Androgen receptor antagonists for the treatment of patients with biochemical recurrence of hormone-sensitive prostate cancer

Abstract

A method for treating patients with biochemical recurrence of hormone-sensitive prostate cancer using a pharmaceutical product comprising an androgen receptor inhibitor, such as darolutamide, is described herein.

Description

Technical Field

[0001] A method of treating patients with biochemical recurrence of hormone-sensitive prostate cancer using a pharmaceutical product containing an androgen receptor inhibitor, such as darolutamide, is described herein.

Background Art

[0002] Prostate cancer is the second most frequently diagnosed and fifth most aggressive neoplasm in men worldwide, accounting for 13.5% (1,276,000) of all cancer cases and 6.7% (359,000) of all cancer deaths in men worldwide (A Barsouk, S.A. Padala, A Vakiti et al.; Epidemiology, Staging and Management of Prostate Cancer; Med. Sci. August 28, 2020; doi: 10.3390 / medsci#8030028 www.mdpi).

[0003] The course of prostate cancer from diagnosis to death is best classified into a series of clinical stages, based on the extent of the disease, hormonal status, and the presence or absence of detectable metastasis: localized disease, elevated prostate-specific antigen (PSA) levels without detectable metastasis after radiotherapy or surgery, and the presence or absence of clinical metastasis in the non-castrated or castrated stage. While radical prostatectomy (RP), primary radical irradiation (RT), or a combination of both may be curative for patients with localized disease, a significant proportion of these patients (up to 50%) have recurrent disease, as evidenced by elevated PSA levels without detectable metastasis, which is called biochemical recurrence (BCR). Generally, BCR can occur before the appearance of clinical metastases, within 8 years of RP and within 7 years of primary curative RT (Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. May 5, 1999; 281(17):1591-7. doi:10.1001 / jama.281.17.1591; Zagars GK, Pollack A: Kinetics of serum prostate-specific antigen after external beam radiation for clinically localized prostate cancer. Radiother Oncol 1997; 44:213-221). The natural history of BCR and the risk of subsequent metastasis can be predicted by pre- and post-treatment clinical characteristics (Artibani W, Porcaro AB, De Marco V et al., Management of Biochemical Recurrence after Primary Curative Treatment for Prostate Cancer: A Review. Urol Int. 2018;100(3):251-62).Patients with BCR are at high risk of developing metastasis (24-34%), and metastasis is a progression to a fatal stage of the disease (Patrikidou A, Zilli T, Baciarello G, Terisse S, Hamilou Z, Fizazi K. Should androgen deprivation therapy and other systemic treatments be used in men with prostate cancer and a rising PSA post-local treatments? Therapeutic Advances in Medical Oncology. 2021;13.doi:10.1177 / 17588359211051870).

[0004] Generally, there is no treatment consensus for patients who develop a blood cell remission (BCR) in hormone-sensitive prostate cancer after local therapy (prostatectomy followed by adjuvant radiotherapy (ART) or salvage radiotherapy (SRT), or after primary RT), but treatment options include androgen deprivation therapy (ADT) or local salvage therapy (S Gillessen, G Attard, T M. Beer et al.; Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019; European Urology 77. 2020, 508-547; Saad F, Canil C, Finelli A, Hotte SJ, Malone S, Shayegan B et al., Controversial issues in the management of patients with advanced prostate cancer: Result from a Canadian consensus forum. Can Urol Assoc J. April 2020; 14(4):E 137-e49). Androgen receptor (AR) signaling is a key promoter of prostate cancer growth; therefore, androgen deprivation therapy (ADT) is used to suppress prostate cancer in high-risk patients (Snaterse, G., Mies, R., van Weerden, WM et al., Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids. Prostate Cancer Prostatic Dis 26, 293-301 (2023)).When high-risk prostatectomy (BCR) occurs after primary or adjuvant / salvage radiotherapy, androgen deprivation therapy (ADT) may be considered a viable treatment option in patients with hormone-naive or hormone-sensitive prostate cancer (Kim, M., Song, C., Jeong, IG et al., Androgen deprivation therapy during and after post-prostatectomy radiotherapy in patients with prostate cancer: a case control study. BMC Cancer 18, 271 (2018). https: / / doi.org / 10.1186 / s12885-018-4189-9). In this population, androgen deprivation therapy (ADT) alone is not initiated routinely. If ADT is initiated, an intermittent regimen of ADT is used.

[0005] How to best manage human men with hormone-sensitive prostate cancer (BCR) after local treatment for prostate cancer remains a critical clinical question. Current evidence provides clinicians with only general guidelines on how to define the risk of developing metastasis, taking into account factors such as previous therapy, PSA doubling time, high-risk factors, time since initial therapy, and the patient's health status and preferences (Artibani W, Porcaro AB, De Marco V et al., Management of Biochemical Recurrence after Primary Curative Treatment for Prostate Cancer: A Review. Urol Int. 2018;100(3):251-62).However, there is no established standard treatment for these patients (Artibani W, Porcaro AB, De Marco V et al., Management of Biochemical Recurrence after Primary Curative Treatment for Prostate Cancer: A Review. Urol Int. 2018;100(3):251-62; Boorjian SA, Thompson RH, Tollefson MK et al., Long term risk of clinical progression after biochemical recurrence following radical prostatectomy: the impact of time from surgery to recurrence. Eur Urol. June 2011;59(6):893-9; Heinlein CA and Chang C: Androgen receptor in prostate cancer. Endoc Rev 25:276-308, 2004; Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy.JAMA. May 5, 1999;281(17):1591-7). Androgen depletion is a treatment option with generally predictable outcomes: a decrease in PSA, a period of stability with no tumor growth, followed by an increase in PSA and regrowth, although the increase in PSA and regrowth can be managed by restarting androgen depletion therapy. This may then be followed by a new decrease in PSA and another period of stability with no tumor growth. However, after a new decrease in PSA, an increase in PSA and tumor regrowth eventually follows. Historically, ADT has been the standard treatment for patients with metastatic prostate cancer, and its use at earlier stages, such as in BCR, remains controversial.

[0006] Standard treatment is required for patients with BCR hormone-sensitive prostate cancer who are at high risk of progressing to the metastatic stage. In addition, patients who are positive on PSMA-PET are at even higher risk, and therefore it is appropriate to employ up-to-date approaches, such as image-guided radiotherapy and novel multi-drug combination approaches, for this specific patient population (Bianchi L, Ceci F, Costa F et al., The Impact of PSMA-PET on Oncologic Control in Prostate Cancer Patients Who Experienced PSA Persistence or Recurrence. Cancers. December 30, 2022;15(1):247.doi:10.3390 / cancers15010247).

[0007] Next-generation androgen receptor (AR) antagonists can play a role in combination with ADT in this context. The disclosed methods target these and other important needs.

Prior Art Documents

Non-Patent Documents

[0008]

Non-Patent Document 1

Non-Patent Document 2

[0009] This specification describes a method for treating biochemical recurrence (BCR) of hormone-sensitive prostate cancer (HSPC), comprising, comprising, or essentially comprising, administering a safe and effective amount of at least one antiandrogen to a male human being who has or is suspected of having BCR of hormone-sensitive prostate cancer. In some embodiments, BCR of hormone-sensitive prostate cancer may be high-risk BCR of hormone-sensitive prostate cancer. In some embodiments, a male human being with BCR of hormone-sensitive prostate cancer may have a prostate-specific antigen doubling time (PSADT) of 12 months or less. In some embodiments, a male human being with BCR of hormone-sensitive prostate cancer may have lesions on prostate-specific membrane antigen positron emission tomography (PSMA PET / CT) that are not visible on conventional imaging methods (bone scans and computed tomography [CT] / magnetic resonance imaging [MRI]).

[0010] In a further embodiment, a male human with a BCR of hormone-sensitive prostate cancer may have previously received radical local therapy (radical prostatectomy followed by adjuvant radiotherapy [ART] or salvage radiotherapy [RT], or primary radiotherapy). There are no reports demonstrating that administration of antiandrogens (darolutamide, apalutamide, or enzalutamide) results in increased radiological progression-free survival (rPFS) by prostate-specific membrane antigen positron emission tomography / computed tomography (PSMA PET / CT). However, administration of the antiandrogen darolutamide may result in increased rPFS by PSMA PET / CT in male human with a BCR of hormone-sensitive prostate cancer.

[0011] Furthermore, no data has been reported demonstrating that administration of (darolutamide, apalutamide, or enzalutamide) results in increased metastasis-free survival (MFS) in patients with hormone-sensitive BCR, as indicated by conventional imaging methods (bone scan, CT / MRI). However, administration of antiandrogens (darolutamide, apalutamide, or enzalutamide) may increase MFS in men with BCR that has evolved into hormone-resistant prostate cancer called nmCRPC (Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S et al., Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. March 28, 2019; 380(13):1235-46; Smith MR, Saad F, Chowdhury S et al., SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018; 378:1408-18; Hussain M, Fizazi K, Saad F et al., Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer.N Engl J Med 2018;378:2465-74).Furthermore, administration of these antiandrogens may significantly improve overall survival and / or rPFS in patients with metastatic prostate cancer diagnosed by conventional imaging methods (bone scan, CT / MRI) (Chi KN, Agarwal N, Bjartell A et al.; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019; 381(1):13-24. doi:10.1056 / NEJMoa1903307; Armstrong AJ, Szmulewitz RZ, Petrylak DP et al. (2019) ARCHES: A randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 37(32):2974-2986; Smith MR, Hussain M, Saad F et al.; ARASENS Trial Investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142.doi:10.1056 / NEJMoa2119115). In some embodiments, administration of antiandrogens in patients with high-risk BCR may result in an improvement in antitumor activity at any point in time, as measured by one or more of the following: time to castration-resistant prostate cancer (CRPC), time to local progression by PSMA PET / CT, PSA undetectable rate at 12 months (<0.2 ng / mL), time to symptomatic bone-related event (SSE), overall survival (OS), time to initiation of the first subsequent systemic antineoplastic therapy, time to PSA progression, and PSA undetectable rate (<0.2 ng / mL).

[0012] In other embodiments, administration of safe and effective amounts of antiandrogens results in only grade 4 or lower adverse events.

[0013] In some embodiments, the anti-androgen is a second-generation androgen receptor inhibitor. In certain embodiments, the androgen receptor inhibitor may include darolutamide, apalutamide, enzalutamide, proxalutamide, or bubdegalutamide, or any combination thereof. In certain embodiments, the androgen receptor inhibitor is darolutamide. In certain embodiments, the androgen receptor inhibitor is enzalutamide. In certain embodiments, the androgen receptor inhibitor is apalutamide. In further embodiments, the androgen receptor inhibitor is bicalutamide, flutamide, or nilutamide. In other further embodiments, the androgen receptor inhibitor is ARV-766, EPI-7386, CC-94676, AC-0176, HP-518, or TAS-3681.

[0014] In some embodiments, a method for treating BCR of hormone-sensitive prostate cancer comprises, consists of, or essentially comprises administering a safe and effective amount of darolutamide to a male human having BCR of hormone-sensitive prostate cancer. In certain embodiments, darolutamide is administered orally. In some embodiments, darolutamide is administered daily. In some embodiments, darolutamide is administered orally in a 24-month continuous daily dosing schedule. In further embodiments, darolutamide is administered orally at a dose of approximately 1200 mg / day. In other embodiments, darolutamide is administered orally at a dose of approximately 600 mg (e.g., two 300 mg tablets) taken twice daily. In some embodiments, darolutamide exists in solid oral dosage form. In some embodiments, darolutamide is formulated as tablets. In some embodiments, darolutamide is formulated as softgels. In some embodiments, darolutamide is formulated as hard-shell capsules.

[0015] In some embodiments, the method may comprise, consist of, or consist essentially of administering a safe and effective amount of apalutamide, for example, when apalutamide is present in a solid oral dosage form. In some embodiments, apalutamide is formulated as a tablet. In some embodiments, apalutamide is formulated as a softgel. In some embodiments, apalutamide is formulated as a hard shell capsule.

[0016] In some embodiments, the method may comprise, consist of, or consist essentially of administering a safe and effective amount of enzalutamide, for example, when enzalutamide is present in a solid oral dosage form. In some embodiments, enzalutamide is formulated as a tablet. In some embodiments, enzalutamide is formulated as a softgel. In some embodiments, enzalutamide is formulated as a hard shell capsule.

[0017] According to another embodiment, there is provided a pharmaceutical product comprising an antiandrogen, such as darolutamide, and a package insert including instructions for improving biochemical recurrence of prostate cancer.

[0018] In certain embodiments, the present invention relates to a pharmaceutical product comprising, consisting of, and / or consisting essentially of darolutamide. In another aspect, in the case of darolutamide, the pharmaceutical product may include a label, for example, the label of the aforementioned listed drug includes a daily dose of 1200 mg of darolutamide. In other embodiments, in the case of enzalutamide, the pharmaceutical product may include a label, for example, the label of the listed drug includes a daily dose of 160 mg of enzalutamide.

[0019] In certain embodiments, the present invention relates to a method of offering for sale an approved pharmaceutical product comprising, consisting of, and / or consisting essentially of at least one of darolutamide, apalutamide, and enzalutamide. In other embodiments, the present invention relates to a method of offering for sale an approved pharmaceutical product, the method comprising, consisting of, and / or consisting essentially of offering such a pharmaceutical product for sale, and the label of the drug listed by reference for such a pharmaceutical product includes instructions for treating non-metastatic castration-resistant prostate cancer. In other embodiments, the pharmaceutical product is an abbreviated new drug application (ANDA) pharmaceutical product or a supplemental new drug application (sNDA) pharmaceutical product.

[0020] These are additional possible embodiments. (A) A method of improving the progression-free survival period in a human male having biochemical recurrence of prostate cancer, the method comprising administering to the human male a pharmaceutical product comprising an androgen receptor inhibitor. (B) The method according to embodiment (A), wherein the progression-free survival period is the radiological progression-free survival period by prostate-specific membrane antigen positron emission tomography. (C) The method according to embodiment (A), wherein the progression-free survival period is the radiological progression-free survival period by computed tomography. (D) The method according to embodiment (A), wherein the biochemical recurrence of prostate cancer is high-risk biochemical recurrence of prostate cancer. (E) The method according to embodiment (A), wherein the androgen receptor inhibitor is darolutamide. (F) The method according to embodiment (A), further comprising the step of administering androgen deprivation therapy. (G) The method according to embodiment (F), wherein the step of administering androgen deprivation therapy is performed sequentially or simultaneously with the step of administering a pharmaceutical product comprising an androgen receptor inhibitor. (H) The method according to embodiment (F), wherein the androgen deprivation therapy comprises orchiectomy or an LHRH agonist or an LHRH antagonist. (I) A method for improving radiological progression-free survival by prostate-specific membrane antigen positron emission tomography or computed tomography in male humans with high-risk biochemical recurrence of prostate cancer, comprising the step of administering to the male human a pharmaceutical product comprising darolutamide, an androgen receptor inhibitor, sequentially or concurrently with orchiectomy or androgen deprivation therapy including the administration of an LHRH agonist or antagonist. (J) A method for treating biochemical recurrence of prostate cancer in a human male, comprising the step of administering a pharmaceutical product containing an antiandrogen to the human male. (K) The method according to embodiment (J), wherein the anti-androgen is an androgen receptor inhibitor. The method according to embodiment (K), wherein (L) the androgen receptor inhibitor is a second-generation androgen receptor inhibitor selected from the group consisting of darolutamide, enzalutamide, apalutamide, and any combination thereof. (M) The method according to embodiment (L), wherein a second-generation androgen receptor inhibitor is administered in a daily dose ranging from approximately 10 mg / day to approximately 1500 mg / day. (N) The method according to embodiment (J), wherein the androgen receptor inhibitor is darolutamide. (O) The method according to embodiment (N), wherein darolutamide is administered in a daily dose ranging from approximately 300 mg / day to approximately 1500 mg / day. (P) The method according to embodiment (N), wherein darolutamide is administered at a daily dose of approximately 1200 mg / day. (Q) The method according to embodiment (N), wherein darolutamide is in the form of a (S,S) diastereomer, a (S,R) diastereomer, and a (S,S) diastereomer and a (S,R) diastereomer in any isomer ratio. The method according to embodiment (J), further comprising the step of administering (R) androgen deprivation therapy. (S) The method according to embodiment (Q), wherein the step of administering androgen deprivation therapy is performed sequentially or concurrently with the step of administering a pharmaceutical product. (T) Darorutamide for improving radiographic progression-free survival by positron emission tomography or computed tomography in chemically or surgically castrated male humans with high-risk biochemical recurrence of prostate cancer. [Modes for carrying out the invention]

[0021] For clarity, it should be understood that certain features of the Invention described herein in relation to individual embodiments may also be provided in combination in one embodiment. That is, unless obviously contradictory or specifically excluded, each individual embodiment is considered to be able to be combined with any one or more other embodiments, and such combination is considered to be another embodiment. Conversely, various features of the Invention described in relation to one embodiment for the sake of brevity may also be provided separately or in any partial combination. Finally, embodiments may be described as part of a series of steps or as part of a more general structure, but each of the steps may also be considered an independent embodiment that can be combined with others.

[0022] The transitional phrases “comprising,” “consisting essentially of,” and “consisting” are intended to imply the meanings generally accepted in patent terminology. Specifically, (i) “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is comprehensive or open-ended, not excluding additional elements or steps of method not enumerated; (ii) “consisting of” excludes any elements, steps, or components not specified in the claims; and (iii) “consisting essentially of” limits the scope of the claims to the specified materials or steps of the claimed invention “and not substantially affect one or more basic and novel features.” Embodiments described with respect to the phrase “comprising” (or its equivalents) also provide embodiments described independently with respect to “consisting of” and “consisting essentially of.”

[0023] Where a list is provided, it should be understood that, unless otherwise specified, each individual element of that list, and all combinations of that list, are separate embodiments. For example, a list of embodiments provided as "A, B, or C" should be interpreted as including embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0024] Androgen receptors (ARs) are members of the steroid and nuclear receptor superfamily. Within this large protein family, only five vertebrate steroid receptors are known: androgen receptors, estrogen receptors alpha and beta, progesterone receptors, glucocorticoid receptors, and mineralocorticoid receptors. ARs are soluble proteins that function as intracellular transcription factors. AR function is regulated by androgen binding, which initiates sequential conformational changes in the receptor, influencing receptor-protein and receptor-DNA interactions.

[0025] AR is primarily expressed in androgen target tissues, such as the prostate, skeletal muscle, liver, and central nervous system (CNS), with the highest expression levels observed in the prostate, adrenal glands, and epididymis. AR can be activated by the binding of endogenous androgens, such as testosterone and 5α-dihydrotestosterone (5α-DHT).

[0026] The androgen receptor (AR), located on chromosomes Xq11-12, is a 110kD nuclear receptor that, upon androgen activation, mediates the transcription of target genes regulating the growth and differentiation of prostate epithelial cells. Unbound AR, like other steroid receptors, is primarily located in the cytoplasm and associates with heat shock protein (HSP) complexes through interaction with its ligand-binding domain. Upon agonist binding, AR undergoes a series of conformational changes. Specifically, the heat shock protein dissociates from the AR, and the conformed AR undergoes dimerization, phosphorylation, and translocation into the nucleus, mediated by nuclear localization signals. The nuclear-translocated receptor then binds to the androgen response element (ARE), characterized by a 6-nucleotide semi-regional consensus sequence 5'-TGTTCT-3' with three random nucleotides interspersed, located in the promoter or enhancer region of the AR gene target. The recruitment of other transcriptional coregulators (including coactivators and corepressors) and transcriptional mechanisms further ensures the transactivation of AR regulatory gene expression. All of these processes are initiated by ligand-induced conformational changes in the ligand-binding domain.

[0027] Prostate cancer is the second leading cause of cancer death in men in the United States, with roughly one in six American men being diagnosed with the disease at some point in their lives. Treatment aims to eradicate the tumor, but up to 50% of prostate cancer patients develop biochemical recurrence (BCR), defined as elevated PSA levels without evidence of metastatic disease on conventional imaging (CI) (Lin et al., 2019). Patients with BCR are at high risk of developing metastasis, and despite recent advances, treatment for metastatic prostate cancer remains palliative (Boorjian et al., 2011; Heinlein and Chang, 2004; Jackson et al., 2018; Pound et al., 1999). Given that the proliferation and survival of prostate cancer cells depend on the androgen receptor (AR), some men with BCR are treated with androgen deprivation therapy (ADT), which involves drugs that block testosterone production (e.g., GnRH agonists) alone or in combination with anti-androgens (e.g., bicalutamide), antagonizing the effect of residual testosterone on AR. This approach is effective, as evidenced by a decrease in PSA and regression of visible tumor (if present) in some patients. However, this is generally followed by regrowth, which can be retreated with ADT. This may be followed by a new decrease in PSA and tumor regression, eventually leading to regrowth as castration-resistant prostate cancer (CRPC), to which most patients eventually succumb. Recent studies on the molecular basis of CRPC have demonstrated that CRPC remains dependent on AR signaling and that an important mechanism of acquired resistance is elevated AR protein levels (CDChen et al., Nat. Med, 2004, 10, 33-39). AR-targeted agents that are active in castration-sensitive and castration-resistant prostate cancer offer great promise in the treatment of this fatal disease.

[0028] The course of prostate cancer from diagnosis to death is best classified into a series of clinical stages, based on the extent of the disease, hormonal status, and the presence or absence of metastases detectable by conventional imaging (CT / MRI and bone scans): localized disease, elevated PSA levels without conventionally detectable metastases after radiotherapy or surgery, and the presence or absence of clinical metastases in the non-castrated or castrated stage. While surgery, radiation therapy, or a combination of both may be curative for patients with localized disease, a significant proportion of these patients have recurrent disease, as evidenced by elevated PSA levels, which can lead to the development of metastases, i.e., a transition to a fatal phenotype of the disease, particularly in high-risk groups.

[0029] Androgen depletion is a treatment option with generally predictable outcomes: a decrease in PSA, a period of stability during which tumors do not grow, followed by an increase in PSA and regrowth.

[0030] Antiandrogens are useful in the early stages of prostate cancer treatment. However, prostate cancer often progresses to a "hormone-refractory" state, in which case the disease progresses in the presence of continuous androgen deprivation or antiandrogen therapy. Cases of antiandrogen withdrawal syndrome have also been reported after long-term antiandrogen treatment. Antiandrogen withdrawal syndrome is clinically well-observed and is defined by tumor regression or symptom reduction observed upon discontinuation of antiandrogen therapy. AR variants result in receptor indiscriminateness, and the ability of these antiandrogens to exhibit agonist activity may at least partially explain this phenomenon. For example, hydroxyflutamide and bicalutamide act as AR agonists in the T878A and W742L / W742C AR mutants, respectively (HLLiu et al., Int.J.Mol.Sci., 2017, 18:1823; T.Hara et al., Cancer Res., 2003, 63:149-153), while enzalutamide and apalutamide act as AR agonists in the F877L AR mutant (JDJoseph, Cancer Discov., 2013, 3:1020-1029).

[0031] In the context of prostate cancer cells made castration-resistant by AR overexpression, certain antiandrogen compounds, such as bicalutamide, have been demonstrated to possess a mixed antagonist / agonist profile (C. Tran et al., Science, 2009, 324:787-90). This agonist activity helps explain a clinical finding known as antiandrogen withdrawal syndrome, in which approximately 30% of men progressing on AR antagonists experience a decrease in serum PSA upon discontinuation of therapy (HIScher et al., J. Clin. Oncol., 1993, 11:1566-72).

[0032] Stages of prostate cancer In the early stages of prostate cancer, the cancer is localized to the prostate gland. Treatment in these early stages typically involves surgical removal of the prostate, radiation therapy to the prostate, or, in some patients, observation without aggressive intervention. In the early stages where prostate cancer is localized and intervention is necessary, surgery or radiation therapy is curative by eradicating the cancerous cells. Up to 50% of these treatments fail, and the prostate cancer continues to progress, typically indicated by elevated PSA levels. Men whose prostate cancer progresses after these early treatment strategies are said to have advanced or recurrent prostate cancer.

[0033] Because prostate cancer cells depend on androgen receptors (ARs) for proliferation and survival, men with advanced prostate cancer are treated either alone with drugs that block testosterone production (e.g., GnRH agonists) or in combination with anti-androgens that counteract the effects of residual testosterone on ARs (e.g., bicalutamide). These treatments lower serum testosterone to castration levels, thereby generally delaying disease progression for a period of time. This approach is effective, as evidenced by the decrease in PSA and regression of visible tumors in some patients. Ultimately, after regrowth, the decrease in PSA no longer continues, and the condition is defined as castration-resistant prostate cancer (CRPC), to which most patients eventually succumb.

[0034] In some embodiments, men with a BCR of hormone-sensitive prostate cancer prior to treatment with second-generation antiandrogens described herein are characterized by having the following: 1. Histologically or cytologically confirmed adenocarcinoma of the prostate, lacking small cell carcinoma or ductal carcinoma components, or having less than 50% neuroendocrine differentiation, and defined as high-risk adenocarcinoma with a prostate-specific antigen doubling time (PSADT) < 12 months after radical prostatectomy and optionally subsequent ART or SRT, and a PSA ≥ 0.2 ng / mL, or an increase from the lowest value after primary radiotherapy to PSA ≥ 2 ng / mL. 2. Hormone-sensitive prostate cancer demonstrated by serum testosterone levels ≥ 150 ng / dL (5.2 nmol / L). 3. Presence of at least one positive lesion of prostate cancer identified by prostate-specific membrane antigen positron emission tomography / computed tomography (PSMA PET / CT). Furthermore 4. No metastases detected by bone scan, CT, or MRI scan.

[0035] BCR is different from other prostate cancers. Generally, most patients with prostate cancer are diagnosed at the localized or regional stage. A critical point is the failure of primary treatment (surgery and / or radiation therapy).

[0036] An increase in prostate-specific antigen (PSA) levels that is not associated with a disease detectable by the naked eye is defined as a biochemical relapse (BCR). The definition of BCR depends on the type of previous curative treatment. In patients who have undergone radical prostatectomy (RP), the European Association of Urology (EAU) 2020 guidelines suggest that an increase in serum PSA levels should be considered a BCR.

[0037] Androgen receptor (AR) signaling is a key promoter of prostate cancer growth. Androgen deprivation therapy (ADT) is used to suppress prostate cancer cells in high-risk BCR patients (Snaterse, G., Mies, R., van Weerden, WM et al., Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids. Prostate Cancer Prostatic Dis 26, 293-301 (2023) https: / / doi.org / 10.1038 / s41391-022-00491-z). Therefore, ADT has been used for decades as a treatment for hormone-naive BCR. Regardless of the regimen used (intermittent or continuous), patients eventually develop prostate cancer resistance to ADT, which is defined as nmCRPC if resistance is defined solely by an increase in PSA, or as mCRPC if treatment resistance is defined by the presence of metastases identified by conventional imaging methods (bone scan, CT / MRI).

[0038] Androgen receptor inhibitors, including enzalutamide, apalutamide, and darolutamide, significantly increased metastasis-free survival (MFS) and overall survival (OS) in nmCRPC patients when combined with ADT.

[0039] The PSMA PET radiotracers 68Ga-PSMA-11 and 18F-DCFPyL were approved by the FDA in 2020 and 2021, respectively, for newly diagnosed high-risk disease patients or patients with biochemically relapsing disease (BCR). While the high sensitivity of PSMA PET / CT allows for the detection of prostate cancer lesions in BCR patients, this patient population presents a challenge for clinicians due to the lack of a clear standard of treatment. Patients with BCR after curative surgery or radiation therapy, who have exhausted all salvage options, present an even greater challenge. These patients were not eligible for all trials in mHSPC and were therefore considered to have BCR (Davis ID, Martin AJ, Stockler MR et al.: Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 381:121-131, 2019; Fizazi K, Tran N, Fein L et al.: Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 377:352-360, 2017; Sweeney CJ, Chen YH, Carducci M et al.: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373:737-746, 2015; Smith MR, Hussain M, Saad F et al.: Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med 386:1132-1142, 2022).

[0040] Some clinicians may consider extrapolating lesions detected by PSMA PET / CT to mHSPC, but this population of patients with less advanced disease may not offer the same utility (Madan RA, Mena E, Lindenberg L, Choyke PL. With New Technology Comes Great Responsibility: Prostate-Specific Membrane Antigen Imaging in Recurrent Prostate Cancer. J. Clin Oncol. 2022 Sept. 10;40(26):3015-3019. doi:10.1200 / JCO.22.00493.). Most patients in the mHSPC trial had invasive disease that could progress sufficiently at the initial stage, despite PSA screening. Biochemical recurrence can progress years after initial treatment (surgery and / or radiation) and, if detected by PSMA PET imaging, requires a different treatment approach. A procedure that has proven useful in a completely different clinical population, such as mHSPC, may not be appropriate for patients with lesions detected by BCR and PSMA PET / CT.

[0041] A key issue evaluated by ARASTEP is whether systemic therapy using image-guided (PSMA PET / CT) therapy can achieve sustained responses.

[0042] anti-androgens As used herein, the term “antiandrogen” refers to a group of hormone receptor antagonist compounds that can prevent or inhibit the biological effects of androgens on normally responsive tissues in the body. In some embodiments, the antiandrogen is a small molecule. In some embodiments, the antiandrogen is an AR antagonist. In some embodiments, the antiandrogen is a complete AR antagonist. In some embodiments, the antiandrogen is a first-generation antiandrogen. In some embodiments, the antiandrogen is a second-generation antiandrogen.

[0043] As used herein, the terms “AR antagonist” or “AR inhibitor” are interchangeable and refer to agents that inhibit or reduce the activity of at least one AR polypeptide. Examples of AR activities include, but are not limited to, coactivator binding, DNA binding, ligand binding, or nuclear translocation.

[0044] As used herein, “complete antagonist” means an antagonist that, at effective concentrations, essentially completely inhibits the activity of the AR polypeptide. As used herein, “partial antagonist” means an antagonist that can partially inhibit the activity of the AR polypeptide but is not a complete antagonist even at its highest concentration. “Essentially completely” means inhibition of at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more of the activity of the AR polypeptide.

[0045] As used herein, the term “second-generation antiandrogen” refers to a drug that exhibits full antagonist activity against wild-type AR polypeptides. Second-generation antiandrogens differ from first-generation antiandrogens in that they act as full antagonists in cells expressing high levels of AR, for example, in castration-resistant prostate cancer (CRPC). Examples of second-generation antiandrogens include darolutamide, apalutamide, enzalutamide, proxalutamide, or bubdegalutamide, bicalutamide, flutamide, or nilutamide, or ARV-766, EPI-7386, CC-94676, AC-0176, HP-518, or TAS-3681.

[0046] In some embodiments, the antiandrogens intended by the methods described herein, such as darolutamide, inhibit nuclear translocation of AR and inhibit DNA binding to androgen response elements and recruitment of coactivators. In some embodiments, the antiandrogens intended by the methods described herein do not exhibit agonist activity in AR-overexpressing prostate cancer cells.

[0047] Darorutamide is a second-generation anti-androgen that directly binds to the ligand-binding domain of AR, impairing nuclear translocation, AR binding to DNA, and the regulation of AR target genes, thereby inhibiting tumor growth. Darorutamide binds to AR with higher affinity than bicalutamide and induces partial or complete tumor regression in non-castration hormone-sensitive human prostate cancer xenograft models and bicalutamide-resistant human prostate cancer xenograft models (A. Moilanen et al., Sci. Rep., 2016, 5:12007; T. Sugawara et al., Int. J. Cancer, 2019, 14:1382-1394). Darorutamide does not possess the partial agonist activity seen with bicalutamide in relation to AR overexpression.

[0048] Darolutamide, also known as BAY 1841788 or ODM-201, is an AR antagonist consisting of two diastereomers, ORM-16497 and ORM-16555 (K. Fizazi et al., Lancet Oncol., 2014, 15:975-985; T. Sugawara et al., Int. J. Cancer, 2019, 14:1394). Darolutamide is active against known AR variants that result in resistance to other second-generation antiandrogens (H. Borgmann et al., 2018, Eur. Urol., 2018, 73:4-8; T. Sugawara et al., Int. J. Cancer, 2019, 14:1394). Darolutamide binds to AR with high affinity and subsequently inhibits androgen-induced nuclear translocation of AR and transcription of AR gene targets (T. Sugawara et al., Int. J. Cancer, 2019, 14:1394; SJBaumgart et al., Mol. Oncol., 2021, 14:2022-2039).

[0049] In one embodiment, a method for treating BCR hormone-sensitive prostate cancer is described herein, comprising, consisting of, or essentially comprising administering a safe and effective amount of antiandrogen to a male human being having BCR hormone-sensitive prostate cancer. In another embodiment, a method for treating a male human being having BCR hormone-sensitive prostate cancer is described herein, comprising, consisting of, or essentially comprising administering a safe and effective amount of antiandrogen to a male human being having BCR hormone-sensitive prostate cancer. In the following disclosure, “a method for treating BCR hormone-sensitive prostate cancer” may be alternatively listed as “a method for treating a male human being having BCR hormone-sensitive prostate cancer.” For brevity, each possible alternative will not be described.

[0050] Further definition As used herein, the term "cancer" refers to the abnormal growth of cells that tend to grow uncontrollably and, in some cases, metastasize (spread).

[0051] As used herein, the term “prostate cancer” refers to histologically or cytologically confirmed adenocarcinoma of the prostate.

[0052] The term "androgen deprivation therapy (ADT)" refers to reducing androgen levels in patients with prostate cancer to castration levels of testosterone (<50 ng / dL). Such procedures may include orchiectomy or the use of gonadotropin-releasing hormone (GnRH) agonists or antagonists. ADTs include surgical castration (orchiectomy) and / or administration of luteinizing hormone-releasing hormone ("LHRH") agonists or antagonists to humans (chemical castration). Examples of LHRH agonists include goserelin acetate, histrelin acetate, leuprolide acetate, and triptorelin pamoate. Physicians may prescribe LHRH agonists according to instructions, recommendations, and practice. LHRH agonists may include approximately 0.01 mg to approximately 20 mg of goserelin over a period of approximately 28 days to approximately 3 months, preferably approximately 3.6 mg to approximately 10.8 mg of goserelin over a period of approximately 28 days to approximately 3 months; approximately 0.01 mg to approximately 200 mg of leuprolide over a period of approximately 3 days to approximately 12 months, preferably approximately 3.6 mg of leuprolide over a period of approximately 3 days to approximately 12 months; or approximately 0.01 mg to approximately 20 mg of triptorelin over a period of approximately 1 month, preferably approximately 3.75 mg of triptorelin over a period of 1 month; or approximately 50 mg of histrelin acetate over a 12-month period, or approximately 50 μg / day of histrelin acetate.

[0053] The term "locally advanced prostate cancer" refers to prostate cancer in which all active cancer cells appear to be confined to the prostate and related or adjacent organs (e.g., seminal vesicles, bladder neck, and rectal wall).

[0054] The term "high-risk localized prostate cancer" refers to locally advanced prostate cancer that is likely to develop metastatic or recurrent disease after curative first-line therapy. In some embodiments, high risk of metastasis is defined as a prostate-specific antigen doubling time (PSADT) <20 months, <19 months, <18 months, <17 months, <16 months, <15 months, <14 months, <13 months, <12 months, or <11 months, <10 months, <9 months, <8 months, <7 months, <6 months, <5 months, <4 months, <3 months, <2 months, or <1 month. In some embodiments, high risk of metastasis is defined as a prostate-specific antigen doubling time (PSADT) <10 months. In some embodiments, high risk of metastasis is defined as having a high Gleason score or a large tumor.

[0055] The terms "castration-sensitive prostate cancer" or "hormone-sensitive prostate cancer" refer to cancer that responds to androgen deprivation therapy (ADT) as a localized disease, a biochemical recurrence, or in a metastatic state.

[0056] The term "metastatic castration-sensitive prostate cancer" or "metastatic hormone-sensitive prostate cancer" refers to cancer that has spread (metastasized) to other areas of the body, such as the bones, lymph nodes, or other parts of a man's body, and is responsive to androgen deprivation therapy (ADT).

[0057] The term "non-metastatic castration-sensitive prostate cancer" or "non-metastatic hormone-sensitive prostate cancer" refers to cancer in men that has not spread (metastasized) and is responsive to androgen deprivation therapy (ADT). In some embodiments, non-metastatic castration-sensitive prostate cancer is evaluated by bone scans and computed tomography (CT) or magnetic resonance imaging (MRI) scans.

[0058] As used herein, the term "CRPC" refers to castration-resistant prostate cancer. CRPC is a type of prostate cancer that continues to grow despite the suppression of male hormones that promote the growth of prostate cancer cells.

[0059] The term "metastatic castration-resistant prostate cancer" refers to castration-resistant prostate cancer that has metastasized to other parts of the body.

[0060] As used herein, the term “NM-CRPC” refers to non-metastatic castration-resistant prostate cancer. In some embodiments, NM-CRPC is evaluated by bone scans and computed tomography (CT) or magnetic resonance imaging (MRI) scans.

[0061] In some embodiments, non-metastatic castration-resistant prostate cancer is high-risk non-metastatic castration-resistant prostate cancer. The term "high-risk NM-CRPC" refers to the likelihood that a man with NM-CRPC will develop metastasis. In some embodiments, high risk of metastasis is defined as a prostate-specific antigen doubling time (PSADT) <20 months, <19 months, <18 months, <17 months, <16 months, <15 months, <14 months, <13 months, <12 months, or <11 months, <10 months, <9 months, <8 months, <7 months, <6 months, <5 months, <4 months, <3 months, <2 months, or <1 month. In some embodiments, high risk of metastasis is defined as a prostate-specific antigen doubling time (PSADT) <10 months. In some embodiments, high risk of metastasis is defined as having localized recurrence (e.g., primary tumor bed, bladder neck, anastomosis, pelvic lymph nodes).

[0062] As used herein, terms such as “concurrent administration” are intended to encompass the administration of multiple selected therapeutic agents to a single patient, including treatment regimens in which those therapeutic agents are administered by the same or different routes of administration and / or at the same or different times.

[0063] As used herein, the term “combination of pharmaceuticals” means a product resulting from a mixture or combination of two or more active ingredients, including both fixed and unfixed combinations of active ingredients. The term “fixed combination” means that the active ingredients, e.g., an antiandrogen and an adjuvant, are both administered to the patient simultaneously in the form of one unit or one dosage form. The term “unfixed combination” means that the active ingredients, e.g., an antiandrogen and an adjuvant, are administered to the patient simultaneously, in parallel, or sequentially in separate units or separate dosage forms, without specific intervention time limitations, thereby bringing safe and effective levels of the two active ingredients into the human male body. The latter also applies to cocktail therapies, e.g., the administration of three or more active ingredients.

[0064] The term "PSMA_PET" refers to prostate-specific membrane antigen positron emission tomography. This technique uses a tracer based on the presence of prostate-specific membrane antigen (PSMA) on prostate cancer cells, allowing for a visual assessment of ligand binding to the patient's androgen receptor. This technique can be used to evaluate the pharmacodynamics of androgen receptor-targeted therapies.

[0065] The term "consecutive daily dosing schedule" refers to the administration of a particular therapeutic agent without any breaks between doses. In some embodiments, a consecutive daily dosing schedule of a particular therapeutic agent includes administering the agent at approximately the same time each day.

[0066] The terms "to treat" and "treatment" refer to the treatment of a patient suffering from a pathological condition, encompassing not only the effect of alleviating the condition by killing cancer cells, but also the effect of inhibiting the progression of the condition, including a decrease in the rate of progression, a halt in the rate of progression, improvement of the condition, and a cure of the condition. Treatment as a preventive measure (i.e., prevention) is also included.

[0067] The term "radiological progression-free survival (rPFS)" is based on PSMA PET / CT and is defined as the period from randomization to the first recording of at least one new distant metastatic lesion by PSMA PET / CT, or death from any cause, whichever occurs first. Distant metastatic lesions are those occurring in the bone, viscera, or lymph nodes distal to the superior / external iliac arteries at the bifurcation of the common iliac artery (CIA).

[0068] The term “metastasis-free survival” or “MFS” refers to the proportion of subjects in a study who survive without cancer progression or death over a defined period of time. MFS is typically reported as time from enrollment in the study, randomization, or initiation of treatment. MFS is reported for individuals or study populations. In relation to treatment of CRPC with antiandrogens, increased metastasis-free survival is the additional period observed without cancer progression or death, whichever occurs first, compared to placebo treatment. In some embodiments, the increased metastasis-free survival is approximately 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, or more than 20 months. In some embodiments, administration of a safe and effective amount of antiandrogens results in increased metastasis-free survival in male humans. In some cases, the increase in metastasis-free survival is due to a comparison between the mean survival rate of a population of male humans with non-metastatic castration-resistant prostate cancer and a population of male humans treated with placebo. In some embodiments, metastasis-free survival refers to the time from randomization to the first evidence of distant metastasis to bone or soft tissue confirmed by BICR, or death from any other cause, whichever occurs first.

[0069] The term "time to CRPC" is defined as the time from randomization to the first castration-resistant event, which is defined as the time to PSA exacerbation with serum testosterone at castration levels <0.50 ng / mL, or the time to radiological exacerbation by CI, whichever occurs first.

[0070] The term "time to first symptomatic bone-related event (SSE)" is defined as the time from randomization to the first occurrence of an SSE. An SSE is defined as the occurrence of one of the following types of events: the occurrence of spinal cord compression, pathological fracture, tumor-related orthopedic intervention or external beam radiation therapy (EBRT) to alleviate skeletal symptoms.

[0071] The term "time to localized localized progression by PSMA PET / CT" is defined as the period from randomization to the first recorded localized localized progression by PSMA PET / CT, or death from any other cause, whichever occurs first.

[0072] The term "undetectable PSA rate at 12 months" is defined as the proportion of participants who have a detectable PSA level (≥0.2 ng / mL) at baseline and become undetectable (<0.2 ng / mL) at 12 months.

[0073] The term "time to decline in total FACT-P score," as the period until a decline in quality of life (QoL), is defined as the period from randomization until a 10-point decrease in the total FACT-P score.

[0074] The term "overall survival" is defined as the period from randomization to the date of death from any cause. Survival data for subjects who were alive at the time of analysis were censored to the last known date of survival. Furthermore, for subjects for whom there was no survival information after baseline, data was censored to the date of randomization. For subjects who could not be followed up or who withdrew their consent, data was censored to the last known date of survival. In some embodiments, administration of a safe and effective amount of antiandrogen resulted in an improvement in antitumor activity, as measured by overall survival.

[0075] The term “time to initiation of first subsequent systemic antineoplasmic therapy” is defined as the period from randomization to the record of the first subsequent systemic antineoplasmic therapy administered to the subject (e.g., CRF in a survival follow-up study). For subjects who do not initiate subsequent systemic antineoplasmic therapy, the time to initiation of first subsequent systemic antineoplasmic therapy is terminated on the last contact day. In some embodiments, administration of a safe and effective amount of antiandrogen results in an improvement in antitumor activity, as measured by the time to cytotoxic chemotherapy.

[0076] As used herein, the term “placebo” means the administration of a pharmaceutical composition that does not contain a second-generation antiandrogen. In connection with the treatment of CRPC, men administered an antiandrogen or placebo must maintain castration levels of testosterone by either concomitant administration of a GnRH agonist / antagonist or orchiectomy.

[0077] When referring to clinical trials, the term "randomization" refers to the point in time when a patient is confirmed to be eligible for the trial and assigned to a treatment group.

[0078] The terms "kit" and "product" are used as synonyms.

[0079] The terms "subject," "patient," and "human" are used interchangeably.

[0080] The term "pharmaceutical" refers to a product containing active pharmaceutical ingredients.

[0081] The terms "sale" or "to sell" mean transferring a pharmaceutical product, such as a pharmaceutical composition or oral dosage form, from a seller to a buyer.

[0082] The term "for sale" means a proposal to sell pharmaceuticals, such as pharmaceutical compositions and oral dosage forms, from a seller to a buyer.

[0083] Route of administration and pharmaceutical composition The therapeutic agents described herein are administered in any suitable form or formulation. Suitable routes of administration of the therapeutic agents include, but are not limited to, oral and parenteral (e.g., intravenous, subcutaneous, intramuscular). All formulations are in doses suitable for administration to humans. Outlines of the pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pennsylvania: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, New York, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins, 1999), and these documents are incorporated herein by reference for such disclosures.

[0084] The term “safe and effective dose” refers to the amount of an active ingredient that induces a desired biological or medical response in the target biological system without risks outweighing the benefits of such response, in accordance with the amended Federal Food, Drug, and Cosmetic Act (§§201-902, see 52 Stat. 1040 et seq., amended; 21 USC §§321-392). Safety is often measured by toxicity tests to determine the maximum permissible or optimal dose of the active ingredient required to achieve the desired benefit. Studies examining safety also seek to identify any potential adverse effects that may result from exposure to the drug. Efficacy is often measured by determining whether the active ingredient demonstrates superior health benefits to a placebo or other intervention when tested in appropriate circumstances, such as a strictly controlled clinical trial.

[0085] As used herein, the term “acceptable” with respect to a formulation, composition, or component means that the beneficial effects on the overall health of the male human being treated by that formulation, composition, or component substantially outweigh any harmful effects that such formulation, composition, or component may have.

[0086] In some embodiments, administration of a safe and effective amount of antiandrogen results in only grade 2 or lower adverse events. In other embodiments, administration of a safe and effective amount of antiandrogen results in only grade 3 or lower adverse events. In other embodiments, administration of a safe and effective amount of antiandrogen results in only grade 4 or lower adverse events.

[0087] In some embodiments, the antiandrogen exists in solid oral dosage form. In some embodiments, the antiandrogen is formulated as a tablet. In some embodiments, the antiandrogen is apalutamide. In some embodiments, the antiandrogen is enzalutamide. Solid oral dosage forms containing either apalutamide or enzalutamide may be given as softgel capsules, as disclosed in International Publication No. 2014113260 and Chinese Patent Application Publication No. 104857157, respectively, which are incorporated herein by reference, or as tablets, as disclosed in International Publication Nos. 2016090098, 2016090101, 2016090105, and 2014043208, respectively, which are incorporated herein by reference. Suitable techniques for preparing the solid oral dosage form of the present invention are described in Remington's Pharmaceutical Sciences, 18th edition, edited by A. R. Gennaro, 1990, Chapter 89, and Remington—The Science, and Practice of Pharmacy, 21st edition, 2005, Chapter 45.

[0088] To prepare the pharmaceutical composition of the present invention, the active pharmaceutical component is densely mixed with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques, the carrier may take on a wide variety of forms depending on the desired form of the preparation for administration (e.g., orally or parenterally). Certain suitable pharmaceutically acceptable carriers are known in the art. Some descriptions of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0089] For solid oral preparations, such as dry powders, granules, capsules, caplets, gel caps, pills, and tablets (each including immediate-release, time-release, and / or sustained-release formulations) for reconstitution or inhalation, suitable carriers and excipients include, but are not limited to, diluents, granulators, lubricants, binders, flow enhancers, and disintegrants. Tablets and capsules are typical oral unit dosage forms that are most advantageous for ease of administration, in which case solid pharmaceutical carriers are naturally used. If desired, tablets may be sugar-coated, gelatin-coated, film-coated, or enteric-coated by standard techniques.

[0090] In certain embodiments, these compositions are unit dosage forms such as tablets, pills, capsules for oral, intranasal, sublingual, intraocular, transdermal, rectal, vaginal, dry powder inhaler, or other inhalation or blowing means; dry powder, granules, lozenges for reconstitution or inhalation; sterile solutions or suspensions; metered aerosols or liquid sprays; drops or suppositories.

[0091] These formulations are manufactured using conventional formulation techniques. To prepare a solid pharmaceutical composition, such as a tablet, the main active ingredient is mixed with a pharmaceutical carrier, such as conventional tableting components, such as diluents, binders, adhesives, disintegrants, lubricants, anti-adhesion agents, and flow enhancers. Suitable diluents include, but are not limited to, starch (i.e., corn, wheat, or potato starch, which may be hydrolyzed), lactose (granular, spray-dried, or anhydrous), sucrose, sucrose-based diluents (powdered sugar; sucrose + approximately 7-10% by weight of invert sugar; sucrose + approximately 3% by weight of modified dextrin; sucrose + invert sugar, approximately 4% by weight of invert sugar, approximately 0.1-0.2% by weight of corn starch, and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e., AVICEL microcrystalline cellulose available from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate, etc. Suitable binders and adhesives include, but are not limited to, acacia gum, guar gum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulose (i.e., methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, etc.), and water-soluble or dispersible binders (i.e., alginic acid and its salts, magnesium aluminum silicate, hydroxyethylcellulose [i.e., TYLOSE available from Hoechst Celanese], polyethylene glycol, polysaccharide acids, bentonite, polyvinylpyrrolidone, polymethacrylate, and pregelatinized starch). Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch glycolate, pregelatinized starch, clay (magnesium aluminum silicate), cellulose (e.g., cross-linked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, pregelatinized starch (i.e., corn starch, etc.), gums (i.e., agar, guar, carob, karaya, pectin, and tragacanth gum), and cross-linked polyvinylpyrrolidone.Suitable lubricants and anti-adhesion agents include, but are not limited to, stearates (magnesium, calcium, and sodium salts), stearic acid, talc wax, stearowet®, boric acid, sodium chloride, DL-leucine, carbowax® 4000, carbowax® 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, and magnesium lauryl sulfate. Suitable flow enhancers include, but are not limited to, talc, corn starch, and silica (i.e., CAB-O-SIL® silica available from Cabot, SYLOID® silica available from WRGrace / Davison, and AEROSIL® silica available from Degussa). Sweeteners and flavorings can be added to chewable solid dosage forms to improve the palatability of oral dosage forms. Furthermore, colorants and coatings can be added to or applied to solid dosage forms to facilitate drug identification or for aesthetic purposes. These carriers are formulated together with pharmaceutically active substances to deliver a precise and appropriate dose of the pharmaceutically active substance with a therapeutic release profile.

[0092] Suitable binders for use in the pharmaceutical compositions provided herein include, but are not limited to, starch, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose), polyvinylpyrrolidone, and mixtures thereof.

[0093] Examples of fillers suitable for use in pharmaceutical compositions provided herein include, but are not limited to, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pregelatinized starch, and mixtures thereof.

[0094] Binders or fillers in a pharmaceutical composition are typically present in an amount of about 50 to about 99% by weight of the pharmaceutical composition or dosage form.

[0095] A disintegrant can be used in the composition to provide tablets that disintegrate when exposed to an aqueous environment. Tablets with too much disintegrant may disintegrate during storage, while tablets with too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Therefore, to form a solid oral dosage form, a sufficient amount of disintegrant should be used, neither too much nor too little, so as to adversely alter the release of the active ingredient. The amount of disintegrant used varies depending on the type of formulation and is readily apparent to those skilled in the art. A typical pharmaceutical composition contains about 0.5 to about 15% by weight of disintegrant, specifically about 1 to about 5% by weight of disintegrant. Disintegrants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, other celluloses, gums, and mixtures thereof.

[0096] Lubricants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, sodium stearyl fumarate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Lubricants are typically used in amounts less than about 1% by weight of the pharmaceutical composition or dosage form in which the lubricant is incorporated.

[0097] Compressed tablet formulations may be film-coated to provide color, light protection, and / or flavor enhancement. Tablets may also be coated to regulate the onset and / or rate of release in the gastrointestinal tract in order to optimize or maximize the patient's biological exposure to the API.

[0098] Hard capsule formulations can be manufactured by filling a blend or granules of apalutamide or enzalutamide into a shell made of, for example, gelatin or hypromellose.

[0099] Softgel capsule formulations can be manufactured.

[0100] Pharmaceutical compositions intended for oral use may be prepared from the above-described solid dispersion formulations and blending materials according to the methods described herein and other methods known in the art for the manufacture of pharmaceutical compositions. Such compositions may further contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to result in pharmaceutically refined and palatable preparations.

[0101] Tablets may contain the active ingredient in combination with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacturing. These excipients may be, for example, inert diluents, granulators, and disintegrants, binders, flow enhancers, lubricants, and antioxidants, such as propyl gallate, butylated hydroxyanisole, and butylated hydroxytoluene. Tablets may be uncoated, film-coated to alter their appearance, or coated with a functional coating to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect.

[0102] Compositions for oral use may also be provided as capsules (e.g., hard gelatin) in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or starch, or as soft gelatin capsules in which the active ingredient is mixed with a liquid or semi-solid, such as peanut oil, liquid paraffin, fractionated glycerides, surfactants, or olive oil. Aqueous suspensions contain the active material in combination with excipients suitable for the preparation of aqueous suspensions. Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the active ingredient in combination with a dispersant or wetting agent, a suspending agent, and one or more preservatives. In certain embodiments of the present invention, the pharmaceutical composition of the present invention comprises a diluent system, a disintegrant, a salt, a lubricant, a flow promoter, and a film coat, each at concentrations of approximately 3% w / w to approximately 58% w / w, approximately 4% w / w to approximately 20% w / w, approximately 4% w / w to approximately 20% w / w, approximately 0.5% w / w to approximately 4% w / w, approximately 0% w / w to approximately 2% w / w, and approximately 1% w / w to approximately 5% w / w, or each at concentrations of approximately 18% w / w to approximately 40% w / w, approximately 7% w / w to approximately 15% w / w, approximately 7% w / w to approximately 18% w / w, approximately 1.0% w / w to approximately 3.0%, approximately 0.1% w / w to approximately 1.0% w / w, and approximately 2.0% w / w to approximately 4.0% w / w. In certain embodiments, the solid dispersion formulation is blended with a diluent, one or more disintegrants, a lubricant, and a flow enhancer. Exemplary blended compositions or oral dosage forms include mannitol, microcrystalline cellulose, croscarmellose sodium, sodium chloride, colloidal silica, stearyl fumarate sodium, and magnesium stearate.

[0103] The disintegrant may be present at concentrations of approximately 4% w / w to 20% w / w, or approximately 7% w / w to 15% w / w. Salts, which may be sodium chloride, potassium chloride, or combinations thereof, may also be present. The combination of salt and disintegrant is present at concentrations of approximately 5% w / w to 35% w / w in the final pharmaceutical composition.

[0104] In certain embodiments, the inert components of the core tablet may include colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose. In other embodiments, the tablet is finished with a film coating consisting of the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

[0105] In other embodiments, a single dose of the pharmaceutical composition of this disclosure may contain about 300 mg of darolutamide, consist of about 300 mg of darolutamide, or essentially consist of about 300 mg of darolutamide. In some embodiments, multiple doses of a single-dose pharmaceutical composition containing about 300 mg of enzalutamide, consisting of about 300 mg of enzalutamide, or essentially consisting of about 300 mg of enzalutamide, such as two multiple unit dosage forms or individual unit dosage forms, are administered to a human. The total daily dose of darolutamide may range from about 300 mg / day to about 1500 mg / day. In certain embodiments, the total daily dose of darolutamide may be about 1200 mg / day. The darolutamide compound may exist as any of the possible diastereoisomers, including mixtures of any combination of diastereoisomers. In certain embodiments, darolutamide may have structures in the form of one or more (R,R) diastereomers, (R,S) diastereomers, (S,R) diastereomers, and (S,S) diastereomers, including various mixtures of two or more possible diastereoisomers in any ratio. In certain embodiments, darolutamide may have structures in the form of (S,R) diastereomers, (S,S) diastereomers, and (S,S) diastereomers and (S,R) diastereomers in any isomer ratio.

[0106] In some embodiments, a single dose of the pharmaceutical composition contains, comprises, or essentially consists of about 60 mg of apalutamide. In some embodiments, multiple doses of a single-dose pharmaceutical composition containing, comprising, or essentially consisting of about 60 mg of apalutamide, such as four multiple dosage forms or individual dosage forms, are administered to a person. The total daily dose of apalutamide may be about 240 mg / day.

[0107] In further embodiments, a single dose of the pharmaceutical composition contains, comprises, or essentially consists of about 40 mg of enzalutamide. In some embodiments, multiple doses of a single-dose pharmaceutical composition containing, comprising, or essentially consisting of about 40 mg of enzalutamide, such as four multiple dosage forms or individual dosage forms, are administered to a human. The total daily dose of enzalutamide may be about 160 mg / day.

[0108] In further embodiments, a single dose of the pharmaceutical composition may contain, consist of, or essentially consist of at least one antiandrogen, such as at least one androgen receptor inhibitor. According to certain embodiments, the at least one antiandrogen may be at least one androgen receptor inhibitor selected from the group consisting of darolutamide, apalutamide, enzalutamide, and combinations thereof. In some embodiments, multiple doses of a single-dose pharmaceutical composition, such as two to four multiple dosage forms or individual dosage forms, containing, consisting of, or essentially consisting of about 40 mg to 300 mg of an androgen receptor inhibitor, are administered to a human. The total daily dose of antiandrogens may range from about 160 mg / day to about 1500 mg / day.

[0109] All formulations for oral administration take on a dosage form suitable for such administration.

[0110] Administration method and treatment regimen In one embodiment, a method for treating BCR hormone-sensitive prostate cancer is described herein, comprising, consisting of, or essentially consisting of administering a safe and effective amount of antiandrogen to a male human having BCR hormone-sensitive prostate cancer. In certain embodiments, the antiandrogen compound may be an androgen receptor inhibitor selected from the group consisting of androgen receptor inhibitors, e.g., darolutamide, apalutamide, enzalutamide, and combinations thereof. The antiandrogen composition or formulation may be administered orally. In some embodiments, the antiandrogen is administered daily. In some embodiments, the antiandrogen is administered twice daily. In some embodiments, the antiandrogen is administered three times daily. In some embodiments, the antiandrogen is administered four times daily. In certain embodiments, the human dose of the antiandrogen compound used to treat the disease or condition described herein is typically in the range of about 10 mg / day to about 1500 mg / day.

[0111] In certain embodiments, the antiandrogen compound may be darolutamide. According to several embodiments, darolutamide is administered orally. In some embodiments, the antiandrogen is administered daily. In some embodiments, the antiandrogen is administered twice daily. In some embodiments, the antiandrogen is administered three times daily. In some embodiments, the antiandrogen is administered four times daily. In some embodiments, apalutamide is administered every other day. In some embodiments, the antiandrogen is administered weekly. In some embodiments, the antiandrogen is administered twice weekly. In some embodiments, the antiandrogen is administered every other week. In some embodiments, the antiandrogen is administered orally on a consecutive daily dosing schedule.

[0112] In one embodiment, the desired dose is provided as a single dose or divided dose, which is conveniently administered simultaneously (or over a short period of time) or at appropriate intervals, for example, as two, three, four, or more partial doses per day. In some embodiments, the antiandrogen is conveniently provided as a divided dose, which is conveniently administered once daily simultaneously (or over a short period of time). In some embodiments, the antiandrogen is conveniently provided twice daily in divided doses, which are conveniently administered in equal portions. In some embodiments, the antiandrogen is conveniently provided three times daily in divided doses, which are conveniently administered in equal portions. In some embodiments, the antiandrogen is conveniently provided four times daily in divided doses, which are conveniently administered in equal portions.

[0113] In some embodiments, the antiandrogen is a second-generation antiandrogen selected from the group consisting of, for example, darolutamide, enzalutamide, apalutamide, and mixtures thereof. In certain embodiments, the antiandrogen is darolutamide. In some embodiments, the antiandrogen is enzalutamide. In some embodiments, the antiandrogen is apalutamide.

[0114] Generally, the human dose of darolutamide used to treat the diseases or conditions described herein is typically in the range of about 300 mg / day to about 1500 mg / day.

[0115] In some embodiments, darolutamide is administered orally at a dose of approximately 1200 mg / day. In some embodiments, darolutamide is administered at doses greater than 1200 mg / day. In some embodiments, darolutamide is administered orally to humans twice daily at a dose of approximately 600 mg.

[0116] In some embodiments, enzalutamide is administered orally at a dose of about 160 mg / day. In some embodiments, doses of enzalutamide exceeding 160 mg / day are administered. Generally, the human dose of apalutamide used to treat the diseases or conditions described herein is typically in the range of 10 mg / day to 1000 mg / day. In some embodiments, apalutamide is administered orally to humans at a dose of about 30 mg / day to about 600 mg / day. In some embodiments, apalutamide is administered orally to humans at doses of about 30 mg / day, about 60 mg / day, about 90 mg / day, about 120 mg / day, about 160 mg / day, about 180 mg / day, about 240 mg / day, about 300 mg / day, about 390 mg / day, about 480 mg / day, about 600 mg / day, about 780 mg / day, about 960 mg / day, or about 1200 mg / day.

[0117] In some embodiments, apalutamide is administered orally to humans at a dose of approximately 240 mg / day. In some embodiments, apalutamide is administered to humans at a dose greater than 240 mg / day. In some embodiments, apalutamide is administered orally to humans four times a day at a dose of approximately 60 mg. In some embodiments, apalutamide is administered orally to humans in a continuous daily dosing schedule.

[0118] In certain embodiments where no improvement in the disease or condition is observed in humans, the daily dose of the antiandrogen is increased. In some embodiments, the once-daily dosing schedule is changed to a twice-daily dosing schedule. In some embodiments, a three-times-daily dosing schedule is used to increase the amount of antiandrogen administered.

[0119] In some embodiments, the amount of antiandrogens administered to humans varies depending on various factors, including, but not limited to, the state and severity of the disease or condition, as well as individual characteristics of the person (e.g., body weight), and (if applicable) specific additional therapeutic agents administered.

[0120] Kits and products Kits and products are also described for use in the methods of use described herein. Such kits include a partitioned package or container for holding one or more doses of the pharmaceutical compositions disclosed herein. Suitable containers include, for example, bottles. In one embodiment, the container is formed from a variety of materials such as glass or plastic.

[0121] The products provided herein include packaging materials. Examples of packaging materials for use in packaging pharmaceutical products include, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for the selected formulation and the intended mode of administration and treatment.

[0122] A kit typically includes a label listing the contents and / or instructions for use, as well as a package insert containing instructions for use. Typically, a set of instructions is also included.

[0123] In one embodiment, the label is either present on the container or attached to the container. In one embodiment, the label is present on the container if the letters or other characters, such as numbers, that make up the label are attached to, molded, or etched onto the container itself. If the label is located within a receptacle or carrier that holds the container, the label is attached to the container, for example, as accompanying documentation.

[0124] In one embodiment, the label is used to indicate that the contents are for use in a specific therapeutic application. The label may also indicate, for example, instructions for the use of the contents in the method described herein.

[0125] In certain embodiments, the pharmaceutical composition is provided in a pack or dispenser device containing one or more unit dosage forms containing the compounds provided herein. The pack may include, for example, metal or plastic foil, and may be a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied by a caution regarding the form of container prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, and this caution reflects the approval of such government agency regarding the form of the drug for human or veterinary administration. Such caution may be, for example, a label approved by the U.S. Food and Drug Administration for a prescription drug, or an approved product insert. In one embodiment, compositions containing the compounds provided herein in a formulated state in a suitable pharmaceutical carrier are also prepared, placed in a suitable container, and labeled for the treatment in the indicated state.

[0126] Examples These examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0127] Example 1 - Preclinical Development Darolutamide (BAY 1841788, ODM-201) is a second-generation antiandrogen that directly binds to the ligand-binding domain of AR, impairing nuclear translocation and AR binding to DNA, thereby inhibiting AR target gene and protein levels and consequently inhibiting tumor growth (A. Moilanen et al., Sci. Rep., 2016, 5:12007; T. Sugawara et al., Int. J. Cancer, 2019, 14:1382-1394; SJBaumgart, Mol. Oncol., 2021, 14:2022-2039). As demonstrated in several cell line-derived and patient-derived models, darolutamide binds to AR with higher affinity than bicalutamide and inhibits the progression of prostate tumors (A. Moilanen et al., Sci. Rep., 2016, 5:12007; T. Sugawara et al., Int. J. Cancer, 2019, 14:1382-1394). Darorutamide consists of two diastereomers with equivalent activity, namely ORM-16497 and ORM-16555 (T. Sugawara et al., Int. J. Cancer, 2019, 14:1394). Darolutamide is active against known AR variants that conflate resistance to other second-generation antiandrogens (H. Borgmann et al., 2018, Eur. Urol., 2018, 73:4-8; T. Sugawara et al., Int. J. Cancer, 2019, 14:1394).

[0128] Darorutamide exhibits high bioavailability and is completely and rapidly absorbed in rats (P. Taavitsainen et al., Xenobiotica, 2020, 50:967-979). Rapid interconversion of the diastereoisomers (S,R)- and (S,S)- via the major circulating metabolite keto-darorutamide is observed both in vitro and in vivo. The (S,R) diastereoisomer shows faster elimination, but the diastereoisomer ratio remains unchanged at high doses. 14In vivo distribution studies using [C]-darolutamide showed broad and uniform distribution in all tissues except the brain after a single oral administration (P. Taavitsainen et al., Xenobiotica, 2020, 50:967-979). In contrast, exposure was higher in prostate tissue, demonstrating effective tissue penetration in the target organ for therapeutic activity (P. Taavitsainen et al., Xenobiotica, 2020, 50:967-979).

[0129] In vitro, darolutamide is primarily metabolized by oxidative biotransformation catalyzed by cytochrome P450 (CYP) 3A4. Only one major metabolite, keto-darolutamide, was observed in the plasma of all species investigated, including humans (P. Taavitsainen et al., 2021 Drug Metab Dispos 49:420-433). Keto-darolutamide is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) (C. Zurth et al., Eur. J. Drug Metab. Pharmacokinet., 2019, 44:747-759). The enzymatic activity of nine CYP isoforms was not inhibited or only slightly inhibited by darolutamide in vitro, and static evaluations based on order and mechanism suggested a very low risk of clinically significant drug interactions (DDIs) due to CYP inhibition. In vitro, darolutamide did not show significant induction of CYP1A2 or CYP2B6 activity. Inhibition of transport mediated by BCRP, P-gp, organic anion transporter (OAT)3, multidrug / toxin efflux (MATE)1, MATE2-K, organic anion transport polypeptide (OATP)1B1, and OATP1B3 was observed in vitro. Phase I data showed that darolutamide exposure increased 1.75-fold with co-administered itraconazole and decreased by 72% with rifampicin. Co-administration of darolutamide with CYP3A4 / P-gp substrates showed no effect or only a slight effect. Rosuvastatin exposure increased 5.2-fold with darolutamide, possibly due to inhibition of BCRP and possibly OATPB1 / OATPB3. In conclusion, darolutamide is unlikely to have clinically significant drug-dependent interactions (DDIs) with drugs that are substrates of CYP or P-gp, and increased exposure to BCRP substrates and possibly OATP substrates was the main interaction of note (C. Zurth et al., Eur. J. Drug Metab. Pharmacokinet., 2019, 44:747-759).

[0130] The safety profile of darolutamide in rats and dogs was characterized by repeated-dose toxicity studies up to 6 and 9 months, toxicological data, genotoxicity, and phototoxicity studies.

[0131] Consistent with its pharmacological activity, the primary target organ was the reproductive system. In repeated-dose toxicity studies in rats and dogs, the main finding was changes in the male genitalia (decreased organ weight with atrophy of the prostate and epididymis). These effects occurred at systemic exposure levels within or below the expected human exposure range (based on AUC comparison). Further changes in the reproductive tissue included a slight increase in vacuolar degeneration of the pituitary gland, atrophy and decreased secretion of the seminal vesicles and mammary glands in rats, and oligospermia, dilation and degeneration of the seminiferous tubules, and testicular oligospermia in dogs. The changes in the male genitalia in both species were consistent with the pharmacological activity of darolutamide and reversed or partially disappeared after a recovery period of 4–8 weeks. No other adverse effects were observed. No deaths occurred during the treatment period.

[0132] Based on available data (nubeqa-epar-public-assessment-report_en_final_Apr2020), darolutamide is considered a non-phototoxic and non-genotoxic compound.

[0133] In a transgenic mouse study of male and female 001178-T (hemizygous) RasH2 mice administered BID darolutamide for at least 26 weeks at a maximum dose of 500 mg / kg / dose, no carcinogenicity of darolutamide was observed.

[0134] Example 2 - Clinical Development A randomized, double-blind, placebo-controlled phase 3 study comparing darolutamide plus androgen deprivation therapy (ADT) with placebo plus ADT in patients with high-risk biochemical recurrence (BCR) of prostate cancer.

[0135] Main purpose To determine whether 24 months of darolutamide + ADT administration improves rPFS as measured by PSMA. PET / CT compared to placebo + ADT administration over 24 months

[0136] Secondary purpose Further evaluation of efficacy and measurement of the treatment's impact on patient quality of life by comparing the following parameters with placebo in men with BCR of hormone-sensitive prostate cancer treated with darolutamide: MFS by CI assessed by BICR, time to CRPC assessed by the investigator, time to initiation of the first subsequent systemic antineoplasm therapy, time to localized progression by PSMA PET / CT, time to the first SSE, OS, PSA undetectable rate at 12 months (<0.2 ng / mL), time to decline in FACT-P total score, and safety and tolerability.

[0137] Other purposes Further evaluate efficacy and measure the impact of the treatment on patients' quality of life by comparing the following: time to PSA progression, PSA undetectable rate at any point in time (<0.2 ng / mL), time to testosterone recovery, time to prostate cancer progression as measured by the EORTC QLQ-PR25 subscale and total score, and time to decline in the PCS subscale of FACT-P. To evaluate biomarkers in order to investigate the pharmacodynamic effects of darolutamide, as well as subgroups of molecules that have a clear prognosis and / or response to darolutamide. Further investigation of the research drug and similar drugs (e.g., mechanism-related effects, safety), as well as further investigation of pathological mechanisms thought to be related to cancer and related health problems.

[0138] research design This is a randomized, double-blind, placebo-controlled phase 3 study to evaluate whether darolutamide administration in addition to ADT over 24 months yields superior efficacy compared to placebo + ADT over 24 months, based on rPFS by PSMA PET / CT assessed by BICR in participants with hormone-sensitive high-risk BCR for prostate cancer.

[0139] The primary endpoint of PSMA PET / CT as assessed by BICR, rPFS, is defined as the time from randomization to the first recording of at least one new distant metastatic lesion by PSMA PET / CT as assessed by BICR, or death from any cause, whichever occurs first.

[0140] MFS, a secondary endpoint assessed by conventional imaging methods as evaluated by BICR, is defined as the period from randomization to the first recording of at least one new distant metastatic lesion as assessed by BICR, or death from any cause, whichever occurs first.

[0141] Approximately 750 research participants will be randomly assigned in a 1:1 ratio to receive one of the following research drugs for 24 months. -Darolutamide 600 mg (2 tablets of 300 mg) twice daily (BID), administered with food, equivalent to a total daily dose of 1200 mg. or - A placebo tablet identical in appearance to darolutamide, administered with food (BID).

[0142] Background therapy: All participants must receive ADT (LHRH agonist / antagonist) as standard therapy for 24 months, at the discretion of the principal investigator.

[0143] Image-guided radiotherapy or surgery for distant and / or local lesions identified by PSMA PET / CT is permitted for all participants.

[0144] Participants are classified as follows at the time of randomization (Section 6.9): -PSADT less than 6 months vs. 6 months to less than 12 months - Previous radical prostatectomy versus primary radiotherapy - Distant metastasis (with or without localized lesions) vs. localized lesions only

[0145] This study comprises four consecutive periods: screening, treatment, active follow-up, and long-term follow-up (with clinical visits and survival tracking). Screening must be performed within 30 days prior to randomization. The start of the treatment period is defined by the first dose of the study treatment, which must be administered within 3 days after the day of randomization and after all activities of the screening period. Participants will receive the study treatment for 24 months unless there is disease exacerbation or unacceptable toxicity during the 24-month treatment period.

[0146] Screening visits must be recorded in an interactive response technology (IRT) system, and participants will be assigned a unique identification number (ID number).

[0147] Some screening and follow-up visit procedures, with the exception of PSMA PET / CT, CT / MRI, and bone scans, can be performed using eTools where appropriate.

[0148] During screening, in addition to sampling at the central laboratory, a local PSA level should be obtained. This value is used to confirm that the patient's PSA ADT for the most recent 12 months is <12 months, prior to randomization, which takes place at least 4 weeks later. PSA ADT should be obtained if the patient's testosterone levels were normal or if blood testosterone levels recovered to >150 ng / mL after discontinuation of neoadjuvant and / or adjuvant therapy.

[0149] The PSA values ​​used to calculate PSADT should preferably be obtained using the same assay and, if possible, in the same laboratory. PSA screening from a routine laboratory should be included in the calculation of PSADT. The PSA values ​​used to calculate PSADT should be >0.2 ng / mL and should track the overall upward trend. All PSA values ​​included should be obtained within the last 12 months at most to reflect current disease activity [AUA / ASTRO / SUO Guidelines 2020, and EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines 2022 (Lowrance et al. 2021, Mottet et al. 2022)]. The PSA values ​​used to calculate PSADT are recorded in the CRF. PSADT is calculated according to the AUA / ASTRO / SUO Guidelines 2020 and the EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines 2022.

[0150] Patients who test positive on PSMA PET / CT for tumor lesions detectable by CI screening (bone scan and CT / MRI) do not meet the eligibility criteria and should not be rescreened. This is because these patients can be treated with standard of care (SoC) available for mHSPC or localized therapy according to local clinical practice.

[0151] research group - Males who are 18 years of age or older at the time of signing the informed consent form.

[0152] Inclusion Criteria Participants enrolled in this study must meet the following key acceptance criteria: - You can submit a signed informed consent form. - Histologically or cytologically confirmed adenocarcinoma of the prostate. -Prostate cancer initially treated by: • Radical prostatectomy (RP) followed by adjuvant radiotherapy (ART) or salvage radiotherapy (SRT) - RP in participants unsuitable for ART or SRT, • Or primary radiotherapy (RT) - High-risk biochemical relapse (BCR) defined as prostate-specific antigen doubling time (PSADT) < 12 months. - and • PSA ≥ 0.2 ng / mL after RP, or in participants unsuitable for ART or SRT, or • The increase from the lowest value after primary RT alone is PSA ≥ 2 ng / mL - Participants must undergo prostate-specific membrane antigen positron emission tomography / computed tomography (PSMA PET / CT) within a 30-day screening period using either 18F-DCFPyL (pifluforastat F18) or 68Ga-PSMA-11, which will be evaluated by BICR to identify the following: • At least one PSMA PET-positive lesion in prostate cancer and • The number and location of lesions used as baseline criteria. - Serum testosterone ≥ 150 ng / dL (5.2 nmol / L). - Performance status of the Eastern Cooperative Oncology Group (ECOG) is 0 or 1. - Blood cell count at screening: • Hemoglobin ≥ 9.0 g / dL (Participants must not have received a blood transfusion within 7 days prior to sample collection.) • Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L (Participants must not receive any growth factors within four weeks prior to sample collection.) Platelet count ≥ 100 × 10 9 / L -Screening value: • Alanine aminotransferase (ALT) ≤ 1.5 × Upper limit of normal (ULN) • Aspartate aminotransferase (AST) ≤ 1.5 × ULN • Total bilirubin (TBL) ≤ 1.5 ULN (excluding participants diagnosed with Gilbert's disease) • Estimated glomerular filtration rate (eGFR) > 40 ml / min / 1.73 m 2 (Calculated using the CKD-EPI formula) - Sexually active male participants must agree to use the contraceptive methods detailed in the protocol during the treatment period and for at least three months after the last dose of the study treatment, and must refrain from donating sperm during this period.

[0153] Exclusion criteria Participants will be excluded from the study if they meet any of the following criteria. - Pathological findings consistent with more than 50% of the components of small cell carcinoma, ductal carcinoma, or neuroendocrine carcinoma of the prostate. - History of bilateral orchiectomy. - Metastatic or recurrent / new malignant lesions in the prostate / prostatic bed, seminal vesicles, or lymph nodes below the CIA bifurcation, as assessed by BICR during screening using conventional imaging (CI). -Brain metastases detected by PSMA PET / CT using BICR during screening. - High-risk BCR after primary radiotherapy with new localized lesions on PSMA PET / CT screening, who are eligible for radical salvage prostatectomy. Note: Participants who meet the PSA criteria (inclusion criterion 5) and who undergo radical salvage prostatectomy after primary RT may be considered for the study. - Prior treatment with second-generation (e.g., enzalutamide, apalutamide) androgen receptor inhibitors (ARIs) and CYP17 inhibitors (e.g., abiraterone) within 18 months prior to signing the ICF. - Prior treatment with PSMA radiotherapy within 12 months prior to randomization. - Previous radiotherapy (including image-guided radiotherapy) as primary, adjunctive, or salvage treatment completed within 8 weeks prior to signing the ICF. - Known hypersensitivity to any of the following: research drugs, contrast agents, research drug classes, or excipients contained in research drug formulations. - Contraindications for PSMA PET / CT tracers, or for both CT and MRI contrast agents. - Any previous malignant tumor within the last 5 years (other than well-treated basal cell carcinoma or squamous cell carcinoma, superficial bladder cancer, or any other carcinoma in situ that is currently in complete remission). - History of pelvic radiotherapy for other malignant tumors. - Persistent or active infections requiring systemic therapy (bacterial, fungal, or viral infections, including reactivation of viral hepatitis and hepatitis B, for example). - Any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) that suggests the presence of a virus. • Active HBV (chronic or acute; defined as a known positive result for hepatitis B surface antigen [HBsAg] test at the time of screening), excluding participants receiving antiviral therapy for undetectable or low viral loads of HBV. If HBV DNA is negative, participants with a history of HBV infection or remission of HBV infection (defined as the presence of hepatitis B core antibodies [HbcAb] and the absence of HbsAg) are eligible. • Participants who are positive for HCV antibodies are not subject to polymerase chain reaction unless their polymerase chain reaction is negative for HCV RNA. Note: Testing for hepatitis B and C is not required unless requested by local authorities. - Known human immunodeficiency virus (HIV) infection accompanied by any of the following: • CD4+ T cell (CD4+) count is less than 350 cells / μL • History of AIDS-related opportunistic infections within the past 12 months • Receiving established antiretroviral therapy for less than 4 weeks • Showed a viral load exceeding 400 copies / mL before registration. • You are receiving antiretroviral therapy or using prophylactic antimicrobial agents that are expected to cause significant drug interactions or co-toxicity with the study procedure and cannot be switched to an alternative drug. Note: HIV testing is not required unless mandated by local authorities. - The patient had experienced any of the following within the six months prior to randomization: stroke, myocardial infarction, severe / unstable angina, coronary / peripheral artery bypass graft, or congestive heart failure (New York Heart Association class III or IV). - Hypertension, as indicated by a resting systolic blood pressure (BP) > 140 mmHg or diastolic BP ≥ 100 mmHg, despite being under medical management. - Gastrointestinal disorders or gastrointestinal surgery that are expected to significantly interfere with the absorption of the study drug. - Prior or concurrent participation in another clinical study using one or more investigational drugs (within 28 days prior to the start of darolutamide / placebo, or the longer of the five half-lives of the investigational treatment in the previous study). - Any other serious or unstable illness or medical, social, or psychological condition that could threaten the safety of the participant and / or adherence to research procedures, or that could interfere with the participant's participation in the study or evaluation of the study results. - Lack of ability to swallow oral medications

[0154] Cancellation / Withdrawal Criteria All participants in the study must complete all applicable study periods. Participants may withdraw from any study period at any time. Simply discontinuing a study procedure does not constitute withdrawal from the study.

[0155] Discontinuation of research procedures In this study, the treatment will be administered over a period of 24 months.

[0156] After completing the 24-month study treatment, participants must discontinue the treatment and participate in active or long-term follow-up. In some cases, participants may be required to permanently discontinue (finally discontinue) the study treatment before completing the planned 24-month treatment. After final discontinuation of the study treatment, participants remain in the study and are evaluated for primary endpoints, secondary endpoints, and other specified endpoints.

[0157] Participants must withdraw from the study drug if any of the following occurs: - If the principal investigator believes that continuing the study drug would be harmful to the participant's health. If a participant experiences clinical exacerbation due to worsening of disease signs / symptoms, leading to discontinuation of the study treatment, radiological evaluation must be continued until exacerbation is established by PSMA PET / CT as defined by BICR, or until systemic antineoplasmic therapy is initiated. - Disease exacerbation (rPFS established by PSMA PET-CT using BICR) - Initiation of a new antineoplastic therapy - Unacceptable toxicity - Interruption of the research drug for more than 28 consecutive days - Darolutamide administration below 300mg BID - Occurrence of Grade 3 or higher study drug-related TEAEs while participants were receiving 300 mg BID. - Elevated hepatic transaminases suggest idiosyncratic drug-induced liver injury (DILI), which is thought to be causally related to the drug being studied. - The occurrence of any concomitant disease or condition that, in the judgment of the principal investigator, could significantly affect the evaluation of the clinical condition and the study's endpoints. - Development of a second primary malignant tumor requiring different treatment.

Claims

1. A method for improving progression-free survival in a male human with biochemical recurrence of prostate cancer, comprising the step of administering a pharmaceutical product containing an androgen receptor inhibitor to the male human.

2. The method according to claim 1, wherein the progression-free survival period is the radiological progression-free survival period measured by positron emission tomography (PTMS) of prostate-specific membrane antigens.

3. The method according to claim 1, wherein the progression-free survival period is the radiological progression-free survival period as determined by computed tomography.

4. The method according to claim 1, wherein the biochemical recurrence of prostate cancer is a high-risk biochemical recurrence of prostate cancer.

5. The method according to claim 1, wherein the androgen receptor inhibitor is darolutamide.

6. The method according to claim 1, further comprising the step of administering androgen deprivation therapy.

7. The method according to claim 6, wherein the step of administering the androgen deprivation therapy is performed sequentially or simultaneously with the step of administering the pharmaceutical product comprising the androgen receptor inhibitor.

8. The method according to claim 6, wherein the androgen deprivation therapy comprises orchiectomy or an LHRH agonist or LHRH antagonist.

9. A method for improving radiological progression-free survival by prostate-specific membrane antigen positron emission tomography or computed tomography in male humans with high-risk biochemical recurrence of prostate cancer, comprising the step of administering to the male human a pharmaceutical product containing darolutamide, an androgen receptor inhibitor, sequentially or concurrently with orchiectomy or androgen deprivation therapy including the administration of an LHRH agonist or antagonist.

10. A method for treating biochemical recurrence of prostate cancer in a human male, comprising the step of administering a pharmaceutical product containing an antiandrogen to the human male.

11. The method according to claim 10, wherein the anti-androgen is an androgen receptor inhibitor.

12. The method according to claim 11, wherein the androgen receptor inhibitor is a second-generation androgen receptor inhibitor selected from the group consisting of darolutamide, enzalutamide, apalutamide, and any combination thereof.

13. The method according to claim 12, wherein the second-generation androgen receptor inhibitor is administered in a daily dose ranging from approximately 10 mg / day to approximately 1500 mg / day.

14. The method according to claim 10, wherein the androgen receptor inhibitor is darolutamide.

15. The method according to claim 14, wherein the darolutamide is administered in a daily dose ranging from approximately 300 mg / day to approximately 1500 mg / day.

16. The method according to claim 14, wherein the darolutamide is administered at a daily dose of approximately 1200 mg / day.

17. The method according to claim 14, wherein the darolutamide is in the form of a (S,S) diastereomer, a (S,R) diastereomer, and the (S,S) diastereomer and the (S,R) diastereomer in any isomer ratio.

18. The method according to claim 10, further comprising the step of administering androgen deprivation therapy.

19. The method according to claim 17, wherein the step of administering the androgen deprivation therapy is performed sequentially or simultaneously with the step of administering the pharmaceutical product.

20. Darorutamide for improving radiographic progression-free survival by positron emission tomography or computed tomography in chemically or surgically castrated male humans with high-risk biochemical recurrence of prostate cancer.

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