (± SEM) of MCF7 orthotopic xenograft efficacy with Compound A in combination with the PI3KĮ inhibitor alpelisib. Compounds dosed as single agents or in combination, 10 mice/arm. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 FIG.4B is a graph showing body weights (± SEM) of MCF7 orthotopic xenograft efficacy with Compound A in combination with the PI3KĮ inhibitor inavolisib. Compounds dosed as single agents or in combination, 10 mice/arm. 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 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. (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 (also referred to herein as “Compound A”) is a compound having the structure:

and is under development as a PROTAC® protein degrader that targets estrogen receptor (ER) for the potential treatment of breast cancer. Compound A has been shown to be a useful modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway. PI-3 kinases comprise a family of lipid and serine/threonine kinases that catalyze the transfer of phosphate to the D-3ƍ position of inositol lipids to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP2) and phosphoinositol-3,4,5-triphosphate (PIP3) that, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin- homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 complexes often at the plasma membrane ((Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol.17:615 (2001)). Of the two Class 1 PI3Ks, Class 1A PI3Ks are heterodimers composed of a catalytic p110 subunit (Į, ȕ, į isoforms) constitutively associated with a regulatory subunit that can be p85Į, p55Į, p50Į, p85ȕ or p55Ȗ. The Class IB sub-class has one family member, a heterodimer composed of a catalytic p110Ȗ subunit associated with one of two regulatory subunits, p101 or p84 (Fruman et al., Annu Rev. Biochem.67:481 (1998); Suire et al., Curr. Biol.15:566 (2005)). The modular domains of the p85/55/50 subunits include Src Homology (SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class 1A PI3Ks. Class IB PI3K is activated directly by G protein- coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89:105 (1997)); Katso et al., Annu. Rev. Cell Dev. Biol.17:615-675 (2001)). Consequently, the resultant phospholipid products of class I PI3K link upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cellular trafficking, motility, metabolism, inflammatory and allergic responses, transcription, and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)). PI-3 kinase inhibitors are useful therapeutic compounds for the treatment of various conditions in humans. Aberrant regulation of PI3K, which often increases survival through Akt activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. In some tumors, the genes for the p110a isoform, PIK3CA, are amplified and increased protein expression of their gene products has been demonstrated in several human cancers. In other tumors, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Kang et al., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573(2005)). Deregulation of phosphoinositol-3 kinase is a common deregulation associated with human cancers and proliferative diseases. Despite the variety of treatment options available for cancer patients, there remains a need for effective and safe therapeutic agents and their preferred use in combination therapy. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 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 a compound) 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 from 4.5 mg to 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 and uses of the present disclosure. As used herein, the terms, “subject,” “participant,” and “patient,” are used interchangeably, to refer to any animal, including mammals. Mammals according to the disclosure include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans, and the like, and encompass mammals in utero. In embodiments, humans are suitable subjects. Human subjects may be of any gender and at any stage of development. (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 (also referred to herein as “Compound A”) is a compound having the structure: Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807

. Compound A and pharmaceutically acceptable salts thereof are disclosed in 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 entirety. Compound A is a Biopharmaceutics Classification System Class IV compound (low solubility/low permeability). Compound A can interconvert to its epimer, Compound B:

. Preclinical data demonstrates that the exposure of Compound B is limited compared to Compound A (<26%). Compound B does not degrade the ER; however, Compound B shows similar antagonism of ER-dependent transcription compared to Compound A. Alpelisib, or (2S)-1-N-[4-Methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3- thiazol-2-yl]pyrrolidine-1,2-dicarboxamide, is an Į-specific PI3K inhibitor that selectively inhibits p110Į approximately 50 times as strongly as other isoforms. Fritsch C, Huang A, Chatenay-Rivauday C, et al. “Characterization of the novel and specific PI3KĮ inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials.” Mol Cancer Ther.2014;13:1117–29. Alpelisib has the structure: Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807

. Alpelisib is disclosed in U.S. Pat. Nos.8,227,462, and 8,476,268, the contents of each of which are incorporated herein by reference in their entirety. Inavolisib a PI3KĮ-specific inhibitor that also promotes degradation of mutant p110Į. Hanan, Emily J., et al.2022. “Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3KĮ.” Journal of Medicinal Chemistry 65 (24): 16589–16621. Inavolisib has the structure:

. Inavolisib is disclosed in U.S. Pat. Nos.9,650,393, 10,851,091, 10,112,932, 10,781,219, and 11,028,100. The contents of each of the foregoing references are incorporated herein by reference in their entirety. Other 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. Other embodiments also relate 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, Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 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 that 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. The compounds described herein that are basic in nature can form 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. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 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. Dosage Regimens Provided herein are methods for treating cancer comprising administering to a subject a daily dose of Compound A, having a structure of:

pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor. In some embodiments, the present disclosure provides a compound having the structure:

, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer, the method comprising administering to a subject a daily dose of the compound in combination with a PI3K inhibitor. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 In embodiments, the daily dose of Compound A, having the structure:

pharmaceutically acceptable salt thereof, is administered once per day (QD). In embodiments, the daily dose of Compound A, having the structure:

thereof, is administered orally to the subject. In embodiments, the subject is in a fed state. In embodiments, the daily dose of Compound A:

thereof, is about 200 mg. In embodiments, Compound A, having the structure: Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807

administered as a free base. In embodiments, the PI3K inhibitor is copanlisib, idelalisib, umbralisib, inavolisib, duvelisib, or alpelisib, or a pharmaceutically acceptable salt thereof. In embodiments, the PI3K inhibitor is alpelisib, or a pharmaceutically acceptable salt thereof. In embodiments, the PI3K inhibitor is alpelisib. In embodiments, the PI3K inhibitor is inavolisib, or a pharmaceutically acceptable salt thereof. In embodiments, the PI3K inhibitor is inavolisib. In embodiments, Compound A is administered daily in 28-day cycles. 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 embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 In embodiments, the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-). In embodiments, the subject is human. Also disclosed herein is Compound A, having the structure:

pharmaceutically acceptable salt, for use according to any one of foregoing embodiments. Also disclosed herein are uses of Compound A, having the structure:

pharmaceutically acceptable salt, in the manufacture of a medicament according to any one of foregoing embodiments. Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined. Combined Preparations Also provided herein are combined preparations of (i) a compound having a structure of: Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807

or a pharmaceutically acceptable salt thereof, and (ii) a PI3K inhibitor, for simultaneous, separate, or sequential use in a method of treating cancer. In the “combined preparations” recited herein, the active agents (e.g., Compound A or a pharmaceutically acceptable salt thereof, and a PI3K inhibitor) may be physically separated, thus allowing for their separate or sequential administration. Administration and Dosing The terms “treat” and “treating” a cancer or a cancer-associated disease, as used herein, mean to administer a combination therapy 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 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 can be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. (2009) 50:1S– 10S). Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 “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. An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, 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 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 “therapeutically effective amount” also means an amount of an agent 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, a therapeutically 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. 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 Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 pharmaceutically acceptable salt thereof. The amount, or the therapeutically effective amount, can be a daily dose of about 200 mg. In another embodiment, a daily dose is 200 mg. In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once per day (QD). 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, uses, or combinations 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 Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 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 combination of the present invention can be administered in a continuous dosing schedule. In embodiments, the compounds of the combination disclosed herein can 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. Also disclosed herein are kits comprising the therapeutic agents of the combination of the present disclosure and written instructions for administration of the therapeutic agents. In embodiments, the written instructions elaborate and qualify the modes of administration of the therapeutic agents, for example, for simultaneous or sequential administration of the therapeutic agents of the present disclosure. In embodiments, the written instructions elaborate and qualify the modes of administration of the therapeutic agents, for example, by specifying the days of administration for each of the therapeutic agents during a 28-day treatment cycle. Methods of Treatment In embodiments, provided herein are methods for treating cancer in a subject comprising administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, as described herein in combination with an amount of a PI3K inhibitor. The term “combination,” as used herein, unless otherwise indicated, refers to the use of Compound A, or a pharmaceutically acceptable salt thereof, with one or more therapeutic agents, wherein Compound A, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are administered intermittently, concurrently, or sequentially, according to the same or different route of administration and according to the same or different dosage schedules. 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. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 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–e410; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Fort Washington, PA: NCCN; 2015. Ver.2.2015.) The term “metastatic” as used herein, as it relates to cancer, cannot be treated with curative intent. For example, metastatic breast cancer refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, e.g., bones, liver, lungs, brain. (www.cancer.org/cancer/breast-cancer.) Those skilled in the art will be able to recognize and diagnose locally advanced and metastatic cancer in a patient or subject. For convenience, certain well-known abbreviations, may be used herein, including: castration resistant prostate cancer (CRPC), estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), hormone receptor (HR), human epidermal growth factor receptor 2 positive (HER2+), non-small cell lung cancer (NSCLC), and progesterone receptor (PR). In embodiments, the cancer is selected from lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, hepatic carcinoma, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, hematology malignancy, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitary adenoma, head and neck cancer, and combinations of two or more of the foregoing cancers. Also disclosed herein are methods of treating cancer in a subject. In embodiments, the methods comprise treating cancer in a subject comprising administering to the subject an amount of the compounds described herein that are effective in treating the cancer. In embodiments, the cancer is breast, lung, colon, brain, head and neck, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder. In embodiments, the cancer is breast, lung, prostate, pancreatic, or ovarian. In embodiments, the cancer is breast, lung, or prostate. In embodiments, the cancer is breast cancer. In embodiments, the breast cancer is metastatic breast cancer. In embodiments, the breast cancer is locally advanced breast cancer. In embodiments, the breast cancer is HR+ breast cancer. In embodiments, the HR+ breast cancer is PR+ and/or ER+ breast cancer. In some embodiments, the breast cancer is PR+ breast cancer. In embodiments, the breast cancer is ER+ breast cancer. In embodiments, the breast cancer is ER+ HER2- breast cancer. In embodiments, the breast cancer is ER+ HER2+ breast cancer. In embodiments, the breast cancer is locally advanced or metastatic ER+ breast cancer. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 In embodiments, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer. In embodiments, the breast cancer is locally advanced or metastatic ER+ HER2+ breast cancer. In embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is also locally advanced. In embodiments, the lung cancer is non-small cell lung cancer. In embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer. In embodiments, the prostate cancer is CRPC. In embodiments, the prostate cancer is locally advanced or metastatic CRPC. Also disclosed herein are methods of treating solid tumors in a subject. In embodiments, disclosed herein are methods of treating solid tumors in a subject comprising administering to the subject an amount of the compounds described herein that are effective in treating the solid tumor. In embodiments, the solid tumor is breast, lung, colon, brain, head and neck, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder. In embodiments, the solid tumor is breast, lung, prostate, pancreatic, or ovarian. In embodiments, the solid tumor is breast, lung, or prostate. In embodiments, the solid tumor is breast cancer. For example, in certain embodiments the breast cancer is HR+ breast cancer. In other embodiments, the HR+ breast cancer is PR+ and/or ER+ breast cancer ER+ breast cancer. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is ER+ HER2- breast cancer. In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is ER+ HER2+ breast cancer. In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer. In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic ER+ HER2+ breast cancer. In embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is non-small cell lung cancer. In embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer. In embodiments, the solid tumor is prostate cancer. For example, in certain embodiments, the prostate cancer is CRPC. In embodiments, the solid tumor is prostate cancer. For example, in certain embodiments, the prostate cancer is locally advanced or metastatic castration resistant prostate cancer. Also disclosed herein are methods of treating hematologic tumors in a subject. In certain embodiments, the method comprises treating hematologic tumors in a subject comprising administering to the subject an amount of the compounds described herein that is effective in treating the hematologic tumor. In embodiments, the hematologic tumor is leukemia, lymphoma, or multiple myeloma. In embodiments, the hematologic tumor is leukemia or lymphoma. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 Also disclosed herein are methods of treating cancer in a subject with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC whose disease progressed on or is intolerant to standard therapy. Also disclosed herein are methods of treating cancer in a subject with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC whose disease progressed on or is intolerant to standard therapy. Also disclosed herein are methods of treating cancer in a subject with locally advanced or metastatic in a second or further line of treatment (2L+) ER+HER2- breast cancer who have received prior hormonal/endocrine therapy and chemotherapy in the locally advanced/metastatic setting. In embodiments, the method comprises administering Compound A in combination with a PI3K inhibitor to the subject. Also disclosed herein are methods of treating cancer in a subject with locally advanced or metastatic 2L+ ER+HER2- breast cancer who have received prior treatment with a PI3K inhibitor. In embodiments, the method comprises administering Compound A in combination with a PI3K inhibitor to the subject. 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. Example 1: Enhanced Efficacy of Compound A in Combination with a PI3K inhibitor in ER+ Breast Cancer Models Objective To assess the effects of Compound A in combination with PIK3 pathway inhibitors in preclinical models of ER+ breast cancer. Methods Live-cell imaging proliferation assay Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 MCF7 or T47D cells were seeded in 6 well plates and treated with the indicated concentrations of compounds. The plate was then placed in the Incucyte® S3 Live-Cell Analysis System and images were acquired every 4 hours for a total of 5 days. Data were analyzed using the Incucyte® Software v2020C, which quantified cell surface area coverage as confluence values. Relative growth was calculated for all timepoints for all growth conditions relative to the confluence value observed for the control at 120 hours (FIGs.1A, 1C, 1E, and 1G). Graphing and statistical analyses were performed using Graphpad Prism (GraphPad Software). Dose-response matrix assay Cells were seeded at 2x10³ cells in 200^l of media per well in 96 well plates and incubated overnight at 37°C. Compound A concentrations curves were started at 100nM for an 8-point concentration curve ranging from 100 to 0.046 nM (FIGs.2A, 2C, 2E, 2G). Inavolisib concentration curves were started at 1000nM for an 8-point concentration curve ranging from 1000 to 0.46nM (FIG.2F). Alpelisib concentration curves were started at 3000nM for an 8- point concentration curve ranging from 3000 to 1.37nM (FIG.2B). At Day 5 cell viability was measured using Cell-Titer Glo and CTG data were analyzed with the Combenefit Software (Veroli GYD, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, et al. Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics. 2016;32:2866–8). The combination of either alpelisib or inavolisib with Compound A demonstrated enhanced cell growth inhibition compared to single agent treatments and resulted in synergism by Bliss, Loewe and HSA models. MCF7 xenograft model Briefly, MCF7 cells were orthotopically implanted into the mammary fat pads of NOD/SCID female mice.17ȕ-estradiol 0.72 mg 90-day pellet (Innovative Research of America) were implanted 2–3 days prior to MCF7 cell implant. For combination arms, Compound A was administered first followed by combination partners 1 hour later. Compound A and/or combination partner- treated mice were dosed orally once daily. Fulvestrant-treated mice were dosed subcutaneously twice per week for 2 weeks followed by once weekly for 2 weeks. More specifically, synergism between Compound A and alpelisib and inavolisib was followed up in vivo using the MCF7 orthotopic xenograft model. Eight- to ten-week-old female NOD/SCID mice were surgically implanted with a 0.36 mg 90-day release 17ȕ-estradiol pellet subcutaneously. One to two days later each mouse was injected with 5x10⁶/200 μL MCF7 cells Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 into one mammary fat pad. Cells were prepared in a 50/50 RPMI-1640 phenol red-free media/Corning Matrigel Membrane Matrix mix at 25x10⁶ cells/ml. Dosing initiated once tumors reached an average of 200 mm³. Where oral combinations were dosed, Compound A was dosed first and alpelisib or inavolisib 30-60 minutes later. Drugs indicated were dosed as single agents or in combination to 10 mice/arm. Compound A and alpelisib or inavolisib were dosed at 5 ml/kg volume once daily for 28 days (qdx28). Vehicles for Compound A was 2% Tween 80/PEG400. Vehicle for alpelisib was 1% CMC/0.5% Tween 80/DI water. Vehicle for inavolisib was 0.5% (w/v) methylcellulose, 0.2% (w/v) polysorbate 80 (Tween-80). Body weights were well maintained (FIGs.4A and 4B). Tumor volumes were measured twice per week in efficacy studies and calculated using (width² x length)/2, where all measurements are in millimeters (mm) and the tumor volume is in mm³. Body weights were recorded twice per week. At study termination mice were euthanized 18 hours post-last dose, and harvested tissue was snap-frozen on dry ice. Tumor growth inhibition (TGI) was calculated as follows, where tumor volume is in mm³: (Tumor volume, compound, Day X) – (Tumor volume, compound, Day 0) TGI (%) = [ 1- ] x 100 (Tumor volume, vehicle, Day X) – (Tumor volume, vehicle, Day 0) Findings In vitro and in vivo studies revealed evidence of synergistic interactions between Compound A and the PI3K inhibitors alpelisib and inavolisib in ER+ breast cancer cells. Compound A and inavolisib demonstrated better efficacy combined (132% tumor growth inhibition) than as single agents. Compound A additionally displayed greater anti-tumor activity in combination with inavolisib than that observed with fulvestrant in combination with inavolisib. Taken together, these data highlight the potential utility of Compound A as a combination partner for PI3K inhibitors (e.g., alpelisib and inavolisib) for treatment of both early and late- stage ER+ disease. EQUIVALENTS Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 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. 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. ENUMERATED EMBODIMENTS The aspects of the present disclosure are further described with reference to the following embodiments: Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 1. A method for treating cancer comprising administering to a subject Compound A:

(Compound A), or a pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor. 2. The method of embodiment 1, wherein the PI3K inhibitor is copanlisib, idelalisib, umbralisib, inavolisib, duvelisib, or alpelisib, or a pharmaceutically acceptable salt thereof. 3. The method of embodiment 1 or 2, wherein the PI3K inhibitor is alpelisib, or a pharmaceutically acceptable salt thereof. 4. The method of embodiment 1 or 2, wherein the PI3K inhibitor is inavolisib, or a pharmaceutically acceptable salt thereof. 5. The method of embodiment 1 or 2, wherein the PI3K inhibitor is alpelisib. 6. The method of embodiment 1 or 2, wherein the PI3K inhibitor is inavolisib. The method of any one of embodiments 1 to 6, wherein 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. 8. The method of embodiment 7, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer. 9. The method of embodiment 7, wherein the cancer is breast cancer, lung cancer, or prostate cancer. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 10. The method of embodiment 7, wherein the cancer is breast cancer. 11. The method of embodiment 10, wherein the breast cancer is metastatic or locally advanced. 12. The method of embodiment 10 or 11, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer. 13. The method of embodiment 12, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-). 14. The method of any one of embodiments 1 to 13, wherein the subject is human. A method for treating cancer comprising administering to a subject a daily dose of Compound A:

(Compound A), or a pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor, wherein the daily dose of Compound A is about 200 mg. 16. The method of embodiment 15, wherein the Compound A and the PI3K inhibitor are administered concurrently or sequentially. 17. The method of embodiment 15 or 16, wherein the daily dose of Compound A is administered once per day (QD). 18. The method of any one of embodiments 15 to 17, wherein the daily dose of Compound A is administered orally to the subject. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 19. The method of any one of embodiments 15 to 18, wherein the subject is in a fed state. 20. The method of any one of embodiments 15 to 19, wherein the PI3K inhibitor is copanlisib, idelalisib, umbralisib, inavolisib, duvelisib, or alpelisib, or a pharmaceutically acceptable salt thereof. 21. The method of embodiment 20, wherein the PI3K inhibitor is alpelisib, or a pharmaceutically acceptable salt thereof. 22. The method of embodiment 20, wherein the PI3K inhibitor is inavolisib, or a pharmaceutically acceptable salt thereof. 23. The method of embodiment 20, wherein the PI3K inhibitor is alpelisib. 24. The method of embodiment 20, wherein the PI3K inhibitor is inavolisib. 25. The method of any one of embodiments 15 to 24, wherein 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. 26. The method of embodiment 25, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer. 27. The method of embodiment 25, wherein the cancer is breast cancer, lung cancer, or prostate cancer. 28. The method of embodiment 25, wherein the cancer is breast cancer. 29. The method of embodiment 28, wherein the breast cancer is metastatic or locally advanced. 30. The method of embodiment 28 or 29, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 31. The method of embodiment 30, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-). 32. The method of any one of embodiments 15 to 31, wherein the subject is human.

(Compound A), or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer, the method comprising administering Compound A to a subject in combination with a PI3K inhibitor. 34. A combined preparation of

(Compound A), or a pharmaceutically acceptable salt thereof, and (ii) a PI3K inhibitor, for simultaneous, separate, or sequential use in a method of treating cancer. 35. The compound for use of embodiment 33, or the combined preparation for use of embodiment 34, wherein the PI3K inhibitor is copanlisib, idelalisib, umbralisib, inavolisib, duvelisib, or alpelisib, or a pharmaceutically acceptable salt thereof. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 36. The compound or the combined preparation for use of any one of embodiments 33 to 35, wherein the PI3K inhibitor is alpelisib, or a pharmaceutically acceptable salt thereof. 37. The compound or the combined preparation for use of any one of embodiments 33 to 35, wherein the PI3K inhibitor is inavolisib, or a pharmaceutically acceptable salt thereof. 38. The compound or the combined preparation for use of any one of embodiments 33 to 35, wherein the PI3K inhibitor is alpelisib. 39. The compound or the combined preparation for use of any one of embodiments 33 to 35, wherein the PI3K inhibitor is inavolisib. 40. The compound or the combined preparation for use of any one of embodiments 33 to 39, wherein 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. 41. The compound or the combined preparation for use of embodiment 40, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer. 42. The compound or the combined preparation for use of embodiment 40, wherein the cancer is breast cancer, lung cancer, or prostate cancer. 43. The compound or the combined preparation for use of embodiment 40, wherein the cancer is breast cancer. 44. The compound or the combined preparation for use of embodiment 43, wherein the breast cancer is metastatic or locally advanced. 45. The compound or the combined preparation for use of embodiment 43 or 44, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 46. The compound or the combined preparation for use of embodiment 45, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-). 47. The compound or the combined preparation for use of any one of embodiments 33 to 46, wherein the subject is human. 48. The compound or the combined preparation for use of any one of embodiments 33 to 47, wherein the PI3K inhibitor is administered concurrently with Compound A or sequentially to Compound A. 49. The compound or the combined preparation for use of any one of embodiments 33 to 48, wherein the subject is in a fed state. 50. The compound or the combined preparation for use of any one of embodiments 33 to 49 wherein the method comprises administering to the subject a daily dose of Compound A, wherein the daily dose is about 200 mg. 51. The compound or the combined preparation for use of embodiment 50, wherein the daily dose of Compound A is administered once per day (QD). 52. The compound or the combined preparation for use of any one of embodiments 50 to 51, wherein the daily dose of Compound A is administered orally to the subject.

Claims

CLAIMS We claim: A method for treating cancer comprising administering to a subject Compound A:

(Compound A), or a pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor. 2. The method of claim 1, wherein the PI3K inhibitor is copanlisib, idelalisib, umbralisib, inavolisib, duvelisib, or alpelisib, or a pharmaceutically acceptable salt thereof. 3. The method of claim 1 or 2, wherein the PI3K inhibitor is alpelisib, or a pharmaceutically acceptable salt thereof. 4. The method of claim 1 or 2, wherein the PI3K inhibitor is inavolisib, or a pharmaceutically acceptable salt thereof. 5. The method of claim 1 or 2, wherein the PI3K inhibitor is alpelisib. 6. The method of claim 1 or 2, wherein the PI3K inhibitor is inavolisib. 7. The method of any one of claims 1 to 6, wherein 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. 8. The method of claim 7, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 9. The method of claim 7, wherein the cancer is breast cancer, lung cancer, or prostate cancer. 10. The method of claim 7, wherein the cancer is breast cancer. 11. The method of claim 10, wherein the breast cancer is metastatic or locally advanced. 12. The method of claim 10 or 11, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer. 13. The method of claim 12, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-). 14. The method of any one of claims 1 to 13, wherein the subject is human. 15. A method for treating cancer comprising administering to a subject a daily dose of Compound A:

(Compound A), or a pharmaceutically acceptable salt thereof, in combination with a PI3K inhibitor, wherein the daily dose of Compound A is about 200 mg. 16. The method of claim 15, wherein the Compound A and the PI3K inhibitor are administered concurrently or sequentially. 17. The method of claim 15 or 16, wherein the daily dose of Compound A is administered once per day (QD). Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 18. The method of any one of claims 15 to 17, wherein the daily dose of Compound A is administered orally to the subject. 19. The method of any one of claims 15 to 18, wherein the subject is in a fed state. 20. The method of any one of claims 15 to 19, wherein the PI3K inhibitor is copanlisib, idelalisib, umbralisib, inavolisib, duvelisib, or alpelisib, or a pharmaceutically acceptable salt thereof. 21. The method of claim 20, wherein the PI3K inhibitor is alpelisib, or a pharmaceutically acceptable salt thereof. 22. The method of claim 20, wherein the PI3K inhibitor is inavolisib, or a pharmaceutically acceptable salt thereof. The method of claim 20, wherein the PI3K inhibitor is alpelisib. 24. The method of claim 20, wherein the PI3K inhibitor is inavolisib. 25. The method of any one of claims 15 to 24, wherein 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. 26. The method of claim 25, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer. 27. The method of claim 25, wherein the cancer is breast cancer, lung cancer, or prostate cancer. 28. The method of claim 25, wherein the cancer is breast cancer. 29. The method of claim 28, wherein the breast cancer is metastatic or locally advanced. Arvinas Ref.: ARVN0171WO2 Attorney Docket No.: ARVN-050/001WO 331216-2807 30. The method of claim 28 or 29, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer. 31. The method of claim 30, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-). 32. The method of any one of claims 15 to 31, wherein the subject is human.