Combination Therapies for Treating Cancer

Abstract

The present disclosure includes methods, pharmaceutical compositions, and kits for treating prostate cancer in which AZD5305 and darolutamide are administered in combination to a subject in need thereof.

Description

[Technical field]

[0001] The present disclosure relates to methods of treating metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) and castration resistant prostate cancer (CRPC) in a patient in need of such treatment. [Background technology]

[0002] Prostate cancer is the second most common cancer in men. It is estimated that 375,304 people died in 2020 worldwide, and prostate cancer is the fifth leading cause of cancer deaths in men, accounting for 6.8% of all cancer deaths in men (Non-Patent Document 1).

[0003] Treatment of prostate cancer with androgen deprivation therapy (ADT), such as luteinizing hormone releasing hormone (LHRH) analogs or orchiectomy, is usually effective in initially controlling metastatic disease. However, patients inevitably progress from androgen to castration-resistant phenotype, which is associated with 90% of all mortality (Non-Patent Document 2).

[0004] Several recently approved new hormonal agents (NHAs) have significantly changed the treatment landscape for patients with metastatic castration-resistant prostate cancer (mCRPC), and NHAs are now considered the standard of care in both the mCRPC and metastatic hormone-sensitive prostate cancer (mHSPC) settings (Non-Patent Document 3, Non-Patent Document 4).

[0005] Both abiraterone acetate and enzalutamide in combination with ADT have demonstrated robust improvements in progression-free survival (PFS) and overall survival (OS) and have been shown to significantly extend the time to initiation of cytotoxic chemotherapy in patients with CRPC (Non-Patent Document 5, Non-Patent Document 6).

[0006] Furthermore, recent data have demonstrated the benefits of NHA in patients with mHSPC. Abiraterone acetate + prednisone with ADT further extended OS and delayed the initiation of chemotherapy and subsequent treatment, demonstrating significant survival benefits compared with ADT alone (Non-Patent Document 7). Enzalutamide + ADT not only significantly reduced the risk of radiological progression or death compared with placebo + ADT, but also reduced the risk of PSA progression, initiation of new antitumor therapy, first symptomatic skeletal-related events, castration resistance, and pain progression (Non-Patent Document 8).

[0007] A phase III trial is ongoing evaluating darolutamide in combination with standard ADT in patients with mHSPC (ARANOTE, NCT04736199).

[0008] The addition of olaparib (a PARP1 / PARP2 inhibitor) to abiraterone acetate plus ADT demonstrated improved radiological progression-free survival (rPFS) compared with abiraterone acetate alone for both men with mCRPC who had previously received docetaxel (Non-Patent Document 9) and men who had not received any prior systemic treatment lines, regardless of homologous recombination repair gene mutation (HRRm) status (Non-Patent Document 10).

[0009] Because enzalutamide is a strong CYP3A4 inducer (Non-Patent Document 11) and olaparib is a CYP3A4 substrate (Non-Patent Document 12), olaparib (a PARP1 / PARP2 inhibitor) is not expected to be used successfully in combination with enzalutamide; therefore, coadministration of enzalutamide and olaparib in multiple dose settings would significantly reduce patient exposure to olaparib.

[0010] Although many advances have been made in the treatment of metastatic prostate cancer, including metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC), hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC), many patients with such cancers live with incurable disease. Therefore, it is important to continue to find new treatments for patients with incurable cancers. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Sung 2021 [Non-Patent Document 2] Scher 2015 [Non-Patent Document 3] Mohler 2019 [Non-Patent Document 4] Parker 2020 [Non-Patent Document 5] Beer 2014 [Non-Patent Document 6] Ryan 2013 [Non-Patent Document 7] Fizazi 2019 [Non-Patent Document 8] Armstrong 2019 [Non-Patent Document 9] Clarke 2018 [Non-Patent Document 10] AstraZeneca Press Release 24 September 2021 [Non-Patent Document 11] Gibbons 2015 [Non-Patent Document 12] Dirix 2016 Summary of the Invention [Means for solving the problem]

[0012] In some embodiments, disclosed is a method of treating metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) or castration resistant prostate cancer (CRPC) in a subject in need thereof, comprising administering to the subject a first amount of AZD5305 or a pharma- ceutically acceptable salt thereof and a second amount of darolutamide or a pharma- ceutically acceptable salt thereof, wherein the first amount and the second amount together constitute a therapeutically effective amount.

[0013] In some embodiments, AZD5305, or a pharma- ceutically acceptable salt thereof, is disclosed for use in the treatment of metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC) in a subject, said treatment comprising separate, sequential or simultaneous administration to said subject of i) said AZD5305, or a pharma- ceutically acceptable salt thereof, and ii) darolutamide, or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, disclosed is darolutamide, or a pharma- ceutically acceptable salt thereof, for use in the treatment of metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC) in a subject, said treatment comprising separate, sequential or simultaneous administration to said subject of i) said darolutamide, or a pharma- ceutically acceptable salt thereof, and ii) AZD5305, or a pharma- ceutically acceptable salt thereof.

[0015] In some embodiments, disclosed is the use of AZD5305, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) or castration resistant prostate cancer (CRPC), wherein said treatment comprises separate, sequential or simultaneous administration to said subject of i) said medicament comprising AZD5305, or a pharmaceutically acceptable salt thereof, and ii) darolutamide, or a pharmaceutically acceptable salt thereof.

[0016] In the above embodiments, the metastatic prostate cancer may be metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC).

[0017] In some embodiments, a pharmaceutical agent is disclosed that comprises i) AZD5305, or a pharma- ceutically acceptable salt thereof, and ii) darolutamide, or a pharma- ceutically acceptable salt thereof.

[0018] In some embodiments, a kit is disclosed that includes a first pharmaceutical composition comprising AZD5305, or a pharma- ceutically acceptable salt thereof; a second pharmaceutical composition comprising darolutamide, or a pharma- ceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

[0019] The combination of AZD5305 and darolutamide may have fewer side effects or be more effective than current monotherapy or combination therapy. This may be due to AZD5305 being a selective PARP1 inhibitor. By "selective PARP1 inhibitor" is meant an inhibitor of the PARP enzyme that has greater selectivity for PARP1 than other members of the PARP family, such as PARP2, PARP3, PARP5a, and PARP6. In some embodiments, the selective PARP1 inhibitor has selectivity for PARP1 over PARP2. In some embodiments, the selective PARP1 inhibitor has selectivity for PARP1 over PARP2 that is greater than 5:1. In some embodiments, the selective PARP1 inhibitor has selectivity for PARP1 over PARP2 that is greater than 10:1. In some embodiments, the selective PARP1 inhibitor has selectivity for PARP1 over PARP2 that is greater than 100:1.

[0020] In some embodiments, disclosed is a method for treating metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) or castration resistant prostate cancer (CRPC) in a subject in need of such treatment, comprising administering to the subject a first amount of a selective PARP1 inhibitor (e.g., AZD5305), or a pharmaceutically acceptable salt thereof, and a second amount of darolutamide, or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together constitute a therapeutically effective amount.

[0021] In some embodiments, a selective PARP1 inhibitor (e.g., AZD5305), or a pharma- ceutically acceptable salt thereof, is disclosed for use in treating metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC) in a subject, wherein said treatment comprises separate, sequential or simultaneous administration to said subject of i) said selective PARP1 inhibitor (e.g., AZD5305), or a pharma- ceutically acceptable salt thereof, and ii) darolutamide, or a pharma- ceutically acceptable salt thereof.

[0022] In some embodiments, disclosed is darolutamide, or a pharma- ceutically acceptable salt thereof, for use in the treatment of metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC) in a subject, said treatment comprising separate, sequential or simultaneous administration to said subject of i) said darolutamide, or a pharma- ceutically acceptable salt thereof, and ii) a selective PARP1 inhibitor (e.g., AZD5305), or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The term "AZD5305" refers to a compound having the chemical name 5-{4-[(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide and the structure shown below: [ka]

[0024] AZD5305 is a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy. AZD5305 is highly selective for PARP1 over other PARP family members, has favorable secondary pharmacological and physicochemical properties and excellent pharmacokinetics in preclinical species, and has reduced effects on human bone marrow progenitor cells in vitro.

[0025] The synthesis of AZD5305 is described in Johannes 2021 and WO 2021 / 013735, the contents of which are incorporated herein by reference in their entireties. In some embodiments, the free base of AZD5305 is administered to the subject. In some embodiments, a pharma- ceutically acceptable salt of AZD5305 is administered to the subject. In some embodiments, crystalline AZD5305 or a pharma- ceutically acceptable salt of AZD5305 is administered to the subject.

[0026] The term "darolutamide" refers to the compound having the chemical name N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide and the structure shown below: [ka]

[0027] Darolutamide is an AR antagonist that specifically inhibits AR nuclear translocation. Darolutamide and its active metabolite (ORM-15341) inhibit wild-type AR and the clinically relevant AR mutations AR(F876L), which cause agonist switching of the enzalutamide and apalutamide antagonists, and AR(W742L) and AR(T877A), which cause agonist switching of the bicalutamide antagonists, respectively (Moilanen 2015). Darolutamide not only offers a promising reduction in brain penetrance with low potential for drug-drug interactions (Shore 2019), but also effectively inhibits all known AR mutations (Fizazi 2015). Darolutamide was approved by the FDA on July 30, 2019 for the treatment of non-metastatic CRPC based on results from the ARAMIS trial (NCT02200614) (Fizazi 2019), in which patients treated with darolutamide had a metastasis-free survival of 40.4 months compared with 18.5 months in patients treated with placebo.

[0028] The synthesis of darolutamide is described in International Publication No. WO 2011 / 051540, the contents of which are incorporated herein by reference in their entirety. In some embodiments, free base darolutamide is administered to the subject. In some embodiments, a pharma- ceutically acceptable salt of darolutamide is administered to the subject.

[0029] The phrase "pharmaceutical composition" includes compositions comprising an active ingredient and a pharma- ceutically acceptable excipient, carrier or diluent, where the active ingredient is AZD5305 or a pharma- ceutically acceptable salt thereof, or darolutamide or a pharma- ceutically acceptable salt thereof. The phrase "pharma- ceutically acceptable excipient, carrier or diluent" includes compounds, materials, compositions, and / or dosage forms that, as ascertained by one of ordinary skill in the art, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problems or complications. In some embodiments, the pharmaceutical composition is a solid dosage form, such as a capsule, tablet, granule, powder, or sachet. In some embodiments, the pharmaceutical composition may be in the form of a sterile injectable solution in one or more aqueous or non-aqueous, non-toxic parenterally acceptable buffer systems, diluents, solubilizers, cosolvents, or carriers. The sterile injectable preparation may be a sterile injectable aqueous or oily suspension or a suspension in a non-aqueous diluent, carrier or co-solvent, which may be formulated according to known procedures using one or more suitable dispersing or wetting agents and suspending agents. The pharmaceutical composition may be a lyophilized system (alone or with excipients) for reconstitution with a solution for iv bolus / infusion injection or a buffer system with or without other excipients. The lyophilized freeze-dried material may be prepared from a non-aqueous or aqueous solvent. The dosage form may also be a concentrate for further dilution for subsequent infusion.

[0030] The terms "treat", "treating" and "treatment" include the amelioration of PARP-1, AR or metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) or castration resistant prostate cancer (CRPC) in a subject, one or more symptoms of metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) or castration resistant prostate cancer (CRPC) in a subject, or the slowing or delaying of the progression of metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) or castration resistant prostate cancer (CRPC) in a subject. The terms "treat", "treating" and "treatment" also include the reduction or inhibition of tumor growth or proliferation of cancer cells in a subject.

[0031] The terms "inhibit," "inhibition," or "inhibiting" include a reduction in the baseline activity of a biological activity or process.

[0032] The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, such as a human. In some embodiments, the subject is afflicted with metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC), or castration-resistant prostate cancer (CRPC).

[0033] The phrase "therapeutically effective amount" includes an amount of AZD5305 and an amount of darolutamide that together induce a biological or medical response in a subject, such as reducing or inhibiting PARP1, AR, or cancer-related enzyme or protein activity; improving symptoms of metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC); or slowing or delaying the progression of metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC). In some embodiments, the phrase "therapeutically effective amount" includes an amount of AZD5305 and darolutamide combined that is effective to at least partially ameliorate, inhibit and / or ameliorate metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC), or inhibit PARP1 or AR, and / or reduce or inhibit tumor growth or cancerous cell proliferation in a subject.

[0034] In some embodiments, disclosed is a method of treating metastatic prostate cancer, hormone sensitive prostate cancer (HSPC) or castration resistant prostate cancer (CRPC) in a subject in need thereof, comprising administering to the subject a first amount of AZD5305 or a pharma- ceutically acceptable salt thereof and a second amount of darolutamide or a pharma- ceutically acceptable salt thereof, wherein the first amount and the second amount together constitute a therapeutically effective amount.

[0035] In some embodiments, AZD5305, or a pharma- ceutically acceptable salt thereof, is disclosed for use in the treatment of metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC) in a subject, said treatment comprising separate, sequential or simultaneous administration to said subject of i) said AZD5305, or a pharma- ceutically acceptable salt thereof, and ii) darolutamide, or a pharma- ceutically acceptable salt thereof.

[0036] In some embodiments, disclosed is darolutamide, or a pharma- ceutically acceptable salt thereof, for use in the treatment of metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC) in a subject, said treatment comprising separate, sequential or simultaneous administration to said subject of i) said darolutamide, or a pharma- ceutically acceptable salt thereof, and ii) AZD5305, or a pharma- ceutically acceptable salt thereof.

[0037] In some embodiments, disclosed is the use of AZD5305, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC) or castration-resistant prostate cancer (CRPC) in a subject, said treatment comprising separate, sequential or simultaneous administration to said subject of i) said medicament comprising AZD5305, or a pharma- ceutically acceptable salt thereof, and ii) darolutamide, or a pharma- ceutically acceptable salt thereof.

[0038] In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof and darolutamide or a pharmaceutically acceptable salt thereof are administered separately, sequentially or simultaneously in a treatment cycle. In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is administered continuously in a treatment cycle and darolutamide or a pharmaceutically acceptable salt thereof is also administered continuously in a treatment cycle.

[0039] The terms "continuous" or "sequentially" refer to the administration of a therapeutic agent, such as AZD5305, at regular intervals without stopping or interruption, i.e., without a void day. A "void day" refers to a day on which a therapeutic agent is not administered.

[0040] "Cycle", "treatment cycle" or "dosing schedule" as used herein refers to a period of combination treatment repeated on a regular schedule. For example, treatment may be for 1 week, 2 weeks, or 3 weeks, with AZD5305 and darolutamide administered in a coordinated manner. In some embodiments, the treatment cycle is from about 1 week to about 3 months. In some embodiments, the treatment cycle is from about 5 days to about 1 month. In some embodiments, the treatment cycle is from about 1 week to about 3 weeks. In some embodiments, the treatment cycle is from about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months.

[0041] In some embodiments, AZD5305 or a pharma- ceutically acceptable salt thereof and darolutamide or a pharma- ceutically acceptable salt thereof are administered to a human subject in one or more treatment cycles, e.g., a course of treatment. A "course of treatment" includes multiple treatment cycles, which may be repeated on a regular schedule or the schedule may be adjusted stepwise while monitoring the patient's disease progression. For example, a patient's treatment cycle may have a longer treatment period and / or a shorter rest period at the beginning of the treatment course (e.g., when the patient is first diagnosed), and when the cancer goes into remission, the length of one treatment cycle may be increased by increasing the rest period. The duration of treatment and rest in a treatment cycle, the number of treatment cycles, and the length of time of the treatment course may be determined and adjusted throughout the treatment course by one of skill in the art based on the patient's disease progression, treatment tolerance, and prognosis. In some embodiments, the method includes 1 to 10 treatment cycles. In some embodiments, the method includes 2 to 8 treatment cycles.

[0042] In some embodiments, AZD5305, or a pharma- ceutically acceptable salt thereof, is administered for 28 days in a 28 day treatment cycle, and darolutamide, or a pharma- ceutically acceptable salt thereof, is administered for 28 days in a 28 day treatment cycle.

[0043] In some embodiments, AZD5305 or a pharma- ceutically acceptable salt thereof is administered orally. In some embodiments, AZD5305 or a pharma- ceutically acceptable salt thereof is in tablet form. In some embodiments, AZD5305 is administered at a dose of up to about 60 mg per day (e.g., up to about 5 mg, up to about 10 mg, up to about 15 mg, up to about 20 mg, up to about 25 mg, up to about 30 mg, up to about 35 mg, up to about 40 mg, up to about 45 mg, up to about 50 mg, up to about 55 mg, or up to about 60 mg of AZD5305). In some embodiments, AZD5305 is administered once daily (QD). In some embodiments, AZD5305 is administered at a dose of about 10 mg QD, about 15 mg QD, about 20 mg QD, about 25 mg QD, about 30 mg QD, about 35 mg QD, about 40 mg QD, about 45 mg QD, about 50 mg QD, about 55 mg QD or about 60 mg QD.

[0044] In some further embodiments, AZD5305 is administered at a dose of up to about 140 mg per day (e.g., up to about 80 mg, up to about 90 mg, up to about 100 mg, up to about 110 mg, up to about 120 mg, or up to about 140 mg of AZD5305). In some further embodiments, AZD5305 is administered at a dose of about 80 mg QD, about 90 mg QD, about 100 mg QD, about 110 mg QD, about 120 mg QD, or about 140 mg QD.

[0045] In some embodiments, darolutamide or a pharma- ceutically acceptable salt thereof is orally administered. In some embodiments, darolutamide or a pharma- ceutically acceptable salt thereof is in tablet form. In some embodiments, darolutamide or a pharma- ceutically acceptable salt thereof is orally administered at a dose of about 600 mg twice per day (BID). In some embodiments, the 600 mg dose comprises two 300 mg tablets.

[0046] In some embodiments, AZD5305 and darolutamide are taken separately, where the dose of AZD5305 is taken on an empty stomach, without food 2 hours prior, and the dose of darolutamide is taken with food at least 1 hour after AZD5305.

[0047] In some embodiments, a pharmaceutical product is disclosed that includes i) AZD5305 or a pharma- ceutically acceptable salt thereof, and ii) darolutamide or a pharma- ceutically acceptable salt thereof. In some embodiments, AZD5305 or a pharma- ceutically acceptable salt thereof and darolutamide or a pharma- ceutically acceptable salt thereof are present in a single dosage form. In some embodiments, AZD5305 or a pharma- ceutically acceptable salt thereof and darolutamide or a pharma- ceutically acceptable salt thereof are present in separate dosage forms.

[0048] In some embodiments, a kit is disclosed that includes a first pharmaceutical composition comprising AZD5305, or a pharma- ceutically acceptable salt thereof; a second pharmaceutical composition comprising darolutamide, or a pharma- ceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

[0049] Metastatic prostate cancer refers to prostate cancer that has spread or metastasized to another part of the body.

[0050] Hormone sensitive prostate cancer (HSPC) refers to prostate cancer whose growth is inhibited by reducing androgen levels or blocking androgen action.

[0051] Castration-resistant prostate cancer (CRPC) refers to prostate cancer that continues to grow even when androgen levels in the body are very low or undetectable.

[0052] Metastatic hormone-sensitive prostate cancer (mHSPC) refers to prostate cancer that has spread or metastasized to another part of the body and whose growth is inhibited by reducing androgen levels or blocking androgen action.

[0053] Metastatic castration-resistant prostate cancer (mCRPC) refers to prostate cancer that has spread, or metastasized, to other parts of the body and continues to grow even when androgen levels in the body are very low or undetectable.

[0054] In some embodiments, especially if the patient has not undergone orchiectomy or subcapsular orchiectomy, treatment with a luteinizing hormone releasing hormone (LHRH) agonist or antagonist may be administered simultaneously. LHRH agonists include leuprolide / leuprorelin, goserelin, triptorelin, histrelin, and buserelin. LHRH antagonists include degarelix, relugolix, bicalutamide, flutamide, and cyproterone acetate. Such additional treatments may be administered with the current standard of care.

[0055] Without wishing to be bound by theory, the combination of AZD5305 and darolutamide may be beneficial because PARP1, in addition to its role in DNA repair, is a positive co-regulator of AR-driven gene expression of AR targets (Schiewer 2012; Schiewer and Knudsen 2014). As a result, AZD5305 should further inactivate the androgen receptor pathway and enhance the effects of darolutamide.

[0056] Furthermore, novel hormonal agents (NHA) have been shown to induce an HRR-deficient phenotype through inhibition of AR signaling (Asim 2017; Goodwin 2013; Li et al. 2017; Polkinghorn 2013; Tarish 2015). Homologous recombination repair gene transcript and protein levels were found to be upregulated in response to enhanced AR signaling in prostate cancer, and increased radioresistance was observed in the presence of functional AR signaling, whereas decreased HRR gene expression was seen in NHA-treated cells and tumor biopsies. As a result, without wishing to be bound by theory, induction of an HRR-deficient phenotype by NHA would result in increased sensitivity to AZD5305, a selective PARP-1 inhibitor.

[0057] In some embodiments, the prostate cancer to be treated may be deficient in homologous recombination (HR)-dependent DNA DSB repair activity. The HR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA through a homologous mechanism and re-forms a continuous DNA helix (Khanna and Jackson 2001). Components of the HR-dependent DNA DSB repair pathway include ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), These include, but are not limited to, RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE11A (NM_005590) and NBS1 (NM_002485). Other proteins involved in the HR-dependent DNA DSB repair pathway include regulators such as EMSY (Hughes-Davies 2003). HR components are also described in Wood 2001.

[0058] A prostate cancer that is deficient in HR-dependent DNA DSB repair may comprise or consist of one or more cancer cells that have a reduced or abolished ability to repair DNA DSBs through that repair pathway compared to normal cells, i.e., activity of the HR-dependent DNA DSB repair pathway may be reduced or abolished in one or more cancer cells.

[0059] The activity of one or more components of HR-dependent DNA DSB repair pathway may be lost in one or more prostate cancer cells of individuals with HR-dependent DNA DSB repair-deficient prostate cancer.The components of HR-dependent DNA DSB repair pathway are well characterized in the art (see, for example, Wood 2001), and include the components listed above.

[0060] In some embodiments, prostate cancer cells may have a BRCA1 and / or BRCA2 deficient phenotype, i.e., BRCA1 and / or BRCA2 activity is reduced or absent in the cancer cells. Prostate cancer cells with this phenotype may be BRCA1 and / or BRCA2 deficient, i.e., BRCA1 and / or BRCA2 expression and / or activity may be reduced or absent in the prostate cancer cells, for example, due to a mutation or polymorphism in the encoding nucleic acid or an amplification, mutation or polymorphism in a gene encoding a regulator (e.g., the EMSY gene encoding the BRCA2 regulator) (Hughes-Davies 2003).

[0061] BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Jasin 2002; Tutt 2002).

[0062] In some embodiments, the individual is heterozygous for one or more variations (e.g., mutations and polymorphisms) in BRCA1 and / or BRCA2, or their regulators. Detection of mutations in BRCA1 and BRCA2 is well known in the art and described, for example, in EP 699754; EP 705903; Neuhausen and Ostrander 1992; Chappuis and Foulkes 2002; Janatova et al., 2003; Jancarkova 2003. Determination of amplification of BRCA2 binding factor EMSY is described in Hughes-Davies 2003.

[0063] Cancer-associated mutations and polymorphisms can be detected at the nucleic acid level, by detecting the presence of variant nucleic acid sequences, or at the protein level, by detecting the presence of variant (i.e., mutant or allelic variant) polypeptides. EXAMPLES

[0064] The compounds of the present application will now be further described with reference to the following non-limiting examples.

[0065] Example 1. Efficacy of AZD5305 in combination with darolutamide in in vitro assays cell line The following cell lines were originally obtained from ATCC:

[0066] [Table 1]

[0067] Cell line identity was verified using the CellCheck assay (IDEXX Bioanalytics, Westbrook, ME, USA). All cell lines were verified to be free of viral mycoplasma contamination using the MycoSEQ assay (Thermo Fisher Scientific, Waltham, MA, USA) or the STAT-Myco assay (IDEXX Bioanalytics). All cell lines were grown in RPMI-1640 growth medium (Corning 17-105-CV) supplemented with 10% fetal bovine serum (FBS) or, where indicated, 10% charcoal-stripped FBS (ThermoFisher Scientific, 12676029) and 2 mM glutamine.

[0068] Cell proliferation assay and calculation of combination benefit Cells were dispensed in 384-well or 96-well plates using an Echo 555 (LabCyte, San Jose, CA, USA) or HP D300e Digital Dispenser (HP Life Science Dispensing), respectively. Viable cell numbers before and after treatment (day 7 after treatment) were determined using CellTiter-Glo according to the manufacturer's instructions (Promega, Madison, WI, USA; G7570).

[0069] Cell viability was determined using the Sytox Green assay as described in Davies 2012, and AC 50 The Highest Single Agent (HSA) synergy score was calculated according to Bernenbaum 1989.

[0070] result

[0071] [Table 2]

[0072] The potency of monotherapy is expressed as M concentration; values ​​are the mean of two independent experiments, each performed in triplicate. HSA (Highest Single Agent) is the synergy score mean of three independent experiments, each performed in triplicate. SD indicates standard deviation and does not indicate that only one experiment was performed.

[0073] These results indicate that the combination of AZD5305 and darolutamide showed synergistic effects in LnCAP, LnCAP 95 and CWR22Pc-R1-AD1 cell lines.

[0074] Example 2. Efficacy of AZD5305 in combination with darolutamide in in vivo preclinical models ST1273PDX models (tumor fragments of approximately 70 mg) were subcutaneously implanted into the flanks of athymic nude male mice (6–12 weeks old). Tumors were approximately 150–300 mm 3 Once this is reached, the 32 mice with the most similar tumor sizes will be randomly assigned to treatment groups as shown in the table below.

[0075] [Table 3]

[0076] Medication Formulation

[0077] [Table 4]

[0078] the study Mice are dosed for 28 days and dosages are calculated for individual animals on the day of dosing, with the dosage being 10 mg / kg.

[0079] Tumor measurements Tumors are measured twice weekly using digital calipers. The length and width of the tumor are measured and the volume is calculated using the following formula: Volume = (length x width 2 )π / 6.

[0080] body weight Body weights of all mice in the study were measured and recorded twice weekly; this information is used to calculate the exact dosage for each animal.

[0081] Example 3. Clinical Study of AZD5305 in Combination with Darolutamide to Treat mCRPC and mHSPC Selection Criteria Patients must have a histologically confirmed diagnosis of metastatic prostate cancer. Candidates for treatment with darolutamide who have current evidence of metastatic prostate cancer, where metastatic status is defined as at least one metastatic lesion documented on either a bone scan or CT / MRI scan. · Surgically or medically castrated and have a serum testosterone level ≤ 50 ng / dL (≤ 1.75 nmol / L) within 28 days (≤) of the first dose of study treatment. Continuous ADT with GnRH agonists or antagonists for patients who have not undergone bilateral orchiectomy must be initiated at least 2 weeks prior to enrollment and must be continued throughout the study. Patients must have one of the following: (a) Metastatic castration-resistant prostate cancer. Patients with mCRPC must have documented prostate cancer progression at screening as assessed by the investigator using at least one of the following: (i) PSA (prostate-specific antigen) progression is defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the screening visit should be ≥ 1 μg / L (1 ng / mL). (ii) radiological progression of soft tissue disease by RECIST criteria with or without PSA progression. (iii) radiological progression of bone metastases with two or more documented new bone lesions on bone scan with or without PSA progression. Patients with mCRPC should be either first-line or second-line in the castration-resistant setting (they should have received ≤1 line of systemic therapy previously). Androgen suppression therapy does not count as a line of treatment. Docetaxel, previously used when the patient was in the hormone-sensitive stage of their disease, does not count as a line of treatment. or (b) Metastatic hormone-sensitive prostate cancer. For patients with mHSPC, the following prior therapies are permitted: (i) Prior treatment with estrogen, cyproterone acetate, or first-generation antiandrogen is permitted as long as treatment was discontinued 3 weeks or 5 half-lives (whichever is shorter) prior to enrollment. (ii) ADT of ≤6 months prior to enrollment is permitted. Androgen deprivation therapy treatment should remain on study. (iii) Patients may have undergone disease-related radiation or surgery; this should have been completed at least 4 weeks prior to enrollment. Adequate organ and bone marrow function (without transfusion or growth factor support within 14 days prior to enrollment), as defined below:

[0082] [Table 5]

[0083] Darolutamide and AZD5305 dose escalation The starting dose of AZD5305 is 60 mg once daily (QD). Darolutamide will be dosed at 600 mg twice daily (BID) starting on Day 1 of Cycle 1 with the combination of AZD5305 and darolutamide.

[0084] In this study, the cycle length is 28 days, AZD5305 is administered once daily and darolutamide is administered twice daily at 600 mg. AZD5305 will be taken on an empty stomach with no food taken 2 hours and 1 hour later, and darolutamide will be taken with food at least 1 hour after the daily dose of AZD5305. The 600 mg dose of darolutamide will be two 300 mg film-coated tablets.

[0085] If a starting dose of AZD5305 of 60 mg QD is tolerated, the dose may be titrated to 90 mg QD as needed (while the darolutamide dose is maintained at 600 mg BD), and if not tolerated, the AZD5305 dose will be tapered to 40 mg QD.

[0086] The dose of AZD5305 may be further escalated up to a maximum of 140 mg QD.

[0087] The dose of AZD5305 may be reduced to 20 mg QD due to tolerability or if such a dose is shown to be effective.

[0088] All potential dose escalation and / or dose de-escalation levels after the starting dose (including consideration of intermediate dose levels and alternative schedules of AZD5305) may be adjusted in light of new safety, tolerability and / or PK data.

[0089] References A number of publications have been cited above in order to more fully describe and disclose the present invention and the prior art to which it pertains. Full citations for these references are set forth below. Each of these references is incorporated herein in its entirety.

[0090] [Table 6]

Table 7

Table 8

Claims

1. A pharmaceutical product for use in the treatment of metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC), or castration-resistant prostate cancer (CRPC) in a subject, comprising AZD5305 or a pharmaceutically acceptable salt thereof, wherein the treatment comprises the separate, sequential, or concurrent administration to the subject of: i) AZD5305 or a pharmaceutically acceptable salt thereof; and ii) darolutamide or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical product according to claim 1, wherein the metastatic prostate cancer is metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC).

3. The pharmaceutical product according to claim 1 or claim 2, wherein AZD5305 is administered once daily.

4. The pharmaceutical product according to claim 3, wherein AZD5305 is administered in a dose of up to approximately 60 mg per day.

5. The pharmaceutical product according to claim 4, wherein AZD5305 is administered at a dose of 60 mg per day.

6. The pharmaceutical product according to claim 1 or claim 2, wherein darolutamide or a pharmaceutically acceptable salt thereof is administered twice daily.

7. The pharmacopoeia according to claim 6, wherein darolutamide or a pharmaceutically acceptable salt thereof is administered twice daily in a dose of 600 mg.

8. The pharmacopoeia according to claim 1 or claim 2, wherein AZD5305 and darolutamide are administered separately, wherein the dose of AZD5305 is taken on an empty stomach, without food intake two hours prior, and the dose of darolutamide is taken with food at least one hour after the dose of AZD5305.

9. A pharmaceutical product for use in the treatment of metastatic prostate cancer, hormone-sensitive prostate cancer (HSPC), or castration-resistant prostate cancer (CRPC) in a subject, comprising darolutamide or a pharmaceutically acceptable salt thereof, wherein the treatment comprises the separate, sequential, or simultaneous administration to the subject of: i) darolutamide or a pharmaceutically acceptable salt thereof; and ii) AZD5305 or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical product according to claim 9, wherein the metastatic prostate cancer is metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC).

11. The pharmaceutical product according to claim 9 or claim 10, wherein AZD5305 is administered once daily.

12. The pharmaceutical product according to claim 11, wherein AZD5305 is administered in a dose of up to approximately 60 mg per day.

13. The pharmaceutical product according to claim 12, wherein AZD5305 is administered at a dose of 60 mg per day.

14. i) a pharmaceutical product comprising AZD5305 or a pharmaceutically acceptable salt thereof, and ii) darolutamide or a pharmaceutically acceptable salt thereof.

15. A kit comprising: a first pharmaceutical composition containing AZD5305 or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition containing darolutamide or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.