PLK1 Inhibitor and PSA Level in Prostate Cancer

Abstract

A method is provided that includes recommending treatment of a prostate cancer patient with a polo-like kinase 1 (PLK1) inhibitor if the patient has an elevated prostate-specific antigen (PSA) level. Also provided is a method that includes measuring the prostate-specific antigen (PSA) levels of at least two samples obtained from the prostate cancer patient at different times; and recommending treatment of the patient with a PLK1 inhibitor if the PSA levels of the samples increase over time, or not recommending treatment of the patient with a PLK1 inhibitor if the PSA levels of the samples do not increase over time. Further provided is a method that includes recommending treatment with a PLK1 inhibitor to a patient with prostate cancer that has a modified androgen receptor that does not require a ligand for activation.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 825,634, filed Mar. 28, 2019, and U.S. Provisional Application No. 62 / 890,209, filed Aug. 22, 2019, which are hereby incorporated herein by reference in their entireties.

[0002] Background of the Invention (1) Field of the Invention This application generally relates to the treatment of prostate cancer. More particularly, this application relates to the treatment of prostate cancer with a PLK1 inhibitor to stabilize the PSA levels in patients treated with anti - androgen drugs or androgen antagonists.

Background Art

[0003] (2) Description of Related Art Metastatic Castration - Resistant Prostate Cancer Prostate cancer (PCa) is the second most frequently diagnosed cancer among men and the fifth most common cause of cancer death, resulting in an estimated 300,000 deaths worldwide in 2012 [WHO, 2014]. Most men with metastatic prostate cancer initially respond to the historical standard treatment, androgen deprivation therapy, but resistance inevitably develops after several months to years, which is known as metastatic castration-resistant prostate cancer (mCRPC). Resistance may be mediated by persistent adrenal androgen production, upregulation of intratumoral testosterone production, changes in the biological properties of the androgen receptor, and reactivation of androgen receptor signaling via steroidogenesis parallel pathways [Yamaoka et al., 2010; Sharp et al., 2019; Armstrong and Lao, 2018; Cao et al., 2016; Vlachostergios et al., 2017; Wadosky and Koochekpour, 2017]. Despite the availability of multiple hormonal and non-hormonal agents, the survival period after mCRPC diagnosis remains limited. Furthermore, biomarker-based targeted approaches have only recently emerged in this setting [Mateo et al., 2015].

[0004] Abiraterone acetate is a prodrug of abiraterone. It targets cytochrome P-450c17, an enzyme that has a significant meaning in androgen biosynthesis. The active D4A metabolite inhibits multiple steroidogenic enzymes and antagonizes the androgen receptor [Li, et al., 2015]. Large-scale randomized trials have demonstrated an overall survival benefit with abiraterone for mCRPC before [de Bono et al., 2011; Fizazi et al., 2012] or after [Ryan et al., 2013] docetaxel therapy. It is in a Phase 3 trial but may also be effective in the neoadjuvant setting for localized PCa [Taplin et al., 2014]. Finally, two recent studies have demonstrated a life-prolonging effect of early use of abiraterone in metastatic castration-sensitive prostate cancer (mCSPC), in contrast to its use as a second-line therapy for castration-resistant prostate cancer [Taplin et al., 2014; Fizazi et al., 2017]. Therefore, the standard of care has been changed to include first-line use of abiraterone, recently in combination with androgen deprivation therapy.

[0005] Abiraterone is clearly effective for both mCSPC and mCRPC, yet patients will inevitably develop resistance. Furthermore, the effectiveness of subsequent hormonal measures after abiraterone is often limited [de Bono and Spears, 2017]. Therefore, abiraterone-resistant PCa remains a major clinical challenge. As abiraterone is increasingly used in the first-line setting, an increasing patient population will ultimately experience secondary disease progression that is resistant to further hormonal treatment [Fizazi et al., 2017]. At present, only docetaxel, cabazitaxel, and radium-223 have shown a survival benefit of several months over control therapies in trials [Chi et al., 2017; Tannock et al., 2004; Petrylak et al., 2004; de Bono et al., 2010]; the median overall survival of all trials was limited to less than 2 years. The benefit may be even more limited in the modern patient population that has utilized abiraterone and androgen receptor antagonists such as enzalutamide. Clearly, new and better treatment options for PCa are urgently needed.

[0006] Polo-like kinase 1 Polo-like kinase 1 (PLK1) is the best-characterized member of a family of five serine / threonine protein kinases and potently promotes cell progression by mitosis. PLK1 plays several important functions throughout the mitotic (M) phase of the cell cycle, including control of centrosome maturation and spindle formation, removal of cohesin from chromosome arms, inactivation of the anaphase-promoting complex / cyclosome inhibitor, and control of mitotic arrest and cytokinesis [Parker et al., 2013]. During various stages of mitosis, PLK1 localizes to the centrosome, kinetochore, and central spindle.

[0007] PLK1 is widely expressed in normal proliferative tissues and is overexpressed in a variety of human tumors, including lung cancer, colon cancer, prostate cancer, ovarian cancer, breast cancer, head and neck squamous cell carcinoma [Wolf et al., 1997; Weichert et al., 2004(a), 2004(b), 2005(a), 2005(b); Knect et al., 1999], and hematological malignancies [Renner et al., 2009; Mito et al., 2005; Ikezoe et al., 2009]. Furthermore, several studies have shown that this overexpression is correlated with poor prognosis. For example, in head and neck squamous cell carcinoma, the 5-year survival rate of patients with tumors overexpressing PLK1 decreases from 43% to 12% in patients with medium expression levels compared to high expression levels [Knect et al., 1999]. Furthermore, PLK1 is not expressed in differentiated post-mitotic cells such as neurons, in which the expression of PLK2 and PLK3 is detected instead [Kauselmann et al., 1999]. Therefore, since PLK1-selective inhibitors do not act on tubulin present in non-proliferative tissues (e.g., neurons), PLK1-selective inhibitors may be advantageous compared to classical mitotic inhibitors such as taxanes or vinca alkaloids that cause serious side effects such as neuropathy [Jackson et al., 2007]. These properties make PLK1 a very attractive new target for cancer therapy [Strebhardt and Ullrich, 2006].

[0008] Onvansertib

Chemical formula

[0009] Onbanseertib (PCM-075, NMS-1286937, NMS-937, also known as the "compound of formula (I)" in U.S. Patent 8,927,530; IUPAC name 1-(2-hydroxyethyl)-8-{[5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide) is the first orally administered PLK1-specific adenosine triphosphate-competitive inhibitor to enter clinical trials with anti-tumor activity demonstrated in various preclinical models [Weiss et al., 2017]. This compound exhibits high potency in proliferation assays with low nanomolar activity against a large number of cell lines from both solid tumors and hematological malignancies. Onbanseertib strongly induces apoptosis after mitotic cell cycle arrest in cancer cell lines and suppresses xenograft tumor growth by an apparent PLK1-related mechanism of action at well-tolerated doses in mice after oral administration. Onbanseertib not only has favorable pharmacological parameters and good oral bioavailability in rodent and non-rodent species, but also has anti-tumor activity demonstrated in various non-clinical models with various dosing regimens, allowing for a high degree of flexibility in dosing schedules and potentially warranting clinical trials in a clinical setting.

[0010] The main metabolic pathways seen in various animal species are N-oxidation of the N-methyl-piperazine ring to give the N-oxide M2 and hydroxylation on the aliphatic carbon atom of the methylene bridge of the pyrazoloquinazoline moiety to give the metabolite M1. Qualitatively, no significant interspecies differences were observed in the metabolism of onbanseertib, and quantitatively, some differences were observed between species. Onbansevtib has been preclinically evaluated not only with more than 10 different chemotherapeutic drugs including cisplatin, cytarabine, doxorubicin, gemcitabine, and paclitaxel, but also in combination with targeted therapies such as abiraterone, HDAC inhibitors, FLT3 inhibitors, and bortezomib. These therapeutic agents are clinically used for the treatment of many hematological and solid cancers including acute myeloid leukemia, non-Hodgkin lymphoma, metastatic castration-resistant prostate cancer, adrenocortical carcinoma, triple-negative breast cancer, small cell lung cancer, and ovarian cancer.

[0011] A Phase 1 safety study of onbansevtib was conducted in adult patients with progressive / metastatic solid tumors at a single study site in the United States [Weiss et al., 2017]. The primary objective was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the first cycle of onbansevtib administered orally for 5 consecutive days every 3 weeks (i.e., a 21-day treatment cycle). The second objective was to determine the safety profile of onbansevtib, determine the pharmacokinetics (PK) of onbansevtib in plasma (at the MTD), and record any antitumor activity. A total of 21 patients were registered and 19 patients were treated. No DLT occurred at the first 3 dose levels (6, 12, and 24 mg / m 2 / day). At the subsequent dose level (48 mg / m 2 / day), DLT occurred in 2 out of 3 patients. Therefore, an intermediate level of 36 mg / m 2 / day was investigated. Four patients were treated and DLT was observed in 2 patients. After further expansion of the cohort, the MTD was determined to be 24 mg / m 2 / day. The most frequently observed treatment response was disease stabilization that occurred in 5 out of 16 evaluable patients. One of the 16 evaluable patients had prostate cancer and the disease was progressing. This study revealed thrombocytopenia and neutropenia as the main toxicities consistent with the expected mechanism of action of onbansevtib and the results of preclinical studies. These hematological toxicities were reversible and usually recovered within 3 weeks.

[0012] There are urgent unmet medical needs for patients with prostate cancer, especially those with mCRPC. PLK1 is one of the most upregulated pathways in castration-resistant prostate cancer [Li et al., 2015]. Deletion of the phosphatase and tensin homolog (PTEN) tumor suppressor, which is deleted on chromosome 10, is a driver of most advanced prostate cancers but causes mitotic stress. Inactivation of PTEN correlates with overexpression of PLK1 and has important implications for PTEN-deleted cells to adapt to mitotic stress [Liu et al., 2011]. The mechanism may be the result of the regulatory effect of nuclear PTEN on the E3 ubiquitin ligase anaphase-promoting complex / cyclosome APC-Cdh1, which ubiquitinates and degrades PLK1 [Song et al., 2011]. PLK1 confers tumorigenic competence on PTEN-deleted prostate cancer cells in a mouse xenograft model, and inhibition by a PLK1 kinase inhibitor or siRNA preferentially suppresses tumor growth of PTEN-deleted cells [Liu et al., 2011]. Preclinical evidence from both in-vitro and in-vivo studies indicates that PLK1 inhibition may enhance the efficacy of abiraterone in PCa [Zhang et al., 2014; Zhang et al., 2015]. Multiple mechanisms have been proposed for the observed synergistic effect of abiraterone in addition to PLK1 inhibition. Liu and co-workers observed that oxidative stress activates the PI3K-AKT-mTOR pathway and androgen receptor (AR) signaling in a PLK1-dependent manner in prostate cancer cells. Furthermore, Plk1 inhibition downregulated SREBP-dependent expression of enzymes involved in androgen biosynthesis. Finally, PLK1 inhibition enhanced the cellular response to abiraterone and overcame abiraterone resistance in cultured PCa cells and patient-derived tumor xenografts [Zhang et al., 2014; Zhang et al., 2015]. SUMMARY OF THE INVENTION

[0013] SUMMARY OF THE INVENTION Provided is a method including recommending treatment of a patient with a polo-like kinase 1 (PLK1) inhibitor when the patient with prostate cancer has rising prostate-specific antigen (PSA) levels. Measuring prostate-specific antigen (PSA) levels of at least two samples obtained from a patient with prostate cancer at different times; and When the PSA level of the sample rises over time, recommending treatment of the patient with a PLK1 inhibitor, or When the PSA level of the sample does not rise over time, not recommending treatment of the patient with a PLK1 inhibitor also provided is a method including the above. Further provided is a method including recommending treatment of a patient having prostate cancer with an AR-V7 androgen receptor with a PLK1 inhibitor.

Brief Description of the Drawings

[0014]

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[0015] Detailed Description of the Invention The present invention is based on the discovery that a PLK1 inhibitor, particularly onvansertib, can stabilize the prostate-specific antigen (PSA) levels in patients being treated with an anti-androgen or androgen antagonist (see the following examples) and patients having cancer with a mutant androgen receptor that does not require a ligand for activation. Accordingly, provided is a method comprising recommending treatment of a patient with a polo-like kinase 1 (PLK1) inhibitor when the prostate cancer patient has elevated prostate-specific antigen (PSA) levels. In some embodiments, the patient is also treated with a PLK1 inhibitor. Measuring the prostate-specific antigen (PSA) levels of at least two samples obtained from a prostate cancer patient at different times; and Also provided is a method comprising recommending treatment of the patient with a PLK1 inhibitor when the PSA level of the sample increases over time, or not recommending treatment of the patient with a PLK1 inhibitor when the PSA level of the sample does not increase over time. Some embodiments of these methods further comprise treating the patient with a PLK1 inhibitor when the PSA level of the sample increases over time and not treating the patient with a PLK1 inhibitor when the PSA level of the sample does not increase over time. In some of these embodiments, the patient is treated with a PLK1 inhibitor. Furthermore, provided is a method comprising recommending treatment of a patient having prostate cancer with a mutant androgen receptor that does not require a ligand for activation with a PLK1 inhibitor. In some of these embodiments, the patient is treated with a PLK1 inhibitor. Further provided are methods comprising recommending treatment with a PLK1 inhibitor to a prostate cancer patient being treated with an androgen antagonist and having elevated PSA levels. In some of these embodiments, treatment with abiraterone in combination with a PLK1 inhibitor is recommended. In other embodiments, treatment with an androgen antagonist is discontinued and the patient begins treatment with a PLK1 inhibitor and, optionally, abiraterone.

[0016] In these inventive methods, elevated PSA levels can be measured in any suitable manner. PSA is currently generally measured in the blood, but the present invention is not limited to elevated PSA levels in the tissue or body fluid of any individual patient. See, for example, Seratec 2011. The PSA test is not used to diagnose or limit prostate cancer, but can be supplemented by other tests used to evaluate the characteristics of prostate cancer, including biopsy and histological examination, PET / CT, PCA3 mRNA, quantification of circulating tumor cells, or any other test currently known or later discovered. See, for example, Szeliski et al., 2018. An elevated PSA level can be determined by assessing whether there is an increase in the PSA level from an earlier patient sample to a later patient sample from two or more patient samples taken at different times. In some embodiments, an elevated PSA level is determined by two elevated PSA values taken at different times separated by a time period of one month or less, such as one day, three days, five days, one week, two weeks, three weeks, four weeks, or any intermediate length of time interval. In various embodiments, the evaluation from two or more samples of the PSA level increase also includes at least one confirmatory PSA quantification in which the elevated PSA level does not show a decrease. The amount of increase in PSA level between at least two temporally separated samples necessary to establish that the PSA level is increasing can be any suitable amount, for example, 0.1 ng / mL, 0.2 ng / mL, 0.3 ng / mL, 0.5 ng / mL, 1.0 ng / mL, 3 ng / mL, 5 ng / mL, 10 ng / ml, or any value in between. In certain embodiments, the rising PSA levels are two rising PSA values separated by at least one week, one showing an increase of at least 0.3 ng / mL and one being a confirmatory value showing no decrease.

[0017] The efficacy of PLK1 inhibitor treatment in any patient can be determined by any suitable method, for example, by any of the prostate cancer tests described above. In some embodiments, the efficacy of PLK1 treatment can be determined by utilizing the stabilization of the PSA level that is expected to increase without PLK1 treatment. In some of those embodiments, effective PLK1 inhibitor treatment maintains the PSA level at less than 50%, or less than 40%, or less than 30%, or less than 25%, or less than 20%, or less than 15% or less than 10% or less than 5% or less than 0%, or less than -10%, or less than -50%, or any lower or intermediate percentage above the PSA level at the start of PLK1 inhibitor treatment. In some embodiments, with or without prednisone, the patient has rising PSA levels while being treated with an anti-androgen or androgen antagonist. These embodiments are not limited to any particular anti-androgen or androgen antagonist. In some of these embodiments, the anti-androgen or androgen antagonist is abiraterone, TOK-001, ARN 509, enzalutamide, apalutibide, darolutamide, or any combination thereof.

[0018] PLK1 inhibitor treatment can be achieved alone or in combination with any other treatment. This other treatment is administered before, after, or concurrently with PLK1 inhibitor treatment. In addition to, or instead of, anti-androgen drugs, androgen antagonists, and / or prednisone treatment, a patient can be treated with, for example, any other chemotherapeutic agent, radiation, etc. The inventive method encompasses the use of any PLK1 inhibitor known currently or discovered later. In some embodiments, the PLK1 inhibitor has a significant specificity for PLK1 compared to other kinases. In some of these embodiments, the PLK1 inhibitor has a significant specificity for PLK1 compared to other polo-like kinases, such as PLK2 and PLK3. In some embodiments, the PLK1 inhibitor is a dihydropteridinone, pyridopyrimidine, aminopyrimidine, substituted thiazolidinone, pteridine derivative, dihydroimidazo[1,5-f]pteridine, meta-substituted thiazolidinone, benzylstyryl sulfone analog, stilbene derivative, or any combination thereof. In some of these embodiments, the PLK1 inhibitor is volasertib, BI2536, borasertib (BI 6727), GSK461364, AZD1775, CYC140, HMN-176, HMN-214, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960, or Ro3280. In certain embodiments, the PLK1 inhibitor is volasertib. In these embodiments, volasertib is administered to the patient at any suitable dosage, for example, 12 mg / m 2 less than, 24 mg / m 2 below, or 24 mg / m 2 above dosage.

[0019] These methods encompass any PLK1 inhibitor dosing schedule. In some of these embodiments, the PLK1 inhibitor is administered daily to the patient. Other non-limiting examples of dosing schedules within the scope of the methods provided herein include the following dosing schedules: the PLK1 inhibitor is administered to the patient in multiple dosing cycles where the dosing cycle during which no PLK1 inhibitor is administered is 9 days or less, 7 days or less, or 5 days or less (see the discussion shown in Example 2 and Figure 2, indicating that more than 9 days after treatment with onvansertib, no appreciable amount of onvansertib is present); the PLK1 inhibitor is administered in multiple cycles of daily dosing for 1 - 10 days and non-dosing for 5 - 16 days; the PLK1 inhibitor is administered in multiple cycles of daily dosing for 3 - 7 days and non-dosing for 10 - 16 days; the PLK1 inhibitor is administered in multiple cycles of daily dosing for 4 - 6 days and non-dosing for 10 - 16 days; the PLK1 inhibitor is administered in multiple cycles of daily dosing for 5 days and non-dosing for 10 - 16 days; the PLK1 inhibitor is administered in multiple cycles of daily dosing for 3 - 7 days and non-dosing for 3 - 10 days; the PLK1 inhibitor is administered in multiple cycles of daily dosing for 4 - 6 days and non-dosing for 4 - 9 days; the PLK1 inhibitor is administered in multiple cycles of daily dosing for 5 days and non-dosing for 5 - 9 days; the PLK1 inhibitor is administered in multiple cycles of daily dosing for 2 - 5 days and non-dosing for 5 - 9 days; the PLK1 inhibitor is administered in multiple cycles of daily dosing for 2 - 3 days and non-dosing for 5 - 7 days; the PLK1 inhibitor is administered in multiple cycles of daily dosing for 2 days and non-dosing for 5 - 6 days; the PLK1 inhibitor is administered in multiple cycles of daily dosing for 1 - 2 days and non-dosing for 3 - 8 days; or the PLK1 inhibitor is administered in multiple cycles of daily dosing for 1 day and non-dosing for 5 - 7 days.

[0020] The inventive method is useful for any type of prostate cancer patient. In some embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC) or castration-sensitive prostate cancer (CSPC). In some of these embodiments, the CRPC or CSPC is metastatic; in other embodiments, the CRPC or CSPC is non-metastatic. In some embodiments, the method of the present invention also includes evaluating prostate cancer to identify androgen receptor variants. In some of these embodiments, prostate cancer is evaluated by evaluating a biopsy tissue. In other embodiments, prostate cancer is evaluated by evaluating circulating tumor cells (CTCs). In further embodiments, for example, cell-free nucleic acids or proteins in a patient's plasma are evaluated to identify androgen receptor variants.

[0021] Prostate cancer can be caused by any mutation that is currently known or later discovered to cause prostate cancer. In some embodiments, CRPC is characterized by persistent adrenal androgen production, upregulation of intratumoral testosterone production, changes in the biological properties of the androgen receptor, and reactivation of androgen receptor signaling via steroid production parallel pathways. In some of these embodiments, CRPC is characterized by a mutant androgen receptor, such as AR-V1, AR-V3, AR-V7, AR-V9, AR-V12, AR8, AR23, AR45, or AR T878A as characterized by [Cao et al., 2016]. In some of these embodiments, the mutant adrenergic receptor is not required for activation. Specific examples of the mutant adrenergic receptor are AR-V7 or AR-V12. In further embodiments, CRPC is characterized by amplification of the wild-type androgen receptor. The following examples describe preferred embodiments. Other embodiments within the scope of the claims of this application will be apparent to those skilled in the art from the details of the invention disclosed herein or the consideration of the implementation. The details, together with the examples, should be regarded as merely illustrative, and the scope and spirit of the present invention shall be represented by the claims following the examples.

Examples

[0022] Example 1. Inhibition of Human Cytochrome P450 by Onvansertib The potential inhibitory ability of onvansertib against the major human cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) responsible for human liver drug metabolism was investigated using human liver microsomes. The results are shown in Table 1 below. Onvansertib was able to inhibit the metabolic activities of CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 isoforms to varying degrees, and the IC 50 value range was 20 μM to 66 μM. No significant inhibitory effect was observed against CYP1A2. Considering that a reasonable concentration for obtaining significant antitumor activity of this compound in mice is about 1 μM, it is considered that onvansertib has a low potential to show clinically relevant metabolic drug-drug interactions between the drug and its metabolites.

[0023]

Table 1

[0024] Example 2. Clinical Trial A Phase 2 study with IND number 105112 was initiated in 2018 to evaluate the effect of onvansertib in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). The inhibition of human cytochrome P450s by onvansertib was also evaluated. The goal of this ongoing study is to investigate the treatment with onvansertib in combination with the standard treatments abiraterone and prednisone in mCRPC patients. The starting dose of onvansertib was 24 mg / m 2 based on the results of the previous Phase 1 trial (Study PLKA-937-001).

[0025] Stabilization of PSA levels by onvansertib The goal of this ongoing study (IND No. 105112) is to investigate the treatment with onvansertib in combination with the standard treatments abiraterone and prednisone in mCRPC patients. The starting dose of onvansertib is 24 mg / m 2 based on the results of the previous Phase 1 trial (Study PLKA-937-001). The patients will be divided into three treatment groups (all groups include daily abiraterone): - Group A: 24 mg / m of onvansertib on Days 1 to 5 of a 3-week dosing cycle 2 - Group B: 18 mg / m of onvansertib on Days 1 to 5 of a 2-week dosing cycle 2 - Group C: 12 mg / m of onvansertib on Days 1 to 14 of a 3-week dosing cycle 2 The additional rationale for Groups B and C (with shorter days between onvansertib treatments) is based on the observed time changes in PSA values of the patients already enrolled in Group A. Specifically, in many patients who received more than one cycle, the change in PSA appears to correlate with the dosing schedule. As shown in Figure 1, after onvansertib administration on Days 1 to 5, the PSA value drops on Day 8 relative to the baseline, but then rises between Day 8 and the start of the next cycle. In particular, for patients 02-002, 03-009, and 03-013, this pattern is observed in both Cycle 1 and Cycle 2. This may indicate that in a 21-day cycle, a 16-day off period allows the tumor to recover and continue to grow (as evidenced by the observed increase in PSA levels).

[0026] Pharmacokinetic data from the previous Phase 1 trial (at a dose of 24 mg / m 2 showed that at 160 hours (about 7 days), the amount of onvansertib was at the IC of onvansertib 50Less than 10 times the value, suggesting that the patient is receiving onbaselchib at therapeutic levels only between days 1 and 7 of a 21-day cycle. This is consistent with the downward change in PSA values observed for the patient. At 290 hours (about 12 days), the drug concentration is less than 0.1 ng / ml, which is the limit of quantification (BLQ) for the assay of onbaselchib. Assuming a cycle length of 14 days, this suggests that there is no detectable amount of onbaselchib present for 3 days (Figure 2). To further evaluate this, neutrophil levels were assessed for patients in cohort A of the current trial. Figure 3 plots the absolute neutrophil count (ANC) for 7 patients. ANC 1.5 is shown as the grade 2 threshold (CTCAE version 4.03). Two patients experienced ≥ grade 2 neutropenia after the first cycle of treatment (02-002 and 02-005). Notably, patient 02-002 had a history of neutropenia from previous docetaxel treatment, and patient 02-005 had a baseline ANC of 1.54 (grade 1 neutropenia).

[0027] As shown in Figure 4, data for additional cycles of the A treatment group for patient 03-01 show stabilization of PSA levels to less than 25% (dotted line) above the baseline PSA level on day 1 of cycle 1 of onbaselchib treatment (C1D1) before onbaselchib administration until cycle 5. Specifically, PSA levels doubled in 60 days during abiraterone / prednisone treatment before onbaselchib treatment, but only increased by 8.4% after adding onbaselchib (84 days), demonstrating disease stabilization. The CT scan at the end of the study showed approximately 30% tumor shrinkage. The tumor was estimated to have the AR-V7 androgen receptor variant at C1D1. This is considered an aggressive tumor resistant to anti-adrenergic therapy. The importance of the results by patient 03-013 is emphasized by the ability of enzalutamide to maintain PSA levels, even when PSA levels rapidly increased with zytiga (abiraterone) and prednisone alone. The clinical significance of PSA level maintenance is confirmed by tumor shrinkage, especially in the presence of tumor types with the AR-V7 androgen receptor variant, which is known to be resistant to anti-androgen therapy. Furthermore, since patient 03-013 was in group A, there was no enzalutamide at therapeutic levels for at least 2 days at the end of each cycle. Therefore, the regimens of groups B and C, which exclude this 2-day non-treatment level at the end of the cycle, are expected to be even more effective.

[0028] Evaluation of Biomarkers That May Respond in Circulating Tumor Cells (CTCs) and Circulating Tumor DNA (ctDNA) The presence of the constitutively active androgen receptor splice variant 7 (AR-V7) in tumor cells has been investigated in several studies to determine whether it confers initial or acquired resistance to novel androgen receptor signaling inhibitors (ARSi) or other therapies, and whether it can be used as a treatment selection tool in clinical practice. Published data consistently demonstrate that the benefits of ARSi occur primarily in AR-V7-negative CRPC patients, while most AR-V7-positive CRPC patients do not respond well to abiraterone or are not durable. We evaluated circulating tumor cells (CTCs) for the presence of AR-V7 and ctDNA (Guardant) to determine genomic changes in patients from this trial of enzalutamide + abiraterone to assess the AR-V7 status. The results are shown in Table 2 below. To date, 2 out of 6 patients who have completed 4 cycles (12 weeks) of treatment are AR-V7 positive, and it has also been confirmed that the addition of enzalutamide to abiraterone shows a PSA response and has a minimal increase in the number of CTCs from C1D1 to C5D1.

[0029]

Table 2

[0030] Example 3. Additional Clinical Trial Results Additional results from the clinical trial described in Example 2 are attached here. Initial disease stabilization or reduction based on PSA levels was achieved in 3 subjects in Group B (Figure 5). Furthermore, disease stabilization after 5 or more treatment cycles was achieved in 2 patients. One of those patients, 03-013 (Figure 4), was in Group A, and the other stabilized patient, 01-024 (Figure 6A), was in Group B. As of now (August 2019), initial PSA stabilization or decrease has been observed in all AR-V7 positive subjects (n = 4). Two of these patients (03-013 (Figure 4), 01-024 (Figure 6A)) met the initial efficacy endpoint, and one patient, 01-025 (Figure 6B), is still in the evaluation stage.

[0031] Example 4. Further Clinical Trial Results As of the filing of this application, 63% (12 out of 19) of the patients achieved partial response (PR) or stable disease (SD) based on PSA values (initial endpoint) and X-ray scans after 12 weeks of treatment with onvansertib + abiraterone. As shown in Figure 7, in Group A (n = 14), 57% (8 out of 14) of the patients had SD or PR at 12 weeks, 5 patients achieved the efficacy endpoint (PSA stabilization), 4 patients continued treatment; 21% (3 out of 14) of the patients in Group A had or had progression-free survival. Two patients have continued treatment for more than 1 year. In Group B (n = 5), 80% (4 out of 5) of the patients had SD at 12 weeks, 3 patients achieved the efficacy endpoint (PSA stabilization), 3 patients continued treatment; 60% (3 out of 5) of the patients in Group B had or had progression-free survival for more than 7 months.

[0032] Figure 8 shows the circulating tumor cell (CTC) evaluation reported as favorable or unfavorable (<5 vs. ≥ CTC / 7.5 ml of blood). At baseline, 25 patients (78%) had an unfavorable number of CTCs with a median of 19 CTC / 7.5 ml. Ten unfavorable patients were reanalyzed after 12 weeks of treatment. Five patients (50%), including two AR-V7 positive patients (01-024 and 01-025), had ≥80% CTC reduction; four patients (40%) changed from unfavorable to favorable CTC levels (<5 CTC / 7.5 ml); and three patients (30%) had undetectable CTCs. The median duration of treatment for patients with reduced CTCs (n = 5) was 7 months so far, and four patients are continuing treatment. In contrast, the median duration of treatment for patients with increased CTCs (n = 5) was 5 months, and none of those patients are continuing treatment. Figure 9 shows the change in PSA levels for all patients. Eighteen of 25 patients (72%) had a decrease in PSA levels with the addition of enzalutamide after one cycle of treatment. Initial PSA stabilization or decrease was observed in all AR-V7 positive patients (n = 5) who completed at least one cycle of treatment. Three of four AR-V7 positive patients who completed 3 months of treatment for efficacy assessment achieved the initial endpoint of disease stability. Examples 2-4 demonstrate that the combination of enzalutamide and abiraterone provides a new treatment option for patients with poor prognosis, including patients with AR-V7 positive androgen receptors, including those who are resistant to AR signaling inhibitor (ARSi) therapy.

[0033] References TIFF0007717614000004.tif67170 TIFF0007717614000005.tif213170 TIFF0007717614000006.tif206170 TIFF0007717614000007.tif154170

[0034] Considering the above, it will be understood that several objects of the present invention are achieved and other advantages are obtained. Since various changes can be made to the above methods and compositions without departing from the scope of the present invention, all matters included in the above description and shown in the accompanying drawings are intended to be construed as illustrative and not in a limiting sense. Without limitation, all references cited herein, including patent publications and non-patent documents, are incorporated herein by reference. The discussion of the references in this specification is intended merely to summarize the author's claims and does not admit that any of the references constitutes prior art.

[0035] As used herein, in certain embodiments, when preceding a numerical value, the term "about" or "approximately" represents plus or minus 10% of that value. When a range of values is provided, each intervening value between the upper and lower limits of the range and between any other explicitly stated value or intervening value within the stated range, to one-tenth of the unit of the lower limit, is to be understood as being included within the disclosure, unless the context clearly dictates otherwise. These narrower ranges of the upper and lower limits are also included within the disclosure, subject to any specifically excluded limits within the stated range. When the stated range includes one or both of the limits, ranges excluding either or both of the included limits are also included within the disclosure.

[0036] The indefinite articles "a" and "an" as used in this specification and the embodiments are to be understood as meaning "at least one" unless clearly indicated to the contrary. As used in this specification and the embodiments, the expression "and / or" should be understood to mean "either or both" of the elements so joined in parallel. That is, in some cases the elements exist conjunctively and in other cases disjunctively. A plurality of elements recited using "and / or" should be construed in the same fashion, i.e., as "one or more" of the elements so joined in parallel. In some cases, there may be other elements, whether or not specifically identified by the "and / or" clause, related or not related to the specifically identified elements. Thus, by way of non-limiting example, a reference to "A and / or B", when used in conjunction with open-ended language such as "comprising", in one embodiment may refer to only A (including, in some cases, elements other than B); in another embodiment, to only B (including, in some cases, elements other than A); in yet another embodiment, to both A and B (including, in some cases, other elements), and so on.

[0037] As used in this specification and the embodiments, "or" should be understood to have the same meaning as the above "and / or". For example, when separating items in a list, "or" or "and / or" should be construed as inclusive, i.e., including some or at least one of the elements of the list, but also including more than one, and, in some cases, further including items not listed. The term "only" clearly means the contrary, e.g., "only one of" or "exactly one of", or when used in an embodiment, "consisting of" will refer to including exactly one of some or the elements of the list. Generally, the term "or" as used in this specification should be construed to represent an exclusive alternative (i.e., "one or the other but not both") only when preceded by exclusive terms such as "either", "one of", "only one of", or "exactly one of". "Consisting essentially of" shall have its general meaning as used in the field of patent law when used in an embodiment.

[0038] As used in this specification and the embodiments, with respect to a list of one or more elements, the expression "at least one" means at least one element selected from any one or more of the elements in the list of elements, but does not necessarily include at least one of every element specifically listed within the list of elements, and does not exclude any combination of elements in the list of elements. It should be understood that this definition allows, in some cases, for the possibility that elements may exist, whether or not they are related to the specifically identified elements, in addition to the specifically identified elements within the list of elements to which the expression "at least one" refers. Thus, by way of non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B", or, equivalently, "at least one of A and / or B") may, in one embodiment, refer to at least one A, including, in some cases, a plurality of A, with no B present (including, in some cases, elements other than B); in another embodiment, refer to at least one B, including, in some cases, a plurality of B, with no A present (including, in some cases, elements other than A); and in yet another embodiment, refer to at least one A, including, in some cases, a plurality of A, and at least one A, including, in some cases, a plurality of B (including, in some cases, other elements), etc. Another aspect of the present invention may be as follows. 〔1〕A method comprising recommending treatment of a patient with prostate cancer having an elevated prostate-specific antigen (PSA) level with a polo-like kinase 1 (PLK1) inhibitor. 〔2〕The method according to 〔1〕above, further comprising treating the patient with a PLK1 inhibitor. 〔3〕The method according to 〔1〕or 〔2〕above, wherein the elevated PSA level is two elevated PSA values separated by at least one week, one showing an increase of at least 0.1 ng / mL and one being a confirmation value showing no decrease. 〔4〕The method according to 〔1〕or 〔2〕above, wherein the patient has an elevated PSA level when being treated with an anti-androgen or androgen antagonist. 〔5〕The method according to 〔3〕above, wherein the patient has also been treated with prednisone. 〔6〕The method according to 〔1〕or 〔2〕above, wherein the PLK1 inhibitor treatment maintains the PSA level below 25% above the PSA level at the start of the PLK1 inhibitor treatment. 〔7〕The method according to 〔4〕above, wherein the anti-androgen or androgen antagonist is abiraterone, TOK-001, ARN 509, enzalutamide, apalutamide, darolutamide, or any combination thereof. 〔8〕The method according to 〔1〕or 〔2〕above, wherein the PLK1 inhibitor is a dihydropteridinone, pyridopyrimidine, aminopyrimidine, substituted thiazolidinone, pteridine derivative, dihydroimidazo[1,5-f]pteridine, meta-substituted thiazolidinone, benzylstilryl sulfone analog, stilbene derivative, or any combination thereof. 〔9〕The method according to 〔1〕or 〔2〕above, wherein the PLK1 inhibitor is onvansertib, BI2536, volasertib (BI 6727), GSK461364, HMN-176, HMN-214, AZD1775, CYC140, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960 or Ro3280. 〔10〕The method according to 〔1〕or 〔2〕above, wherein the PLK1 inhibitor is onvansertib. 〔11〕The onvansertib is administered to the patient at a dose of 12 mg / m 2 The method according to 〔10〕above, administered at the following dosage. 〔12〕The onvansertib is 24 mg / m 2 The method according to

[10] , which is administered to the patient at the following dosage. 〔13〕The method according to

[10] , wherein the onvansertib is administered to the patient at a dosage exceeding 24 mg / m 2The method according to

[10] , wherein the onvansertib is administered to the patient at a dosage exceeding 24 mg / m. 〔14〕The method according to [1] or [2], wherein the PLK1 inhibitor is administered to the patient daily. 〔15〕The method according to [1] or [2], wherein the PLK1 inhibitor is administered to the patient in a plurality of dosing cycles in which the period without administration of the PLK1 inhibitor is 9 days or less. 〔16〕The method according to

[14] b, wherein the period without administration of the PLK1 inhibitor is 5 days or less. 〔17〕The method according to [1] or [2], wherein the PLK1 inhibitor is administered in a plurality of cycles of daily administration for 1 to 10 days and non - administration for 5 to 16 days. 〔18〕The method according to [1] or [2], wherein the PLK1 inhibitor is administered in a plurality of cycles of daily administration for 3 to 7 days and non - administration for 10 to 16 days. 〔19〕The method according to [1] or [2], wherein the PLK1 inhibitor is administered in a plurality of cycles of daily administration for 4 to 6 days and non - administration for 10 to 16 days. 〔20〕The method according to [1] or [2], wherein the PLK1 inhibitor is administered in a plurality of cycles of daily administration for 3 to 7 days and non - administration for 3 to 10 days. 〔21〕The method according to [1] or [2], wherein the PLK1 inhibitor is administered in a plurality of cycles of daily administration for 4 to 6 days and non - administration for 4 to 9 days. 〔22〕The method according to [1] or [2], wherein the PLK1 inhibitor is administered in a plurality of cycles of daily administration for 2 to 5 days and non - administration for 5 to 9 days. 〔23〕The method according to [1] or [2], wherein the PLK1 inhibitor is administered in a plurality of cycles of daily administration for 2 to 3 days and non - administration for 5 to 7 days. 〔24〕The method according to any one of

[10] to

[26] , wherein the patient is also administered abiraterone daily. 〔25〕The method according to [1] or [2], wherein the prostate cancer is castration - resistant prostate cancer (CRPC) or castration - sensitive prostate cancer (CSPC). 〔26〕The method according to

[25] , wherein the CRPC or CSPC is metastatic. 〔27〕The method according to

[25] , wherein the CRPC or CSPC is non - metastatic. 〔28〕The method according to [1] or [2], further comprising evaluating circulating tumor cells (CTC) to identify androgen receptor variants. The method according to [1] or [2], further comprising evaluating a cell-free nucleic acid or protein to identify an androgen receptor variant. The method according to [1] or [2], further comprising evaluating tumor cells by tissue biopsy to identify an androgen receptor variant. The method according to [1] or [2], wherein the prostate cancer is CRPC characterized by persistent adrenal androgen production, upregulation of intratumoral testosterone production, changes in the biological properties of the androgen receptor, or reactivation of androgen receptor signaling via the steroid production parallel pathway. The method according to

[31] , wherein the CRPC is characterized by a mutated androgen receptor. The method according to

[32] , wherein the mutated androgen receptor does not require a ligand for activation. The method according to

[33] , wherein the mutated androgen receptor is AR-V7 or AR. T878A The method according to

[33] , wherein the mutated androgen receptor is AR-V7 or AR. The method according to

[31] , wherein the CRPC is characterized by amplification of the wild-type androgen receptor. 〔36〕The following Measuring the prostate-specific antigen (PSA) levels of at least two samples obtained from a prostate cancer patient at different times; and When the PSA level of the sample increases over time, recommending treatment of the patient with a PLK1 inhibitor, or When the PSA level of the sample does not increase over time, not recommending treatment of the patient with a PLK1 inhibitor A method comprising. 〔37〕Further comprising the following Treating the patient with a PLK1 inhibitor when the PSA level of the sample increases over time The method according to

[36] , comprising. 〔38〕The method according to

[36] or

[37] , wherein the increase in PSA level is identified by two rising PSA values separated by at least one week, one showing at least 0.1 ng / mL and one being a confirmation value showing no decrease. The method according to

[36] or

[37] , wherein the patient is being treated with an anti-androgen drug or androgen antagonist and prednisone. The method according to

[39] , wherein the anti-androgen drug or androgen antagonist is abiraterone, TOK-001, ARN 509, enzalutamide, apalutamide, darolutamide, or any combination thereof. 〔41〕The method according to 〔36〕 or 〔37〕, wherein the PLK1 inhibitor is a dihydropteridinone, pyridopyrimidine, aminopyrimidine, substituted thiazolidinone, pteridine derivative, dihydroimidazo[1,5-f]pteridine, meta-substituted thiazolidinone, benzylstilbenesulfone analog, stilbene derivative, or any combination thereof. 〔42〕The method according to 〔36〕 or 〔37〕, wherein the PLK1 inhibitor is onvansertib, BI2536, volasertib (BI 6727), GSK461364, HMN-176, HMN-214, AZD1775, CYC140, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960 or Ro3280. 〔43〕The method according to 〔36〕 or 〔37〕, wherein the PLK1 inhibitor is onvansertib. 〔44〕The method according to 〔36〕 or 〔37〕, wherein the prostate cancer is castration-resistant prostate cancer (CRPC) or castration-sensitive prostate cancer (CSPC). 〔45〕The method according to 〔44〕, wherein the CRPC or CSPC is metastatic. 〔46〕The method according to 〔44〕, wherein the CRPC or CSPC is non-metastatic. 〔47〕A method comprising recommending treatment with a PLK1 inhibitor to a patient having prostate cancer with a mutant androgen receptor that does not require a ligand for activation. 〔48〕The method according to 〔47〕, further comprising treating the patient with the PLK1 inhibitor. 〔49〕The method according to 〔47〕 or 〔48〕, wherein the mutant androgen receptor is AR-V7 or an androgen receptor T878A 〔50〕The method according to 〔47〕 or 〔48〕, wherein the patient also has elevated PSA levels. 〔51〕The method according to 〔47〕 or 〔48〕, wherein the patient is being treated with an anti-androgen drug or an androgen antagonist. 〔52〕The method according to 〔51〕, wherein the patient is also being treated with prednisone. 〔53〕The method according to 〔51〕, wherein the anti-androgen drug or androgen antagonist is abiraterone, TOK-001, ARN 509, enzalutamide, apalutamide, darolutamide, or any combination thereof. ​ 〔54〕The method according to 〔47〕 or 〔48〕, wherein the PLK1 inhibitor is onvansertib, BI2536, volasertib (BI 6727), GSK461364, HMN-176, HMN-214, AZD1775, CYC140, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960 or Ro3280. 〔55〕The method according to 〔47〕 or 〔48〕, wherein the PLK1 inhibitor is onvansertib. 〔56〕A method comprising recommending treatment with a PLK1 inhibitor to a prostate cancer patient who has been treated with an androgen antagonist and has elevated PSA levels. 〔57〕The method according to 〔56〕, wherein treatment with a combination of the PLK1 inhibitor and abiraterone is recommended. 〔58〕The method according to 〔56〕, wherein treatment with the androgen antagonist is discontinued and the patient starts treatment with the PLK1 inhibitor and abiraterone. 〔59〕The method according to any one of 〔56〕 to 〔58〕, wherein the androgen antagonist is enzalutamide, apalutamide, or darolutamide. 〔60〕The method according to any one of 〔56〕 to 〔58〕, wherein the PLK1 inhibitor is onvansertib, BI2536, volasertib (BI 6727), GSK461364, HMN-176, HMN-214, AZD1775, CYC140, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960 or Ro3280. 〔61〕The method according to any one of 〔56〕 to 〔58〕, wherein the PLK1 inhibitor is onvansertib. 〔62〕The method according to any one of 〔56〕 to 〔58〕, wherein the prostate cancer is CRPC characterized by persistent adrenal androgen production, upregulation of intratumoral testosterone production, changes in the biological properties of the androgen receptor, or reactivation of androgen receptor signaling via the steroid production parallel pathway. 〔63〕The method according to 〔62〕, wherein the CRPC is characterized by a mutant androgen receptor. 〔64〕The method according to 〔63〕, wherein the mutant androgen receptor does not require a ligand for activation. 〔65〕The method according to 〔64〕, wherein the mutant androgen receptor is AR-V7 or AR T878A and the like.

Claims

1. A pharmaceutical composition comprising enzalutamide for use in a method of treating castration-resistant prostate cancer (CRPC) in a patient, The patient has elevated prostate-specific antigen (PSA) levels when being treated with an anti-androgen drug or an androgen antagonist, and the prostate cancer is characterized by a variant androgen receptor AR-V7 or AR T878A characterized by wherein the method comprises (i) recommending treatment of the patient's prostate cancer with the pharmaceutical composition, and treatment with the pharmaceutical composition reduces or stabilizes the PSA level and / or reduces circulating tumor cells in the patient. The above pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the rising PSA level is two rising PSA values separated by at least one week, one showing an increase of at least 0.1 ng / mL and one being a confirmation value showing no decrease.

3. The pharmaceutical composition according to claim 1, wherein the anti-androgen or androgen antagonist is abiraterone, TOK-001, ARN 509, enzalutamide, apalutamide, darolutamide, or any combination thereof, and optionally, when the patient is also being treated with prednisone, may have a rising PSA level.

4. The pharmaceutical composition according to claim 1, wherein treatment with the pharmaceutical composition maintains the PSA level of the patient at less than 25% above the PSA level at the start of treatment with the pharmaceutical composition.

5. In the method, the dose of the onban cell tib to the patient is 12 mg / m 2 or less, or 24 mg / m 2 or less, or 24 mg / m 2 The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered to the patient at a dose exceeding that.

6. In the method, the pharmaceutical composition is administered to the patient in a plurality of dosing cycles in which the dosing cycle during which the pharmaceutical composition is not administered is 9 days or less, preferably the dosing cycle during which the pharmaceutical composition is not administered is 5 days or less. The pharmaceutical composition according to claim 1.

7. In the method, the pharmaceutical composition is administered to the patient daily, Preferably, the pharmaceutical composition is administered in a plurality of cycles of daily administration for 1 to 10 days and non-administration for 5 to 16 days, or administered in a plurality of cycles of daily administration for 3 to 7 days and non-administration for 10 to 16 days, or administered in a plurality of cycles of daily administration for 4 to 6 days and non-administration for 10 to 16 days, or administered in a plurality of cycles of daily administration for 3 to 7 days and non-administration for 3 to 10 days, or administered in a plurality of cycles of daily administration for 4 to 6 days and non-administration for 4 to 9 days, or administered in a plurality of cycles of daily administration for 2 to 5 days and non-administration for 5 to 9 days, or administered in a plurality of cycles of daily administration for 2 to 3 days and non-administration for 5 to 7 days. The pharmaceutical composition according to claim 1.

8. The pharmaceutical composition according to claim 1, wherein in the method, the patient is also administered abiraterone daily.

9. The pharmaceutical composition according to claim 1, wherein (a) the CRPC is metastatic, or (b) the CRPC is non-metastatic.

10. The pharmaceutical composition according to claim 1, further comprising evaluating circulating tumor cells (CTCs), cell-free nucleic acids or proteins, or tumor cells in a tissue biopsy to identify androgen receptor variants.

11. The patient has rising PSA levels when being treated with an androgen antagonist, and the method comprises treating the patient with the pharmaceutical composition and abiraterone, and discontinuing the treatment with the androgen antagonist, optionally, the androgen antagonist to be discontinued may be enzalutamide, apalutamide, or darolutamide. The pharmaceutical composition according to claim 1.

12. An AR-V7 or AR T878A A pharmaceutical composition comprising enzalutamide for use in a method of treating castration-resistant prostate cancer having a mutant androgen receptor that is an androgen receptor The pharmaceutical composition, wherein treatment with the pharmaceutical composition reduces or stabilizes prostate-specific antigen (PSA) levels and / or reduces circulating tumor cells in the patient.

13. (a) The patient also has rising PSA levels prior to the treatment with the pharmaceutical composition, or (b) the patient is being treated with an anti-androgen or androgen antagonist, preferably the anti-androgen or androgen antagonist is abiraterone, TOK-001, ARN 509, enzalutamide, apalutamide, darolutamide, or any combination thereof, optionally, the patient may also be treated with prednisone. The pharmaceutical composition according to claim 12.

14. The pharmaceutical composition according to claim 12, wherein in the method, the pharmaceutical composition is used in combination with abiraterone.

15. The patient is resistant to androgen receptor signaling inhibitor (ARSi) therapy, and in the method, the pharmaceutical composition is used in combination with abiraterone. The pharmaceutical composition according to claim 12.

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