COMBINATION FOR TREATMENT OF HIGH-RISK METASTATIC HORMONE¬

SENSITIVE PROSTATE CANCER

FIELD

[0001] The disclosure relates to the field of treatment of men with metastatic hormonesensitive prostate cancer, and more particularly, high-risk metastatic hormone-sensitive prostate cancer.

BACKGROUND

[0002] Prostate cancer is a leading cause of mortality and morbidity globally and represents a substantial public health burden. With nearly 1.4 million new cases and 375,000 deaths worldwide, prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men in 2020 (Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021, 71(3):209-249).

[0003] Men with metastatic hormone-sensitive prostate cancer (mHSPC) have either primary progressive disease or present with metastases at initial diagnosis (de novo mHSPC). While androgen deprivation therapy (ADT) alone or in combination with first-generation antiandrogens has been the mainstay of treatment for mHSPC, the treatment landscape has changed radically in recent years. Life-prolonging treatments now include ADT with docetaxel chemotherapy, or with hormonal agents, such as abiraterone, apalutamide, and enzalutamide, or with docetaxel and novel hormonal agents (triplet therapy). Despite these significant recent improvements, there is still a pressing medical need for tailored treatment approaches, particularly for patients with high-risk disease who experience shorter survival outcomes with current approved treatments. For these high-risk patients, early treatment intensification with novel combination therapy has the potential to meaningfully improve clinical outcomes.

[0004] Abemaciclib is a potent and selective oral inhibitor of CDK4 & 6 that is approved for the treatment of early and advanced/metastatic HR+/HER2- breast cancer (Verzenio package insert, 2021). There is evidence that the AR signaling pathway activates the CDK4 & 6-cyclin DI axis to sustain prostate cancer cell proliferation and survival (Knudsen ES, Pazzagli C, Born TL, et al. Elevated cyclins and cyclin-dependent kinase activity in the rhabdomyosarcoma cell line RD. Cancer Res. 1998;58(9):2042-2049; Xu Y, Chen SY, Ross KN, Balk SP. Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin dependent translation of D-cyclins and subsequent activation of CDK4 & 6 (Xu et al. 2006). In addition, cyclin DI has been proposed as a potential mechanism of resistance to novel anti -androgen agents (Pal et al. 2018). These findings suggest that CDK4 & 6 may play an important role in the development and/or progression of prostate cancer. In line with this, preclinical studies in cell cultures and mouse xenograft prostate cancer models, showed that abemaciclib induces cell cycle arrest and tumor growth inhibition (Torres-Guzman R, Baquero C, Ganado MP, et al. Abstract 4850: Targeting prostate cancer with the CDK4 and CDK6 inhibitor abemaciclib. Cancer Res. 2020;80(suppl 16)).

DETAILED DESCRIPTION

[0005] Methods, uses, and compositions for the treatment of a patient with high-risk metastatic hormone-sensitive prostate cancer are disclosed herein. For these high-risk patients, early treatment intensification with novel combination therapy has the potential to meaningfully improve clinical outcomes. The present disclosure provides a combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0006] Abemaciclib is a potent and selective oral inhibitor of CDK4 & 6 that is approved for the treatment of early and advanced/metastatic HR+/HER2- breast cancer (Verzenio package insert, 2021). Dual inhibition of the AR axis and cell cycle entry with the coadministration of abiraterone and abemaciclib may demonstrate superior clinical activity compared to inhibition of the AR axis alone in patients with high-risk mHSPC.

[0007] In one aspect, the present disclosure provides a method of treating a patient with high- risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0008] In another aspect, the present disclosure provides a combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing; for use in treating a patient with high-risk metastatic hormone-sensitive prostate cancer.

[0009] In another aspect, the present disclosure provides use of a CDK4 and 6 inhibitor in the manufacture of a medicament for the treatment of a patient with high-risk metastatic hormonesensitive prostate cancer, wherein the medicament is to be administered in simultaneous, separate, or sequential combination with abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0010] Administration of the combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing, can be, for example, simultaneous or sequential in any order, such as for example, at repeated intervals as during a standard course of treatment for a single cycle or more than one cycle, such that one agent can be administered prior to, at the same time, or subsequent to the administration of the other agent, or any combination thereof.

[0011] A "CDK4 and 6 inhibitor," a "CDK4/6 inhibitor," or alternatively a “CDK4 & 6 inhibitor” refers to molecules that inhibit the activity of D-type cyclins (e.g., cyclin D3) and cyclin-dependent kinases (CDK4 and 6) protein complexes (e.g., cyclinD:CDK4 and 6 complexes), and generally function to block transition from the G1 to S phase of cell cycle through inhibition of kinase activity. In some embodiments of the disclosure, the CDK4 and 6 inhibitor is palbociclib, ribociclib, or abemaciclib.

[0012] Palbociclib, [6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-l-yl)pyrid ine-2- yl]amino}pyrido[2,3,-t ]pyrimidin-7(8J7)-one], is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer (i) in combination with an aromatase inhibitor as an initial endocrine based therapy in postmenopausal women or in men, or (ii) in combination with fulvestrant in patients with disease progression following endocrine therapy. It has the chemical structure:

[0013] Palbociclib is taken orally and is available as capsules (125 mg, 100 mg, and 75 mg) with a recommended starting dosage of 125 mg, once daily for 21 days followed by 7 days of off treatment. Palbociclib may be prepared as the free base or as pharmaceutically acceptable salts, including mono- and di-acid addition salts such as, for example, the mono-isethionate salt, polymorphic forms of the isethionate salt, or the hydrochloride salt (see, e.g., WO 2003/062236, WO 2005/005426, WO 2008/032157, U.S. Pat. Nos. 6,936,612; 7,208,489; 7,345,171;

7,456,168; 7,781,583; and 7,863,278). Palbociclib in its free base form may be anhydrous or may contain varying amounts of water or one or more solvents, (see, e.g., U.S. Pat. No. 10,723,730). [0014] Ribociclib, [7-cyclopentyl-A,7V-dimethyl-2-{[5-(piperazin-l-yl)pyridine- 2-yl]amino}- 7H-pyrrolo[2,3-t ]pyrimidine-6-carboxamide], is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer (i) in combination with an aromatase inhibitor as an initial endocrine-based therapy in pre/perimenopausal or postmenopausal women, or (ii) in combination with fulvestrant in postmenopausal women as an initial endocrine-based therapy or following disease progression on endocrine therapy. It has the chemical structure:

[0015] Ribociclib is taken orally and is available as tablets (200 mg, equivalent to 254.40 mg ribociclib succinate) with a recommended starting dosage of 600 mg, (3x 200 mg tablets) taken once daily for 21 days followed by 7 days of off treatment. Ribociclib may be prepared as the free base or as pharmaceutically acceptable salts, including as ribociclib succinate (see, e.g., U.S. Pat. Nos. 9,868,739; and 9,193,732).

[0016] Abemaciclib (LY2835219), [5-(4-ethyl-piperazin-l-ylmethyl)-pyridin-2-yl]-[5-fluoro-4- (7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimi din-2-yl]-amine, is a potent and selective oral inhibitor of CDK4 & 6 that is approved for the treatment of early and advanced/metastatic HR+/HER2- breast cancer (Verzenio® package insert, 2021). Abemaciclib, its salt forms including the hydrochloride and mesylate salts, and methods of making and using the compound including for the treatment of cancer, in particular, breast cancer are disclosed in WO 2010/075074. Methods for using abemaciclib in combination with endocrine therapy for the adjuvant treatment of adult patients diagnosed with HR+, HER2- node positive, early breast cancer at high risk of recurrence and a Ki-67 score >20% are disclosed in WO 2018/204138. Abemaciclib has the following structure:

[0017] In aspects and embodiments comprising abemaciclib, the following dosing can be employed in accordance with the methods and uses described herein. In some preferred embodiments, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg to 200 mg twice a day. Also preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg to 150 mg twice a day. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg twice a day. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg twice a day in a 28-day cycle. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg twice a day in a 28-day cycle. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg twice a day in a 28-day cycle. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg twice a day in a 28-day cycle. Preferably, abemaciclib is administered orally. Preferably, abemaciclib is administered by capsule. Also preferably, abemaciclib is administered by tablet. [0018] Abiraterone, the active metabolite of abiraterone acetate, irreversibly inhibits cytochrome P450 (CYP)17 (17a-hydroxylase/C17, 20-lyase), an essential enzyme in androgen biosynthesis that is expressed in testicular, adrenal, and prostatic tumor tissues. Abiraterone acetate is approved in combination with prednisone or prednisolone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) or metastatic high-risk castration- sensitive prostate cancer (CSPC) (Zytiga® package insert, 2021). Abiraterone and abiraterone acetate have the structures:

Abiraterone Abiraterone acetate.

[0019] In some preferred embodiments, abiraterone acetate is administered at a dose of 1000 mg once a day. More preferably, abiraterone acetate is administered at a dose of 1000 mg once a day in a 28-day cycle. Preferably, abiraterone acetate is administered orally. Preferably, abiraterone acetate is administered by tablet. In some preferred embodiments, abiraterone acetate is micronized. In some preferred embodiments, abiraterone acetate (preferably micronized abiraterone acetate) is administered at a dose of 500 mg once a day. More preferably, abiraterone acetate (preferably micronized abiraterone acetate) is administered at a dose of 500 mg once a day in a 28-day cycle. Preferably, micronized abiraterone acetate is administered orally. Preferably, micronized abiraterone acetate is administered by tablet.

[0020] Prednisone, prednisolone, and methylprednisolone are glucocorticoids. Prednisone, prednisolone, and methylprednisolone have the following structures.

Methy Ipredni sol one

[0021] In some preferred embodiments, prednisone or prednisolone is administered at a dose of 5 mg once a day. More preferably, prednisone or prednisolone is administered at a dose of 5 mg once a day in a 28-day cycle. Preferably, prednisone or prednisolone is administered orally. Preferably, prednisone or prednisolone is administered by tablet. In some preferred embodiments, methylprednisolone is administered at a dose of 4 mg twice a day. More preferably, methylprednisolone is administered at a dose of 4 mg twice a day in a 28-day cycle. Preferably, methylprednisolone is administered orally. Preferably, methylprednisolone is administered by tablet.

[0022] In some preferred embodiments, abemaciclib is administered at a dose of 200 mg twice a day; abiraterone acetate is administered at a dose of 1000 mg once a day; and prednisone or prednisolone is administered at a dose of 5 mg once a day. In some preferred embodiments, abemaciclib is administered at a dose of 200 mg twice a day in a 28-day cycle; abiraterone acetate is administered at a dose of 1000 mg once a day in the 28-day cycle; and prednisone or prednisolone is administered at a dose of 5 mg once a day in the 28-day cycle.

[0023] In some preferred embodiments, abemaciclib is administered at a dose of 200 mg twice a day; abiraterone acetate (preferably micronized abiraterone acetate) is administered at a dose of 500 mg once a day; and methylprednisolone is administered at a dose of 4 mg twice a day. In some preferred embodiments, abemaciclib is administered at a dose of 200 mg twice a day in a 28-day cycle; abiraterone acetate (preferably micronized abiraterone acetate) is administered at a dose of 500 mg once a day in the 28-day cycle; and methylprednisolone is administered at a dose of 4 mg twice a day in the 28-day cycle.

[0024] Generally, and as one of ordinary skill in the art will appreciate, a CDK4 and 6 inhibitor in accordance with the aspects and embodiments of the disclosure may be prepared and administered as the inhibitor compound, or as a pharmaceutically acceptable salt thereof. In some embodiments, abemaciclib may be prepared and/or administered as the free base. In some other embodiments, abemaciclib may be prepared and/or administered as a pharmaceutically acceptable salt such as, for example, the hydrochloride or mesylate salt. In some embodiments, ribociclib may be prepared and/or administered as the free base. In some other embodiments, or ribociclib may be prepared and/or administered as a pharmaceutically acceptable salt such as, for example, ribociclib succinate. In some embodiments, palbociclib may be prepared and/or administered as the free base. In some other embodiments, palbociclib may be prepared and/or administered as a pharmaceutically acceptable salt such as, for example, the isethionate or the hydrochloride salt.

[0025] Generally, and as one of ordinary skill in the art will appreciate, abiraterone or abiraterone acetate may be prepared and administered as their free bases, or as a pharmaceutically acceptable salt thereof. For example, pharmaceutically acceptable salts of abiraterone acetate are disclosed in WO 2015/000451.

[0026] Generally, and as one of ordinary skill in the art will appreciate, prednisone, prednisolone, or methylprednisolone may be prepared and administered as their free bases, or as a pharmaceutically acceptable salt thereof. For example, pharmaceutically acceptable salts of prednisolone are disclosed in U.S. Pat. No. 8,637,076.

[0027] The formation of pharmaceutically acceptable salts is generally well known. See, for example, Gould, P. L., “Salt selection for basic drugs,” International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R. J., et al. “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4: 427- 435 (2000); and Berge, S. M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19, (1977).

[0028] In some preferred embodiments, the patient has >4 bone metastases. [0029] In some preferred embodiments, the patient has >1 visceral metastases.

[0030] In some preferred embodiments, the patient has de novo high-risk metastatic hormonesensitive prostate cancer.

[0031] In some preferred embodiments, the patient has recurrent high-risk metastatic hormonesensitive prostate cancer.

[0032] In some preferred embodiments, the patient has histologically confirmed adenocarcinoma of the prostate.

[0033] In some embodiments, the patient received one or more other therapeutic interventions (e.g., androgen deprivation therapy, first generation anti-androgens, or taxane therapy) for prostate cancer prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0034] In some embodiments, the patient received treatment with androgen deprivation therapy (ADT) prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the ADT included administration of a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist. In some embodiments, the LHRH agonist or antagonist was riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the ADT included bilateral orchiectomy.

[0035] In some embodiments, the patient received treatment with a taxane prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the taxane was docetaxel.

[0036] In some embodiments, the patient received treatment with androgen deprivation therapy (ADT) and taxane therapy (e.g., docetaxel) prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the ADT included administration of a luteinizing hormone- releasing hormone (LHRH) agonist or antagonist. In some embodiments, the LHRH agonist or antagonist was riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the ADT included bilateral orchiectomy.

[0037] In some embodiments, the patient received treatment with an anti-androgen prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the anti-androgen was bicalutamide, nilutamide, or flutamide.

[0038] The period of time the patient received the one or more other therapeutic interventions prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing, may be years, months, weeks, days, a single day. In some embodiments, the patient received three months or less of androgen deprivation therapy (when given without docetaxel) prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the patient received up to six cycles of docetaxel with androgen deprivation therapy prior to the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0039] The period of time between the end of the one or more other prior therapeutic interventions and the first administration of the combination therapy including (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing, may be years, months, weeks, days, a single day, or less than 24 hours.

[0040] In some embodiments, the patient receives treatment with ADT on one or more days of administration of the combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the patient receives concurrent treatment with a luteinizing horm one-releasing hormone (LHRH) agonist or antagonist during the combination therapy; or the patient has had bilateral orchiectomy. In some embodiments, the LHRH agonist or antagonist is riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.

[0041] In some embodiments, the administration of the combination therapy provided herein results in an increase in radiographic progression-free survival as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0042] In some embodiments, the administration of the combination therapy provided herein results in an increase in overall survival as compared to the administration of a combination of

(ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and

(iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0043] In some embodiments, the administration of the combination therapy provided herein results in an increase in clinical progression-free survival (cPFS) as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0044] In some embodiments, the administration of the combination therapy provided herein results in an increase in castration-resistant prostate cancer (CRPC)-free survival as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0045] In some embodiments, the administration of the combination therapy provided herein results in an increase in time to PSA progression as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0046] In some embodiments, the administration of the combination therapy provided herein results in an increase in time to initiation of new anticancer therapy as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0047] In some embodiments, the administration of the combination therapy provided herein results in an increase in time to symptomatic progression as compared to the administration of a combination of (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0048] Various aspects of the invention are set forth in the following numbered clauses.

[0049] Clause 1. A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0050] Clause 2. The method according to clause 1, wherein the CDK4 and 6 inhibitor is selected from abemaciclib, palbociclib, and riboci clib.

[0051] Clause 3. The method according to clause 1, wherein the CDK4 and 6 inhibitor is abemaciclib. [0052] Clause 4. The method according to clause 1, wherein the CDK4 and 6 inhibitor is palbociclib.

[0053] Clause 5. The method according to clause 1, wherein the CDK4 and 6 inhibitor is ribociclib.

[0054] Clause 6. The method according to clause 3, wherein abemaciclib is administered as a 50-200 mg oral dose twice daily.

[0055] Clause 7. The method according to clause 3, wherein abemaciclib is administered as a 50 mg oral dose twice daily.

[0056] Clause 8. The method according to clause 3, wherein abemaciclib is administered as a 100 mg oral dose twice daily.

[0057] Clause 9. The method according to clause 3, wherein abemaciclib is administered as a 150 mg oral dose twice daily.

[0058] Clause 10. The method according to clause 3, wherein abemaciclib is administered as a 200 mg oral dose twice daily.

[0059] Clause 11. The method according to any one of clauses 1-10, wherein abiraterone acetate is administered as a 500 mg oral dose once daily.

[0060] Clause 12. The method according to clause 11, wherein the abiraterone acetate is micronized abiraterone acetate.

[0061] Clause 13. The method according to any one of clauses 1-10, wherein abiraterone acetate is administered as a 1000 mg oral dose once daily.

[0062] Clause 14. The method according to any one of clauses 1-13, wherein prednisone or prednisolone is administered as a 5 mg oral dose once daily.

[0063] Clause 15. The method according to any one of clauses 1-13, wherein methylprednisolone is administered as a 4 mg oral dose twice daily.

[0064] Clause 16. The method according to clause 3, wherein abemaciclib is administered as a 50 mg oral dose twice daily on days 1-28 of a 28-day cycle.

[0065] Clause 17. The method according to clause 3, wherein abemaciclib is administered as a 100 mg oral dose twice daily on days 1-28 of a 28-day cycle.

[0066] Clause 18. The method according to clause 3, wherein abemaciclib is administered as a 150 mg oral dose twice daily on days 1-28 of a 28-day cycle. [0067] Clause 19. The method according to clause 3, wherein abemaciclib is administered as a 200 mg oral dose twice daily on days 1-28 of a 28-day cycle.

[0068] Clause 20. The method according to any one of clauses 16-19, wherein abiraterone acetate is administered as a 500 mg oral dose once daily on days 1-28 of the 28-day cycle. [0069] Clause 21. The method according to clause 20, wherein the abiraterone acetate is micronized abiraterone acetate.

[0070] Clause 22. The method according to any one of clauses 16-19, wherein abiraterone acetate is administered as a 1000 mg oral dose once daily on days 1-28 of the 28-day cycle. [0071] Clause 23. The method according to any one of clauses 16-22, wherein prednisone or prednisolone is administered as a 5 mg oral dose once daily on days 1-28 of the 28-day cycle.

[0072] Clause 24. The method according to any one of clauses 16-22, wherein methylprednisolone is administered as a 4 mg oral dose twice daily on days 1-28 of the 28-day cycle.

[0073] Clause 25. A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) abemaciclib; (ii) abiraterone acetate; and (iii) prednisone.

[0074] Clause 26. A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily; (ii) a 1000 mg oral dose of abiraterone acetate once daily; and (iii) a 5 mg oral dose of prednisone once daily.

[0075] Clause 27. A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily on days 1-28 of a 28-day cycle; (ii) a 1000 mg oral dose of abiraterone acetate once daily on days 1-28 of the 28-day cycle; and (iii) a 5 mg oral dose of prednisone once daily on days 1-28 of the 28-day cycle.

[0076] Clause 28. A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) abemaciclib; (ii) abiraterone acetate; and (iii) prednisolone.

[0077] Clause 29. A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily; (ii) a 1000 mg oral dose of abiraterone acetate once daily; and (iii) a 5 mg oral dose of prednisolone once daily.

[0078] Clause 30. A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily on days 1-28 of a 28-day cycle; (ii) a 1000 mg oral dose of abiraterone acetate once daily on days 1-28 of the 28-day cycle; and (iii) a 5 mg oral dose of prednisolone once daily on days 1-28 of the 28-day cycle.

[0079] Clause 31. A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) abemaciclib; (ii) abiraterone acetate; and (iii) methylprednisolone.

[0080] Clause 32. A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily; (ii) a 500 mg oral dose of micronized abiraterone acetate once daily; and (iii) a 4 mg oral dose of methylprednisolone twice daily.

[0081] Clause 33. A method of treating a patient with high-risk metastatic hormone-sensitive prostate cancer, the method comprising administering to the patient a combination of (i) a 200 mg oral dose of abemaciclib twice daily on days 1-28 of a 28-day cycle; (ii) a 500 mg oral dose of micronized abiraterone acetate once daily on days 1-28 of the 28-day cycle; and (iii) a 4 mg oral dose of methylprednisolone twice daily on days 1-28 of the 28-day cycle.

[0082] Clause 34. The method according to any one of clauses 1-33, wherein the patient has >4 bone metastases.

[0083] Clause 35. The method according to any one of clauses 1-34, wherein the patient has >1 visceral metastases.

[0084] Clause 36. The method according to any one of clauses 1-35, wherein the patient has recurrent high-risk metastatic hormone-sensitive prostate cancer.

[0085] Clause 37. The method according to any one of clauses 1-36, wherein the patient received treatment with androgen deprivation therapy (ADT) prior to the first administration of the combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0086] Clause 38. The method according to clause 37, wherein the ADT comprised administration of a luteinizing horm one-releasing hormone (LHRH) agonist or antagonist.

[0087] Clause 39. The method according to clause 38, wherein the LHRH agonist or antagonist was riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.

[0088] Clause 40. The method according to clause 37, wherein the ADT comprised bilateral orchiectomy.

[0089] Clause 41. The method according to any one of clauses 1-40, wherein the patient received treatment with a taxane prior to the first administration of the combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0090] Clause 42. The method according to clause 41, wherein the taxane was docetaxel.

[0091] Clause 43. The method according to any one of clauses 1-35, wherein the patient has de novo high-risk metastatic hormone-sensitive prostate cancer.

[0092] Clause 44. The method according to any one of clauses 1-43, wherein the patient receives treatment with ADT on one or more days of administration of the combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0093] Clause 45. The method according to clause 44, wherein the ADT comprises administration of a luteinizing horm one-releasing hormone (LHRH) agonist or antagonist.

[0094] Clause 46. The method according to clause 45, wherein the LHRH agonist or antagonist is riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.

[0095] Clause 47. The method according to any one of clauses 1-46, wherein the administration of the combination results in an increase in radiographic progression-free survival as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0096] Clause 48. The method according to any one of clauses 1-47, wherein the administration of the combination results in an increase in overall survival as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0097] Clause 49. The method according to any one of clauses 1-48, wherein the administration of the combination results in an increase in clinical progression-free survival (cPFS) as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0098] Clause 50. The method according to any one of clauses 1-49, wherein the administration of the combination results in an increase in castration-resistant prostate cancer (CRPC)-free survival as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0099] Clause 51. The method according to any one of clauses 1-50, wherein the administration of the combination results in an increase in time to PSA progression as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0100] Clause 52. The method according to any one of clauses 1-51, wherein the administration of the combination results in an increase in time to initiation of new anticancer therapy as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0101] Clause 53. The method according to any one of clauses 1-52, wherein the administration of the combination results in an increase in time to symptomatic progression as compared to administration of a combination of only (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. [0102] Clause 54. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing; in the treatment of a patient with high-risk metastatic hormone-sensitive prostate cancer.

[0103] Clause 55. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with (i) abiraterone acetate; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing; in the treatment of a patient with high-risk metastatic hormone-sensitive prostate cancer.

[0104] Clause 56. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with (i) abiraterone acetate; and (ii) prednisone; in the treatment of a patient with high-risk metastatic hormone-sensitive prostate cancer.

[0105] Clause 57. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with (i) abiraterone acetate; and (ii) prednisolone; in the treatment of a patient with high-risk metastatic hormone-sensitive prostate cancer.

[0106] Clause 58. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with (i) abiraterone acetate; and (ii) methylprednisolone; in the treatment of a patient with high-risk metastatic hormone-sensitive prostate cancer.

[0107] Clause 59. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of clauses 54 to 58, wherein the CDK4 and 6 inhibitor is selected from abemaciclib, palbociclib, and ribociclib.

[0108] Clause 60. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 59, wherein the CDK4 and 6 inhibitor is abemaciclib.

[0109] Clause 61. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 59, wherein the CDK4 and 6 inhibitor is palbociclib.

[0110] Clause 62. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 59, wherein the CDK4 and 6 inhibitor is ribociclib. [OHl] Clause 63. Abemaciclib for use in simultaneous, separate, or sequential combination with (i) abiraterone acetate; and (ii) prednisone; in the treatment of a patient with high-risk metastatic hormone-sensitive prostate cancer.

[0112] Clause 64. Abemaciclib for use in simultaneous, separate, or sequential combination with (i) abiraterone acetate; and (ii) prednisolone; in the treatment of a patient with high-risk metastatic hormone-sensitive prostate cancer.

[0113] Clause 65. Abemaciclib for use in simultaneous, separate, or sequential combination with (i) abiraterone acetate; and (ii) methylprednisolone; in the treatment of a patient with high- risk metastatic hormone-sensitive prostate cancer.

[0114] Clause 66. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 60 or Abemaciclib for use according to any one of clauses 63 to 65, wherein abemaciclib is administered as a 50-200 mg oral dose twice daily.

[0115] Clause 67. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 60 or Abemaciclib for use according to any one of clauses 63 to 65, wherein abemaciclib is administered as a 50 mg oral dose twice daily.

[0116] Clause 68. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 60 or Abemaciclib for use according to any one of clauses 63 to 65, wherein abemaciclib is administered as a 100 mg oral dose twice daily.

[0117] Clause 69. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 60 or Abemaciclib for use according to any one of clauses 63 to 65, wherein abemaciclib is administered as a 150 mg oral dose twice daily.

[0118] Clause 70. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 60 or Abemaciclib for use according to any one of clauses 63 to 65, wherein abemaciclib is administered as a 200 mg oral dose twice daily.

[0119] Clause 71. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of clauses 55 to 62 or Abemaciclib for use according to any one of clauses to 63 to 70, wherein abiraterone acetate is administered as a 500 mg oral dose once daily.

[0120] Clause 72. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 71, wherein abiraterone acetate is administered on days 1-28 of a 28-day cycle. [0121] Clause 73. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of clauses 55 to 62 or Abemaciclib for use according to any one of clauses to 63 to 70, wherein abiraterone acetate is administered as a 1000 mg oral dose once daily.

[0122] Clause 74. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 73, wherein abiraterone acetate is administered on days 1-28 of a 28-day cycle.

[0123] Clause 75. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 71 to 74, wherein abiraterone acetate is administered as micronized abiraterone acetate.

[0124] Clause 76. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 56 or Abemaciclib for use according to clause 63, wherein prednisone is administered as a 5 mg oral dose once daily.

[0125] Clause 77. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to 76, wherein prednisone is administered on days 1-28 of a 28- day cycle.

[0126] Clause 78. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 57 or Abemaciclib for use according to clause 64, wherein prednisolone is administered as a 5 mg oral dose once daily.

[0127] Clause 79. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 78, wherein prednisolone is administered on days 1-28 of a 28-day cycle.

[0128] Clause 80. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use according to clause 58 or Abemaciclib for use according to clause 65, wherein methylprednisolone is administered as a 4 mg oral dose twice daily.

[0129] Clause 81. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 80, wherein methylprednisolone is administered on days 1-28 of a 28-day cycle.

[0130] Clause 82. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 81, wherein the patient has >4 bone metastases. [0131] Clause 83. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or

Abemaciclib for use according to any one of clauses 54 to 82, wherein the patient has >1 visceral metastases.

[0132] Clause 84. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 83, wherein the patient has recurrent high-risk metastatic hormone-sensitive prostate cancer.

[0133] Clause 85. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for use or Abemaciclib for use according to any one of clauses 54 to 84, wherein the patient received treatment with androgen deprivation therapy (ADT) prior to the first administration of the simultaneous, separate, or sequential combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0134] Clause 86. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 85, wherein the ADT comprised administration of a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist.

[0135] Clause 87. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 86, wherein the LHRH agonist or antagonist was riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.

[0136] Clause 88. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 85, wherein the ADT comprised bilateral orchiectomy. [0137] Clause 89. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 88, wherein the patient received treatment with a taxane prior to the first administration of the simultaneous, separate, or sequential combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0138] Clause 90. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 89, wherein the taxane was docetaxel. [0139] Clause 91. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 83, wherein the patient has de novo high-risk metastatic hormone-sensitive prostate cancer.

[0140] Clause 92. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 91, wherein the patient receives treatment with ADT on one or more days of administration of the simultaneous, separate, or sequential combination of (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0141] Clause 93. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 92, wherein the ADT comprises administration of a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist.

[0142] Clause 94. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to clause 93, wherein the LHRH agonist or antagonist is riptorelin, deslorelin, nafarelin, histrelin, buserelin, goserelin, gonadorelin, leuprorelin, triptorelin, or degarelix, or a pharmaceutically acceptable salt of any of the foregoing.

[0143] Clause 95. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 94, wherein the treatment results in an increase in radiographic progression-free survival as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0144] Clause 96. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 95, wherein the treatment results in an increase in overall survival as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0145] Clause 97. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 96, wherein the treatment results in an increase in clinical progression-free survival (cPFS) as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0146] Clause 98. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 97, wherein the treatment results in an increase in castration-resistant prostate cancer (CRPC)-free survival as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0147] Clause 99. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 98, wherein the treatment results in an increase in time to PSA progression as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0148] Clause 100. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 99, wherein the treatment results in an increase in time to initiation of new anticancer therapy as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0149] Clause 101. A CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof or Abemaciclib for use according to any one of clauses 54 to 100, wherein the treatment results in an increase in time to symptomatic progression as compared to administration of a combination of only (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing; and (ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0150] Clause 102. The use of a CDK4 and 6 inhibitor in the manufacture of a medicament for the treatment of a patient with high-risk metastatic hormone-sensitive prostate cancer, wherein the medicament is to be administered in simultaneous, separate, or sequential combination with (i) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and

(ii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing.

[0151] As used herein, the term "patient" refers to an adult male, who has or is diagnosed with high-risk metastatic hormone-sensitive prostate cancer.

[0152] As used herein, the terms "cancer" and "cancerous" refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation.

[0153] As used herein, the term "effective amount" refers to the amount or dose of (i) a CDK4 and 6 inhibitor (such as e.g., abemaciclib, palbociclib, or ribociclib), or a pharmaceutically acceptable salt thereof, (ii) the amount or dose of abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) the amount or dose of prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing, which provides an effective response in the patient under treatment.

[0154] As used herein, the term "effective response" of a patient or a patient's "responsiveness" to treatment with a combination of agents refers to the clinical or therapeutic benefit imparted to a patient upon administration of (i) a CDK4 and 6 inhibitor (such as e.g., abemaciclib, palbociclib, or ribociclib) or a pharmaceutically acceptable salt thereof, (ii) abiraterone or abiraterone acetate, or a pharmaceutically acceptable salt of the foregoing, and (iii) prednisone, prednisolone, or methylprednisolone, or a pharmaceutically acceptable salt of the foregoing. For example, a measure of an effective response can include, but is not limited to, any one or more of progression free survival (PFS) (e.g., based on investigator assessment or blinded independent review (BICR)), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), duration of response (DoR), safety, patient-reported outcomes (PRO), pharmacokinetics (PK), or a best overall response (BOR) that may include complete response (CR), partial response (PR), or stable disease (SD). Accordingly, an effective response is not limited to curing, eliminating, or ameliorating the disease or the clinical symptoms associated with the disease.

[0155] As used herein, the term “radiographic progression-free survival” (rPFS) refers to the time from the date of randomization in the Study to the earliest date of investigator-assessed radiographic disease progression in soft tissue per Response Evaluation Criteria in Solid Tumors version 1.1 [(RECIST 1.1) Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009, 45(2):228-247)] or bone disease per adapted Prostate Cancer Clinical Trials Working Group 3 [(PCWG3) Journal of Clinical Oncology 34, no. 12 (April 20, 2016) 1402-1418], or death from any cause, whichever occurs first.

[0156] As used herein, the term “overall survival” (OS) refers to the time from the date of randomization in the Study to the date of death from any cause.

[0157] As used herein, the term “clinical progression-free survival” (cPFS) refers to the time from the date of randomization in the Study to the earliest date of investigator-assessed radiographic disease progression, symptomatic progression, or death from any cause, whichever occurs first.

[0158] As used herein, the term “castration-resistant prostate cancer (CRPC)-free survival” refers to the time from the date of randomization in the Study to the earliest date of castration resistance, as demonstrated by any of the following (whichever occurs earliest): confirmed PSA progression with serum testosterone <50 ng/dL (<1.73 nmol/L); investigator-assessed radiographic progression with serum testosterone <50 ng/dL (<1.73 nmol/L); or death from any cause.

[0159] As used herein, the term “time to symptomatic progression” refers to the time from randomization in the Study to any of the following (whichever occurs earlier): symptomatic skeletal event (SSE), defined as cancer-related symptomatic fracture, surgery or radiation to bone, or spinal cord compression; pain progression or worsening of disease-related symptoms requiring initiation of a new systemic anticancer therapy; or development of clinically significant symptoms due to loco-regional tumor progression requiring surgical intervention or radiation therapy.

[0160] As used herein, the term “time to PSA progression” refers to the time from the date of randomization in the Study to the date of first observation of prostate-specific antigen (PSA) progression. The PSA progression is defined as a >25% increase and an absolute increase of >2 ng/mL above the nadir (or baseline value if baseline is the lowest on study), which is confirmed by a second value obtained three or more weeks later. Any post-baseline PSA measurements within twelve weeks since baseline will be ignored in determining PSA progression. [0161] As used herein, the term “time to initiation of new anticancer therapy” refers to the time from randomization in the Study until the first initiation of a new anticancer therapy.

[0162] As used herein, the term "advanced" or "metastatic" means cancers that have spread to one or more parts of the body that were not the site of the original cancerous tissue.

[0163] As used herein, the term "treating", or "treatment", means the administration of a drug or drugs to a patient. The terms can also be used in connection with diminishing, inhibiting, reducing, arresting, or ameliorating the disease, or to delay the onset of the biological manifestation of disease progression.

[0164] As used herein, the term “high-risk” refers to the presence of >4 bone metastases or >1 visceral metastases.

[0165] As used herein, the term “bone metastases” refers to cancer that has spread to the bone (e.g., the ribs, pelvis, or spine), wherein the metastases originated from a primary cancer site (e.g., prostate).

[0166] As used herein, the term “visceral metastases” refers to cancer that has spread to the internal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the metastases originated from a primary cancer site (e.g., prostate).

[0167] As used herein, the term “de novo metastatic hormone-sensitive prostate cancer” refers to metastatic hormone-sensitive prostate cancer at initial diagnosis.

[0168] As used herein, the term “recurrent metastatic hormone-sensitive prostate cancer” or “relapsed metastatic hormone-sensitive prostate cancer” refers to prostate cancer that has reoccurred and metastasized after initial treatment.

[0169] The following Examples merely serve to illustrate various aspects and embodiments of the disclosure and should not be considered as limiting the scope of the disclosure.

[0170] Example 1. Randomized, Double-Blind, Placebo-Controlled Study of Abemaciclib in Combination with Abiraterone plus Prednisone in Men with High-Risk Metastatic Hormone-Sensitive Prostate Cancer (“The Study”)

[0171] As detailed below, a clinical trial is conducted as a multicenter, multinational, randomized, double-blind, placebo-controlled, Phase 3 study to assess the safety and efficacy of adding abemaciclib to abiraterone acetate plus prednisone in patients with high-risk mHSPC. Approximately 900 participants will be randomized in a 1 : 1 ratio. [0172] This study will enroll participants with prostate cancer that has spread to other parts of the body and expected to respond to treatments to lower testosterone, a condition referred to as metastatic hormone-sensitive prostate cancer (mHSPC). In addition, participants must have at least 1 of the 2 following high-risk features:

• Disease that has spread to the bones with evidence of 4 or more lesions.

• Disease that has spread to the viscera, which are the soft internal organs of the body (for example, the lungs, liver, and the organs of the digestive system).

[0173] Participants must have initiated ADT with LHRH agonist or antagonist or had bilateral orchiectomy prior to randomization. Up to 3 months of ADT prior to randomization is permitted with or without first-generation anti-androgen (for example, bicalutamide).

[0174] Participants who have not undergone bilateral orchiectomy are required to continue background ADT with an LHRH agonist or antagonist throughout the study.

[0175] Medical conditions, including but not limited to, inflammation of the lungs, cardiac arrhythmia, clinically significant cardiovascular disease, uncontrolled hypertension, chronic liver disease, adrenal dysfunction, or active systemic infections may preclude participation in the study.

[0176] The complete list of eligibility criteria is provided below.

Treatment Arms:

[0177] Abiraterone and prednisone (or prednisolone) :

[0178] All participants will receive therapy with abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally once daily, per the recommended standard posology in the mHSPC population. Prednisolone may be used in lieu of prednisone per local abiraterone prescribing information or where prednisone is not commercially available.

[0179] Blinded study drug:

• Experimental arm: Abemaciclib 200 mg orally twice daily.

• Control arm: Placebo 200 mg orally twice daily.

[0180] Abiraterone acetate, prednisone, and abemaciclib/placebo, will be initiated <7 days following randomization and administered on Days 1 through 28 of a 28-day cycle until disease progression, unacceptable toxicity, or other discontinuation criteria are met. [0181] Participants who have not undergone bilateral orchiectomy are required to continue background ADT with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist throughout the study.

[0182] Stratification:

[0183] Randomization will be stratified according to the following factors:

• de novo metastatic prostate cancer (metastatic disease at initial diagnosis) (Yes vs. No).

• visceral metastases (Yes vs. No).

[0184] These stratification criteria were selected because they represent important prognostic factors and/or an imbalance that may bias study results.

[0185] Primary endpoint:

[0186] The primary endpoint of the study is investigator-assessed radiographic progression- free survival (rPFS) or death from any cause, whichever occurs first.

[0187] Participants will be monitored throughout the study for safety and have procedures performed as outlined in the schedule of activities.

[0188] All participants discontinuing study treatment will enter the short- and long-term follow-up periods and have procedures performed as shown in the schedule of activities, except those lost to follow-up, the participant withdrew consent or died.

[0189] In addition, participants discontinuing treatment prior to documented radiographic progression will continue to have scheduled disease assessments until documented radiographic progression and will be followed for the development of symptomatic progression.

[0190] Participants discontinuing treatment due to documented radiographic progression will be followed for the development of symptomatic progression.

[0191] All patients will be followed for survival.

[0192] In addition to the primary endpoint of rPFS by investigator-assessed radiographic disease progression or death, rPFS by BICR will be assessed. A central radiology vendor will collect and store images for BICR review. Secondary efficacy endpoints include clinical progression-free survival (cPFS), castration-resistant prostate cancer (CRPC)-free survival, time to PSA progression, time to initiation of new anticancer therapy, time to symptomatic progression and overall survival (OS).

[0193] Objectives and Endpoints:

Abbreviations: AE = adverse event; ECG = electrocardiogram; EQ-5D-5L = European Quality of Life - 5 dimensions - 5 level; FACT-P = Functional Assessment of Cancer Therapy - Prostate; HRQoL - health-related quality of life; PK = pharmacokinetics; PSA = prostate-specific antigen; PCS = physical component summary; rPFS = radiographic progression-free survival; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

[0194] Inclusion Criteria:

1. Adult males (>18 years or age of majority per local regulation) willing and able to provide written informed consent and comply with study procedures.

2. Histologically confirmed predominant adenocarcinoma of the prostate. Well- differentiated neuroendocrine carcinoma, small cell or large cell neuroendocrine carcinoma, sarcomatoid, and carcinoid tumors are excluded.

3. High-risk metastatic hormone-sensitive prostate cancer documented on conventional imaging. High-risk is defined as:

>4 bone metastases by bone scan and/or

• >1 visceral metastasis (for example, liver, lung, adrenal) by CT or MRI. Local invasion (for example, bladder) or lymph node involvement does not qualify as visceral metastases. A previously irradiated visceral lesion as the sole site of disease can meet high-risk metastatic disease criteria provided there has been subsequent radiographic progression at that site.

4. Participants must have initiated ADT with LHRH agonist/antagonist or bilateral orchiectomy prior to randomization.

• Up to 3 months of ADT prior to randomization is permitted with or without first- generation anti-androgen (for example, bicalutamide). The start of ADT is the earliest date an LHRH agonist/antagonist was administered, or date of surgical castration.

• For participants receiving an LHRH agonist, first generation anti-androgens are allowed to continue for up to 2 weeks after Cycle 1 Day 1, all other use subsequent to Cycle 1 Day 1 is prohibited.

• Participants who have not undergone bilateral orchiectomy must continue the LHRH agonist/antagonist throughout the study.

5. For patients receiving bone-modifying agents (for example, bisphosphonates or denosumab) for management of bone metastasis, dose must be stable for at least 4 weeks prior to randomization. This does not apply to patients on osteoporosis dosing.

6. Have adequate organ function, as defined below:

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; G-CSF = granulocyte colonystimulating factor; LVEF = left ventricular ejection fraction; ULN = upper limit of normal. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.

8. Participants with female partners of childbearing potential must agree to use a condom along with another effective contraception during the study and for at least 3 weeks following the last dose of study treatment.

[0195] Exclusion Criteria:

[0196] Participants are excluded from the study if ANY of the following criteria apply:

1. Known or suspected contraindications or hypersensitivity to abiraterone, prednisone/prednisolone, or abemaciclib or to any of the excipients; inability to swallow oral medications or gastrointenstinal disorder affecting absorption.

2. Prior treatment with abemaciclib or any other CDK4 & 6 inhibitor.

3. Development of metastatic prostate cancer in the context of castrate levels of testosterone (e.g., <50 ng/dL; <1.73 nmol/L).

4. Received any prior systemic therapy for metastatic prostate cancer (including investigational agents), except for ADT and first-generation anti-androgen (see inclusion criterion 4).

5. Radiation therapy to treat the primary prostate tumor in the context of metastatic disease and/or radiation or surgery to all metastatic lesions. One course of palliative radiation or surgical therapy is permitted if it was administered at least 2 weeks prior to randomization.

6. Untreated spinal cord compression, spinal metastases with emergent risk of spinal cord compression, or structurally unstable bone lesions at high-risk for impending fracture.

7. Known untreated CNS metastases or any history of leptomeningeal disease. Screening of asymptomatic patients for CNS metastases is not required. Note: Patients with a history of treated brain metastases by either surgery or radiation therapy are eligible provided that disease is stable following treatment for at least 8 weeks prior to randomization and with no requirement for corticosteroids for at least 2 weeks prior to randomization

8. Serious preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).

9. Clinically significant cardiovascular disease as evidenced by myocardial infarction, arterial thrombotic events, and/or severe or unstable angina in the past 6 months, or New York Heart Association Class II to IV heart failure.

10. History of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Chronic and hemodynamically stable atrial arrhythmia well-controlled on medical therapy is permitted. Uncontrolled hypertension (systolic blood pressure [BP] >160 mmHg or diastolic BP >95 mmHg). Patients with a history of hypertension are allowed provided BP is controlled by anti-hypertensive treatment. Clinically active or chronic liver disease, moderate/severe hepatic impairment (Child- Pugh Class B and C), ascites, or bleeding disorders secondary to hepatic dysfunction. History of adrenal dysfunction. Had a major surgery within 2 weeks prior to randomization. All incisions must be healed or healing, aseptic and without signs or symptoms of infection. Prior or active concurrent malignancy (with the exception of non-melanomatous skin cancer). Patients with carcinoma in situ of any origin and patients with prior malignancies who are in remission and whose likelihood of recurrence is very low per investigator’s judgment are eligible for this study. The Lilly CRP/CRS will approve enrollment of patients with prior malignancies in remission before these patients are enrolled. Active systemic infections (for example, bacterial infection requiring intravenous [IV] antibiotics at time of initiating study treatment, fungal infection, or detectable viral infection requiring systemic therapy) or viral load (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]). Screening is not required for enrollment. Have received live vaccination < 4 weeks prior to randomization. Inactivated vaccines are permitted. Current enrollment in a clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study. Have participated in any clinical trial for which treatment assignment is still blinded. If patient has participated in a clinical study involving an investigational product, 3 months or 5 half-lives (whichever is shorter) should have passed prior to randomization. If a patient is currently enrolled in a clinical trial involving non-approved use of a device, then agreement with the investigator and the Lilly CRP/CRS is required to establish eligibility.