How to reduce the risk of developing prostate cancer

Abstract

The present disclosure provides a method of reducing the risk of progression of prostate cancer in a patient histologically known to have prostate cancer characterized as low or intermediate risk, where no other treatment for prostate cancer is indicated, comprising administering enzalutamide to said patient as monotherapy in an amount and for a duration proven clinically effective in reducing the risk of progression of prostate cancer in a control population of patients under surveillance and histologically known to have prostate cancer characterized as low or intermediate risk, where no other treatment for prostate cancer is indicated.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] Each document cited herein is incorporated by reference in its entirety. [Technical field]

[0002] The present disclosure relates generally to the treatment of prostate cancer. [Background technology]

[0003] In some prostate cancer patients, active surveillance or follow-up may delay prostate cancer treatment or prevent unnecessary treatment. However, some patients will ultimately experience progression of prostate cancer. Therefore, methods to reduce the risk of prostate cancer progression in patients on active surveillance or follow-up would be advantageous. [Brief description of the drawings]

[0004] [Figure 1] 1 is a chart showing patient allocation. [Diagram 2]Kaplan-Meier plot of time to disease progression (full analysis set). Fig. 2 Footnotes: aPathological progression was defined as an increase of >1 in primary or secondary GS or >15% increase in cancer-positive cores; bTherapeutic progression was defined as the first occurrence of first-line treatment for prostate cancer (prostatectomy, radiotherapy, local therapy, or systemic therapy); cPatients without prostate cancer progression at the end of the study, patients who withdrew, and patients who died were censored at the date of last evaluation. Patients who changed therapy during the study were censored at the time of their first therapy change, and patients who discontinued therapy were censored at the time of study discontinuation; dCalculated using a two-sided log-rank test; eCalculated using a Cox regression model assuming proportional hazards, with treatment arm, stratification factors, age, race, and time since prostate cancer diagnosis as fixed effects, and study site and patient as random effects. HR<1 favors enzalutamide; fCalculated using a two-sided stratified log-rank test. AS active surveillance; CI confidence interval; GS Gleason score; HR hazard ratio; NR not reached. [Diagram 3] Kaplan-Meier plot (Port) of time to prostate-specific antigen (PSA) progression. Footnotes to Figure 3: aPSA progression was defined as a secondary rise in serum PSA ≥25% above baseline or ≥25% above nadir, or absolute ≥2 ng / mL. Patients without PSA progression at study end, patients who withdrew, and patients who died were censored at the last assessment date. Patients who changed therapy during the study were censored at the time of their first therapy change, and patients who discontinued therapy were censored at study discontinuation; b Calculated using a two-sided log-rank test; c Calculated using a Cox regression model assuming proportional hazards, with treatment group, stratification factors, age, race, and time since prostate cancer diagnosis as fixed effects, and study site and patient as random effects. HR<1 favors enzalutamide; d Calculated using a two-sided stratified log-rank test. AS active surveillance; CI confidence interval; HR hazard ratio; PSA prostate-specific antigen. Description of the Invention

[0005] The present disclosure provides a method for reducing the risk of progression of prostate cancer. The method includes administering enzalutamide as monotherapy for low-risk or intermediate-risk prostate cancer. Enzalutamide (sold as XTANDI®) is a second-generation nonsteroidal androgen receptor inhibitor currently approved for the treatment of castration-resistant and metastatic castration-sensitive prostate cancer. The approved dose is 160 mg (two 80 mg tablets or four 40 mg tablets, or four 40 mg capsules) orally once daily. Enzalutamide is disclosed in U.S. Patent Nos. 8,183,274; 7,709,517; and 9,126,941, which are incorporated by reference in their entireties.

[0006] As used in this disclosure, "monotherapy" (or "monotherapy for prostate cancer") means the only therapy administered to treat prostate cancer, and does not exclude therapies for other purposes.

[0007] Suitable patients for this enzalutamide monotherapy are those with histologically proven prostate cancer characterized as low or intermediate risk for which no other treatment for prostate cancer is required, i.e., active surveillance (AS) or follow-up patients. As used in this disclosure, "active surveillance" and "follow-up" refer to the periodic monitoring of a patient's condition (e.g., prostate-specific antigen (PSA) blood tests, digital rectal examination, biopsy, and / or imaging tests) but no treatment for prostate cancer.

[0008] Unless defined elsewhere in this disclosure, "low risk" is defined as one or more of the following: T1c-T2a, PSA level <10 ng / mL, no positive lymph nodes (N0), no metastasis (M0) (or presumed N0 and M0 if CT / bone scan not performed), Gleason score (GS) ≤6, and Eastern Cooperative Oncology Group (ECOG) status ≤2.

[0009] Unless defined elsewhere in this disclosure, "intermediate risk" is defined as one or more of the following: T2b-T2c; PSA <20 ng / mL; N0, M0 (or presumed N0 and M0 if CT / bone scan not performed); GS ≤7 (3+4 pattern); ECOG status ≤2.

[0010] In some embodiments, the life expectancy of the patients in the above-mentioned patients and control population is more than 5 years; that is, the patients are otherwise under active surveillance.In some embodiments, the life expectancy of the patients in the above-mentioned patients and control population is 5 years or less; that is, the patients are otherwise under active surveillance or under observation.

[0011] Enzalutamide monotherapy is typically administered orally. Enzalutamide is typically administered orally at a daily dose of 160 mg. For patients co-administered with a strong CYP3A4 inducer, enzalutamide monotherapy is administered orally at a daily dose of 240 mg. In some embodiments, enzalutamide monotherapy is administered locally to tumor site (e.g., by intratumoral injection, or by using an implantation device or sustained release system, etc.).

[0012] Enzalutamide monotherapy is administered for a period of time sufficient to reduce the risk of prostate cancer progression (eg, 30, 60, 90 days; 3, 6, 9, 12, 18, 24 months).

[0013] As shown in the Examples below, enzalutamide monotherapy is well tolerated and offers several clinically proven advantages.

[0014] First, enzalutamide monotherapy is effective in reducing the risk of prostate cancer progression by 46% compared with patients in a control population under surveillance who are histologically known to have prostate cancer characterized as low or intermediate risk for which no other treatment for prostate cancer is required and who have not received therapy for prostate cancer. "Prostate cancer progression" can be pathological prostate cancer progression, therapeutic prostate cancer progression, or both. "Pathological prostate cancer progression" is characterized by an increase in primary or secondary Gleason pattern of more than 1 or an increase in cancer-positive cores of more than 15%. "Therapeutic prostate cancer progression" is the first occurrence of additional therapy for prostate cancer (e.g., androgen deprivation therapy, prostatectomy, radiation therapy, local therapy, and systemic therapy).

[0015] Second, compared with the control population, patients receiving enzalutamide monotherapy were at least three times more likely to have a negative biopsy at one year.

[0016] Third, patients receiving enzalutamide monotherapy had a delay of 6 months in PSA progression, defined as a serum PSA increase of 25% or more above baseline or above the nadir, or an absolute value of 2 ng / mL or more.

[0017] Other prostate cancer monotherapies may be used in the methods of the present disclosure; i.e., the present disclosure also provides a method of reducing the risk of prostate cancer progression in a patient histologically known to have prostate cancer characterized as low risk or intermediate risk for which no other treatment for prostate cancer is required, comprising administering enzalutamide monotherapy to the patient in an amount and for a duration proven clinically effective in reducing the risk of prostate cancer progression compared to patients in a control population under surveillance, the patients in the control population being histologically known to have prostate cancer characterized as low risk or intermediate risk for which no other treatment for prostate cancer is required, and who are not receiving therapy for prostate cancer.

[0018] In some embodiments, the prostate cancer monotherapy is a second-generation nonsteroidal androgen receptor, such as abiraterone acetate, apalutamide or darolutamide.Abiraterone acetate is typically administered orally at a dose of 1,000 mg once a day, together with 5 mg of prednisone twice a day; thus, "abiraterone acetate monotherapy" includes administration of both abiraterone acetate and prednisone.Apalutamide is typically administered orally at a daily dose of 240 mg.Darolutamide is typically administered orally at a daily dose of 600 mg.

[0019] The present disclosure also provides a method for treating low-risk or intermediate-risk prostate cancer by administering a therapeutically effective amount of enzalutamide, abiraterone acetate, apalutamide or darolutamide as monotherapy to a patient with low-risk or intermediate-risk prostate cancer. In one embodiment, the method includes administering enzalutamide as monotherapy. In one embodiment, the method includes administering abiraterone acetate as monotherapy, where "abiraterone acetate monotherapy" includes administration of both abiraterone acetate and prednisone. In one embodiment, the method includes administering apalutamide as monotherapy. In one embodiment, the method includes administering darolutamide as monotherapy. EXAMPLES

[0020] Example 1 Test Overview

[0021] A description of the ENACT trial (NCT02799745) was posted on the website clinicaltrials.gov on June 15, 2016, and that description is incorporated herein by reference. The primary objective of the study was to evaluate the efficacy and safety of enzalutamide in extending the time to prostate cancer progression (pathological or therapeutic) in patients with histologically proven prostate cancer classified as low- or intermediate-risk, who were under AS, and who had not previously received local or systemic therapy for prostate cancer.

[0022] Study population

[0023] Eligible patients were those under AS who were diagnosed within 6 months of screening. Patients under AS with clinically localized, histologically proven prostate cancer classified as low- or intermediate-risk were randomized (1:1) to receive enzalutamide 160 mg / day (N=114) or active surveillance (N=113) for 1 year or until pathological or therapeutic progression. Mean age at baseline was 66.1 years.

[0024] Study Design and Methodology

[0025] Patients were stratified into low or intermediate risk and by type of biopsy performed (multiparametric magnetic resonance imaging (mpMRI)-targeted prostate biopsy or non-mpMRI-targeted transrectal ultrasound-guided prostate biopsy). "Low risk" was defined as T1c-T2a, PSA <10 ng / mL, N0, M0, GS ≤6, ECOG status ≤2, and estimated life expectancy >5 years. "Intermediate risk" was defined as T2b-T2c, PSA <20 ng / mL, N0, M0, GS ≤7 (3+4 pattern only), ECOG status ≤2, and estimated life expectancy >5 years.

[0026] After randomization to enzalutamide or AS, patients were followed for 1 year (treatment period), followed by a 1-year follow-up period until the last patient completed the 24-month visit, with a minimum of 1 year of continued follow-up. Biopsies were evaluated by a blinded central review center.

[0027] Primary and selected secondary endpoints

[0028] The primary endpoint was time to prostate cancer progression (pathological progression or therapeutic progression). "Prostate cancer progression" is defined as pathological or therapeutic progression of prostate cancer. "Pathological progression" is defined as an increase of >1 in primary or secondary Gleason pattern or an increase of >15% in cancer positive cores. "Therapeutic progression" is defined as the first occurrence of additional therapy for prostate cancer (e.g., androgen deprivation therapy, prostatectomy, radiation therapy, local therapy, and systemic therapy).

[0029] Secondary endpoints were (1) incidence of negative cancer biopsies at 1 and 2 years, (2) percentage of cancer-positive cores at 1 and 2 years, (3) time to PSA progression, and (4) incidence of secondary increases in serum PSA at 1 and 2 years. "PSA progression" was defined as an increase in serum PSA of 25% or more above baseline or 25% above the nadir, or an absolute value of 2 ng / mL or more.

[0030] statistical methods

[0031] Sample size calculations assumed a trial duration of 3 years, a loss to follow-up rate of 16%, an assumed hazard ratio of 0.52, and a median time to progression for the control group of 3 years (hazard ratio = 0.2310); resulting in 72 events, with a power of 80%.

[0032] The full analysis set (FAS) included patients who were enrolled in the study and randomly assigned to one of the study arms. The safety set (SAF) was redefined in the statistical analysis plan (SAP) to include only patients who received study drug. The FAS included 227 patients (113 in the active surveillance group and 114 in the enzalutamide group). The SAF included 112 patients in the enzalutamide group.

[0033] A total of 94 men completed the entire study period (enzalutamide, n = 54; AS, n = 40; Figure 1). Baseline demographic and disease characteristics were similar between treatment groups (Table 1).

[0034] A total of 121 (53.3%) men had low-risk prostate cancer and 172 (75.8%) men underwent mpMRI nontargeted biopsy (Table 1).The median duration of enzalutamide treatment was 352 days (range 1-393).

[0035] [Table 1]

[0036] All statistical comparisons were performed using two-sided tests with an α=0.05 significance level and 95% confidence intervals.

[0037] The primary efficacy endpoint, time to prostate cancer progression (pathological or therapeutic), was analyzed using the Kaplan-Meier (KM) method, and median time to disease progression and 95% confidence intervals were calculated for each treatment group. Patients were censored if they did not experience disease progression. Discontinuation or death was censored at the date of discontinuation or last evaluation. In addition, patients who changed therapy during the study were censored at the time of their first therapy change. To test the hypothesis that the time to disease progression between the two groups was not the same, hazard ratios (enzalutamide / AS) and 95% confidence intervals were calculated based on a Cox regression model with treatment group, stratification factors, age, race, and time since prostate cancer diagnosis as fixed factors and site as a random effect.

[0038] The secondary endpoint of negative cancer biopsy was summarized using frequency and percentage at 1 and 2 years by treatment group. Comparisons between enzalutamide and AS groups were calculated using exact logistic regression with treatment group, randomization stratification factors [prostate cancer risk (low / intermediate), type of biopsy performed (mpMRI-targeted / non-mpMRI-targeted)], age, race, and time since prostate cancer diagnosis as fixed effects, and site and patient as random effects. Analysis of time to PSA progression was performed with the same method used for the analysis of the primary endpoint. For selected secondary endpoints, P values ​​were adjusted using the Bonferroni-Holm method to control for type I error at 0.05.

[0039] Test results Patient Allocation

[0040] A total of 227 patients were randomly assigned to either the enzalutamide group (114 patients) or the AS group (113 patients). Overall, 165 patients completed the 1-year treatment period, with 70.8% (80 / 113 patients) in the AS group and 74.6% (85 / 114 patients) in the enzalutamide group. Of 117 patients, 45.1% (51 / 113 patients) in the AS group and 57.9% (66 / 114 patients) in the enzalutamide group completed the 1-year follow-up period. Of 94 patients, 35.4% (40 / 113 patients) in the AS group and 47.4% (54 / 114 patients) in the enzalutamide group completed the entire study period.

[0041] Demographic and baseline characteristics

[0042] Ethnic, racial, and age categories were similar in the two treatment groups. Baseline disease characteristics were similar between the treatment groups.

[0043] Treatment exposure

[0044] Throughout the 1-year treatment period, the mean (SD) treatment duration of 112 patients treated with enzalutamide in the FAS was 300.1 (112.73) days. The proportion of patients who had their dose reduced was 12.3% (14 / 114), mainly due to adverse events, 2.6% (3 / 114) who had their dose increased, and 13.2% (15 / 114) who discontinued treatment. Patients did not receive study drug during the 1-year follow-up period or the 1-year extension follow-up period.

[0045] Primary Efficacy Endpoint

[0046] Kaplan-Meier curves for time to disease progression are shown in Figure 2. The results favored the enzalutamide group over the active surveillance group. The median time to pathological or therapeutic prostate cancer progression was not reached in either treatment group. Enzalutamide significantly reduced the risk of prostate cancer by 46%.

[0047] Of the 227 patients, 28.1% (32 / 114) in the enzalutamide group experienced disease progression, whereas 37.2% (42 / 113) in the active surveillance group experienced disease progression. As shown in Table 2, the median progression-free survival was not reached in each treatment group. The hazard ratio (95% CI) was 0.542 (0.330, 0.892) in favor of enzalutamide compared with the active surveillance group, with a statistically significant P value of 0.016.

[0048] [Table 2]

[0049] Secondary Efficacy Endpoints

[0050] Table 3 summarizes the secondary efficacy endpoints.

[0051] [Table 3-1] [Table 3-2]

[0052] Enzalutamide significantly increased the odds of a negative biopsy at 1 year versus the AS group; the proportion of patients with a negative biopsy was greater in the enzalutamide group than in the AS group at 2 years, but the difference between groups was not statistically significant (Table 3). The proportion of enzalutamide patients with a negative biopsy at 1 year was 35.1% (40 / 114) versus 14.2% (16 / 113) in the active surveillance group. The odds ratio (95% CI) was 3.5 (1.76, 6.92), P < 0.0001. Of patients who initiated 1-year follow-up, 66 patients in the enzalutamide group and 50 in the AS group reported biopsy results. The rates at year 2 were 19.0% (19 / 100) in the enzalutamide group and 12.0% (10 / 83) in the active surveillance group. The odds ratio (95% CI) was 1.6 (0.66, 4.00), with a P value of 0.289 for the enzalutamide group vs. the active surveillance group.

[0053] Enzalutamide significantly delayed the time to PSA progression by 6 months compared with AS (Figure 3). Results could not be distinguished between the effect of enzalutamide on PSA and progression defined as a secondary increase in serum PSA of 25% or more from baseline or above the nadir, which may have biased the results in favor of AS. PSA rebound was observed after treatment cessation in the enzalutamide-treated group (observed after 15 months).

[0054] Of the 227 patients, 84.2% (96 / 114) of those in the enzalutamide group experienced PSA progression compared with 84.1% (95 / 113) of those in the active surveillance group. The median time to PSA progression in each treatment group is shown in Table 4. The hazard ratio (95% CI) was 0.714 (0.525, 0.972) in favor of enzalutamide versus active surveillance, with a statistically significant p-value of 0.032.

[0055] [Table 4]

[0056] Enzalutamide significantly reduced the odds of a secondary rise in serum PSA versus AS at 1 year, but not at 2 years (Table 3).

[0057] There was a statistically significant reduction in the mean percentage of cancer-positive cores in the enzalutamide group versus the AS group at 1 year, but no statistically significant difference between the treatment groups at 2 years (Table 3). However, the enzalutamide group showed a statistically significant 6.7% reduction in the mean percentage of cancer-positive cores between baseline and 2 years.

[0058] Safety Variables Adverse events

[0059] As expected, 92.0% (103 / 112) of enzalutamide patients reported experiencing a drug-related adverse event (AE) during the treatment period +30 days. Among active surveillance patients, 54.9% (62 / 113) experienced an AE from randomization through the end of the 12th month of the study +30 days. The most common drug-related AE in the enzalutamide group was fatigue (52.7%). Adverse events occurring in ≥3.5% of enzalutamide patients were fatigue (55.4%), gynecomastia (36.6%), nipple pain (30.4%), breast tenderness (25.9%), and erectile dysfunction (17.9%). The only AE occurring in ≥3.5% of active surveillance patients was hypertension (7.1%). Table 5A lists the most common AEs. Table 5B provides an overview of the AEs. The observed AE data were consistent with the known safety profile of enzalutamide.

[0060] [Table 5A]

[0061] [Table 5B]

[0062] There were three deaths (2.7%) in the enzalutamide group. One death occurred after the patient discontinued the treatment period due to non-compliance with enzalutamide treatment; the patient died of homicide within the 1-year treatment period. The other two deaths (due to intracranial hemorrhage and metastatic bile duct cancer) occurred during the patient's continued follow-up treatment period. No deaths occurred during enzalutamide treatment.

[0063] Health-related quality of life

[0064] The impact of enzalutamide treatment on health-related quality of life (HRQoL) was assessed using patient-reported outcomes (PROs) assessed at baseline and during follow-up using the Brief Fatigue Inventory, Expanded PC (Prostate Cancer) Index Composite (EPIC), 12-Item Short-Form Survey (SF-12), and Memorial Anxiety Scale for PC (MAX-PC).

[0065] Fatigue was mild (<3) at baseline and remained so in both the enzalutamide and AS groups until the end of treatment (12 months) and follow-up (24 months) (Table 6). No functional impairment or distress was noted in the hormonal and urinary components of the EPIC score in either group, but a clinically meaningful effect was observed in the enzalutamide group on sexual function, evident after 6 months (33.4±22.2 vs. 56.7±23.4). No effect was noted in either group on the SF-12 psychiatric components, but an increase in physical functional impairment was noted in the enzalutamide group at 12 months, which resolved by 24 months (Table 5). No PC-related anxiety was noted in either group on the MAX-PC.

[0066] [Table 6]

[0067] The above results indicate that treatment with enzalutamide is not associated with a clinically significant worsening of HRQoL compared to patients undergoing AS; however, a clinically relevant effect on sexual function was observed that disappeared after cessation of treatment.

[0068] conclusion

[0069] Patients treated with enzalutamide had a 46% reduced risk of disease progression compared with patients who underwent active surveillance. The median time to disease progression was not reached in either group.

[0070] Secondary endpoints were the incidence of negative biopsies and time to PSA progression, with results favoring the enzalutamide group. Patients in the enzalutamide group were significantly more likely to have a negative biopsy at 1 year compared with active surveillance, but this was not observed at 2 years. The odds of a negative biopsy were 3.5 times higher at 1 year than with active surveillance. A statistically significant reduction in the mean percentage of cancer-positive cores was observed at 1 year compared with active surveillance. Treatment with enzalutamide delayed PSA progression by approximately 6 months, and this delay was statistically significant.

[0071] Safety was evaluated among the secondary endpoints. Not surprisingly, treated patients experienced more adverse events than did active surveillance patients, particularly gynecomastia, breast tenderness, and nipple pain. No unexpected adverse events were observed during treatment. Mortality was higher in the enzalutamide group, but no deaths occurred during enzalutamide treatment.

[0072] The results are summarized in Table 7.

[0073] [Table 7]

Claims

1. A pharmaceutical composition comprising enzalutamide for reducing the risk of prostate cancer progression in a patient histologically proven to have prostate cancer characterized as low risk or intermediate risk for which no other treatment for prostate cancer is required, comprising administering enzalutamide monotherapy to the patient in an amount and for a duration proven clinically effective in reducing the risk of prostate cancer progression.

2. The pharmaceutical composition of claim 1, wherein the risk of progression of prostate cancer in the patient is reduced compared to patients in a control population under surveillance, the patients in the control population being histologically known to have prostate cancer characterized as low risk or intermediate risk for which no other treatment for prostate cancer is required and who are not receiving therapy for prostate cancer.

3. 2. The pharmaceutical composition of claim 1, wherein the patient's life expectancy and the patient's life expectancy in the control population are greater than 5 years.

4. 2. The pharmaceutical composition of claim 1, wherein the patient's life expectancy and the patient's life expectancy in the control population are 5 years or less.

5. The pharmaceutical composition of claim 1 , wherein the prostate cancer in the patient and the control population are characterized as low risk.

6. 6. The pharmaceutical composition of claim 5, wherein the low risk is defined by one or more of the following stage distinctions: T1c-T2a, a prostate-specific antigen (PSA) level less than 10 ng / mL, a Gleason score of 6 or less, and an Eastern Cooperative Oncology Group (ECOG) status of 2 or less.

7. The pharmaceutical composition of claim 1 , wherein the prostate cancer of the patient and the control population are characterized as medium risk.

8. 8. The pharmaceutical composition of claim 7, wherein the intermediate risk is defined by one or more of the following stage distinctions: T2b-T2c, PSA level less than 20 ng / mL, Gleason score less than 7 (3+4 pattern), and ECOG status less than 2.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the progression of prostate cancer comprises pathological progression of prostate cancer.

10. The pharmaceutical composition of claim 9, wherein the pathological progression of prostate cancer comprises an increase in primary or secondary Gleason patterns of more than 1 or an increase in cancer positive cores of more than 15%.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the progression of prostate cancer comprises therapeutic progression of prostate cancer.

12. The method of claim 11 , wherein the therapeutic progression of prostate cancer comprises the first occurrence of an additional therapy for prostate cancer.

13. 13. The pharmaceutical composition of claim 12, wherein the additional therapy is selected from the group consisting of androgen deprivation therapy, prostatectomy, radiation therapy, local therapy and systemic therapy.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein said period is one year.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the likelihood of the patient having a negative biopsy after one year of administration of enzalutamide monotherapy is increased by at least 3-fold compared to the likelihood of patients in the control population having a negative biopsy after one year of active surveillance.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein PSA progression in said patient is delayed by 6 months compared to PSA progression in patients in the control population.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein enzalutamide monotherapy is administered in a daily dose of 160 mg.

18. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein a strong inducer of CYP3A4 is co-administered to the patient and enzalutamide monotherapy is administered at a daily dose of 240 mg.

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