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Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results

European Urology

Abstract

Background

Enzalutamide is an androgen receptor inhibitor with a demonstrated overall survival benefit in metastatic castration-resistant prostate cancer. A phase 2 study of enzalutamide monotherapy in patients with hormone-naïve prostate cancer (HNPC) showed a high response rate for the prespecified primary endpoint (ie, prostate-specific antigen [PSA] response at week 25), regardless of metastases at baseline, and favorable tolerability.

Objective

To determine the long-term efficacy and safety of enzalutamide monotherapy at 1 and 2 yr.

Design, setting, and participants

Open-label, single-arm study in patients with HNPC and noncastrate testosterone (≥230 ng/dl).

Intervention

Oral enzalutamide 160 mg/d until disease progression or unacceptable toxicity.

Outcome measurements and analysis

PSA response (≥80% decline from baseline) assessed at 1 yr (49 wk) and 2 yr (97 wk).

Results and limitations

The median (range) age was 73 (48–86) yr and 26 patients (39%) presented with metastases at study entry. Of 67 patients enrolled, 45 (67%) remained on enzalutamide at week 97. For patients remaining on therapy, the PSA response rate at week 97 was 100% (95% confidence interval 92–100%). Of 26 patients with metastases at baseline, 13 (50%) had a complete and four (15.4%) had a partial response as best overall tumor response up to 97 wk on treatment. There was overall maintenance of total-body bone mineral density (BMD) and moderate changes in lean and fat body mass at 49 and 97 wk. The most common adverse events were gynecomastia, nipple pain, fatigue, and hot flushes. The study limitations include lack of a control group and of endocrine, glycemic, and lipid data at 97 wk.

Conclusions

Long-term enzalutamide monotherapy in men with noncastrate HNPC is associated with large sustained reductions in PSA, signals indicating a favorable tumor response, and favorable safety/tolerability profile, with relatively small negative effects on total-body BMD.

Patient summary

In this long-term follow-up of the efficacy and safety of enzalutamide monotherapy in patients with hormone-naïve prostate cancer, enzalutamide maintained long-term reductions in prostate-specific antigen, with a minimal impact on total-body bone mineral density.

Trial registration

NCT01302041

Take Home Message

Long-term enzalutamide monotherapy for up to 2 yr in men with noncastrate hormone-naïve prostate cancer is associated with large, sustained reductions in prostate-specific antigen, signals indicating a favorable tumor response, and favorable tolerability, with minimal negative effects on total body bone mineral density.

Keywords: Androgen receptor, Enzalutamide, Hormone-naïve prostate cancer, Prostate-specific antigen response.

1. Introduction

Androgen deprivation therapy (ADT) is the current standard of care for advanced prostate cancer [1] . Nonsteroidal androgen receptor (AR) inhibitors, or antiandrogens, offer an alternative treatment strategy to ADT with different side effects, inhibiting ARs while maintaining or increasing testosterone [2] . It has been shown that treatment of locally advanced prostate cancer with high-dose bicalutamide monotherapy provides equivalent overall survival benefits and different toxicity than ADT, with fewer castration-associated symptoms[3], [4], [5], and [6].

Enzalutamide is an oral AR signaling inhibitor approved in the United States for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and in the EU for the treatment of asymptomatic or mildly symptomatic men with mCRPC after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated, or those whose disease has progressed on or after docetaxel therapy [7] . Enzalutamide has greater affinity for the AR compared with bicalutamide [8] and its mode of action is distinct in that it inhibits nuclear translocation of the AR, DNA binding, and coactivator recruitment [9] . In an early trial, enzalutamide demonstrated antitumor effects irrespective of chemotherapy status [10] . In the subsequent phase 3 AFFIRM trial, enzalutamide significantly prolonged the survival of men with mCRPC after docetaxel chemotherapy and showed favorable results for all secondary endpoints [11] . More recently, enzalutamide significantly improved overall survival in men with chemotherapy-naïve mCRPC in the phase 3 PREVAIL trial [12] . Clinical studies of enzalutamide have largely been in castrate men (maintained on a luteinizing hormone-releasing hormone [LHRH] analog or after surgical castration) with prior and continued hormone treatment. On the basis of its mode of action, there is a strong rationale for evaluation of enzalutamide in noncastrate men with hormone-naïve prostate cancer (HNPC). We previously reported 25-wk results of a phase 2, open-label, single-arm study of enzalutamide monotherapy in noncastrate men with HNPC at any disease stage eligible for ADT [13] . Enzalutamide monotherapy for 25 wk resulted in a prostate-specific antigen (PSA) decline of ≥80% in 92.5% of patients and was generally well tolerated [13] . We now report follow-up data describing the long-term efficacy, safety, and tolerability of enzalutamide monotherapy after 1-yr and 2-yr treatment periods.

2. Patients and methods

The study methods have previously been described in detail [13] . In brief, this phase 2, open-label, single-arm study (NCT01302041) across 12 European sites investigated the efficacy, safety, and tolerability of enzalutamide in patients with HNPC and noncastrate testosterone levels (≥230 ng/dl). The cutoff dates for the 1-yr (49 wk) and 2-yr (97 wk) follow-up periods were December 28, 2012 and December 28, 2013, respectively. The protocol was approved by local institutional review boards and independent ethics committees and authorities. Participants provided written informed consent before study entry.

2.1. Procedures

Patients received enzalutamide (160 mg/d orally) until disease progression or unacceptable toxicity occurred. Patients discontinued therapy in the event of objective or clinical disease progression, including PSA progression defined as a 50% increase from nadir that was ≥5 ng/ml, confirmed at least 2 wks later, or the development of an adverse event (AE) or toxic effect for which continued administration of the study drug was deemed not to be in the patient's best interest.

Blood samples were taken to measure PSA and hormone levels. PSA was assessed on day 1, at weeks 2 and 5, and every 4 wk thereafter until week 25, and then every 12 wk thereafter. Hormone levels were assessed every 12 wk until week 49 (1 yr). Fasting serum lipids, insulin, and glucose levels were measured in samples collected on day 1 and at weeks 13, 25, and 49.

Bone mass density (BMD) and lean and fat body mass were measured by dual-energy x-ray absorptiometry scans at weeks 1 and 25, and at subsequent 24-wk intervals up to and including week 97.

Abdominopelvic computerized tomography or magnetic resonance imaging and a bone scan were carried out at study entry. If metastases were identified, imaging was performed at week 25 or on discontinuation (if earlier), and at subsequent 24-wk intervals, up to and including week 97.

Health-related quality of life was assessed using the self-administered European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire (EORTC QLQ-C30) and quality-of-life questionnaire for patients with prostate cancer (EORTC QLQ-PR25)[14] and [15]on day 1, in weeks 13 and 25, and then every 24 wk up to and including week 97. Health-related quality-of-life data (specifically, sexual functioning and sexual activity as measured by the EORTC QLQ-PR25) are only reported in brief here and will be presented fully in a separate publication. AEs were recorded at each clinic visit and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [16] .

2.2. Outcomes

The primary outcome was PSA response defined as a decline in PSA level from baseline of ≥80%. Prespecified secondary and exploratory outcomes included objective and best overall tumor response, and changes in fasting serum lipids, insulin sensitivity, BMD, and lean and fat body mass. Levels of PSA decline by metastatic status at study entry were also investigated. Safety measures included reporting of discontinuations and AEs.

2.3. Statistical analyses

Sample size calculations were based on the primary endpoint of PSA response assessed at week 25 [13] . With a sample size of 47 patients, the study had 80% power to reject a PSA response rate of ≤50% at a 5% significance level, with an expected 70% response for enzalutamide. A total patient number of 60 was planned to allow for a 20% dropout rate. PSA response rates were calculated as the number of patients with a ≥80% PSA decline from baseline at a given time point, divided by the number of patients who started treatment (patients who discontinued before the time point were considered nonresponders) or the number of patients remaining on treatment at the time point. Corresponding 95% confidence intervals (CIs) were calculated based on the exact binomial distribution. All patients who received at least one dose of the study drug were included in the analysis. Demographics, secondary outcomes, and safety variables were summarized descriptively. The objective tumor response was calculated in patients with measurable disease at study entry. A mixed-model repeated-measures analysis was used to assess changes in sexual functioning and sexual activity from baseline to 49 and 97 wk. Assessments made at 49 wk were regarded as the 1-yr results and those at 97 wk as the 2-yr results. AEs were reported per calendar year of treatment. Data were analyzed using SAS version 9.2 or later.

3. Results

Sixty-seven patients enrolled in the study and received at least one dose of study drug. All patients were included in the safety population. Data on baseline demographics and medical disease history are presented in Table 1 . The median (range) age of patients was 73 (48–86) yr and the duration of disease ranged from 0 to 16 yr. Overall, 39% of patients presented with metastases at study entry; 36% had previously undergone prostatectomy and 24% had received radiotherapy. Four patients discontinued treatment before week 25, as previously described [13] . Five additional patients discontinued treatment at the 25-wk visit and four others before the 49-wk visit, with 54 patients (81%) remaining on treatment up to week 49. Of the nine patients who discontinued treatment between 25 and 49 wk, two patients died (one due to acute myocardial infarction and one due to cardiorespiratory arrest; neither death was considered related to treatment or disease progression), two patients discontinued because of AEs, two discontinued because of progressive disease, and three withdrew for therapeutic breaks (cessation of study drug secondary to improved disease evaluation). Nine additional patients discontinued treatment at or after week 49: one because of an AE, five because of progressive disease, and three for therapeutic breaks. In total, 18 patients discontinued treatment before or at the 49-wk visit, and four more during the second year on treatment, with 45 patients (67.2%) remaining on treatment at and after week 97.

Table 1 Baseline characteristics for the 67 patients

Parameter Value
Age, yr (range) 73 (48–86)
Body mass index, kg/m2 (range) 26.2 (20.8–39.7)
Prostate-specific antigen, ng/ml (interquartile range) 18.2 (6.4–45.0)
Duration of prostate cancer, yr (range) 1 (0–16)
Characteristics at initial diagnosis
Total Gleason score, n (%)
 ≤6 16 (24)
 7 34 (51)
 ≥8 16 (24)
Clinical stage of primary tumor, n (%)
 T0–T2 41 (61)
 T3 18 (27)
 T4 1 (2)
 TX a 7 (10)
Clinical lymph node stage, n (%)
 N0 22 (33)
 N1 6 (9)
 Nx, unknown or not assessed 39 (58)
Distant metastases, n (%)
 M0 35 (52)
 M1 10 (15)
 Mx, unknown or could not be assessed 22 (33)
Metastases at study entry, n (%) 26 (39)
Number of metastatic lesions by bone scan, n (range) 1 (1–8)
Previous interventions, n (%)
 Radiotherapy 16 (24)
 Prostatectomy 24 (36)
 Transurethral resection of the prostate 4 (6)
 Pelvic lymph node dissection 6 (9)
 Watchful waiting 14 (21)

a Includes unknown (n = 6) and tumors that could not be assessed (n = 1). Table reprinted and modified from The Lancet. Tombal B, Borre M, Rathenborg P, et al. Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study. Lancet Oncol 2014;15:592–600 [13] with permission from Elsevier. © 2014 Elsevier.

Among all 67 patients who started the study, 81% (95% CI 69–89%) and 67% (95% CI 55–78%) of patients had a PSA response (≥80% decline from baseline) at 49 and 97 wk, respectively. A PSA response at 49 and 97 wk was observed in all patients remaining on treatment at these time points: 54 patients (100%, 95% CI 93–100%) and 45 patients (100%, 95% CI 92–100%), respectively ( Fig. 1 A).

gr1

Fig. 1 (A) Mean percentage change in prostate-specific antigen from baseline and (B) mean prostate-specific antigen level by week. Bars show standard deviation.

Among patients who remained on treatment, mean (standard deviation) PSA levels were 0.54 (1.46) ng/ml at 49 wk and 0.16 (0.36) ng/ml at 97 wk ( Fig. 1 B). A maximum PSA decline from baseline of 99–100% by week 97 was achieved in 55 patients (82%), with a decline of 95–99% in eight patients (12%) and a decline of at least 86% in the remaining four patients. These declines were, for the most part, already observed by week 25. Among the patients with assessment available at 49 and 97 wk, PSA was ≤0.1 ng/ml in 34 patients (63%) at 49 wk and in 33 patients (73%) at 97 wk. PSA responses were generally comparable at both follow-up time points for those with and without metastases ( Table 2 ).

Table 2 PSA outcomes at weeks 49 and 97 for patients with and without metastases at screening, and objective and best overall tumor response rates at weeks 49 and 97

  Week 49 (54 of 67 patients) Week 97 (45 of 67 patients)
  No metastases Metastases No metastases Metastases
  (n = 31) (n = 23) (n = 26) (n = 19)
PSA decline ≥80%, n (%) 31 (100) 23 (100) 26 (100) 19 (100)
PSA decline ≥90%, n (%) 31 (100) 22 (96) 26 (100) 19 (100)
PSA ≤4 ng/ml, n (%) 30 (97) 21 (91) 26 (100) 19 (100)
PSA ≤0.1 ng/ml, n (%) 21 (68) 13 (57) 19 (73) 14 (74)
Response, n (%) a Week 49 Week 97 Best overall response by week 97
  (n = 26) b (n = 26) b (n = 26) b
Complete response 7 (27) 12 (46) 13 (50)
Partial response 3 (12) 3 (12) 4 (15)
Non-CR/non-PD 5 (19) 2 (8) 3 (12)
Stable disease 1 (4) 1 (4) 2 (8)
Progressive disease 1 (4) 0 (0) 3 (12)
Not evaluated 6 (23) 1 (4) 1 (4)
Stopped treatment before time point 3 (12) 7 (27) NA

a Response was assessed using RECIST v1.1 for soft-tissue lesions and The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) for bone lesions.

b Number of patients with metastatic disease at study entry. All patients were assessed for bone and soft-tissue metastases using magnetic resonance imaging or computed tomography and a bone scan within 28 d before study drug administration.

CR = complete response; PD = progressive disease; NA = not applicable; PSA = prostate-specific antigen.

The best overall response up to week 97 was assessed for the 26 patients who had metastases at baseline. Of these, 13 (50%) had a complete response, four (15%) had a partial response, two (8%) had stable disease, three (12%) had noncomplete response/nonprogressive disease, three (12%) had progressive disease, and one (4%) was not evaluated. Objective tumor responses at 49 and 97 wk are reported in Table 2 .

All hormone levels increased from baseline to 49 wk ( Table 3 ). The largest increases were in luteinizing hormone, testosterone, and sex hormone–binding globulin levels. Luteinizing hormone and testosterone levels increased sharply between 1 and 5 wk, after which luteinizing hormone continued to rise steadily until 49 wk, while testosterone leveled off between 13 and 49 wk ( Fig. 2 ).

Table 3 Endocrine, lipid, and glycemic outcomes at week 49

  n Mean change from baseline, % (SD)
Endocrine outcomes
 Testosterone 51 +102 (76)
 Dihydrotestosterone 45 +74 (102)
 Sex hormone-binding globulin 53 +89 (42)
 Dehydroepiandrosterone 51 +11 (55)
 Luteinizing hormone 52 +215 (164)
 Follicle-stimulating hormone 52 +62 (78)
 Androstenedione 51 +50 (55)
 Prolactin 53 +10 (30)
 Estradiol 52 +81 (83)
Lipid profile
 Total cholesterol 36 +5 (20)
 High-density lipoprotein cholesterol 36 +6 (14)
 Low-density lipoprotein cholesterol 35 +9 (41)
 Triglycerides 36 +9 (43)
Glycemic profile
 Hemoglobin A1c 32 –4 (4)
 Fasting glucose 32 –1 (9)
 Fasting insulin 31 +21 (57)
 HOMA-IR 31 +20 (56)

SD = standard deviation; HOMA-IR = homoeostasis model assessment of insulin resistance.

gr2

Fig. 2 Mean percentage change in luteinizing hormone and testosterone from baseline to week 49.

Small to moderate increases were observed across fasting lipid profiles from baseline to 49 wk ( Table 3 ), whereas hemoglobin A1c and fasting glucose remained relatively stable. Moderate increases from baseline to 49 wk were seen for fasting insulin and the homoeostasis model assessment of insulin resistance ( Table 3 ). Total, spine, and forearm BMD was generally maintained from baseline to 97 wk, with small decreases (2–3%) in BMD from baseline measured in the femoral neck and trochanter at 97 wk ( Table 4 ). Fat body mass increased from baseline to 49 and 97 wk, while lean body mass decreased ( Table 4 ). Biomarkers of osteoblast activity (bone alkaline phosphatase) and osteoclast activity (N-telopeptide and N-telopeptide/creatinine) increased from baseline to 49 wk, and N-telopeptide and N-telopeptide/creatinine increased from baseline to 97 wk. Bone alkaline phosphatase was not measured at 97 wk. Clinically meaningful (≥10.7 points) reductions in sexual functioning from baseline were observed at 49 and 97 wk. There were no clinically meaningful changes in sexual activity (Supplementary Table 1).

Table 4 Body composition and bone turnover biomarkers at weeks 49 and 97

  Baseline Week 49 Week 97
  n Mean (SD) n Mean change from baseline, % (SD) n Mean change from baseline, % (SD)
Body composition
Bone mineral density (g/cm2)
 Total 50 1.2 (0.1) 36 –0.2 (2.1) 29 –0.4 (2.2)
 Femoral neck 50 0.9 (0.2) 41 –0.4 (2.6) 33 –2.2 (3.0)
 Trochanter 50 0.8 (0.2) 41 –1 (3) 33 –2.2 (3.7)
 Spine L1–L4 51 1.2 (0.2) 40 –0.6 (3.3) 32 –0.6 (4.3)
 Forearm (radius 33%) 52 0.8 (0.1) 41 +0.5 (2.7) 31 –0.3 (3.1)
Fat body mass (kg) 50 25 (7) 36 +9 (18) 29 +11 (9)
Lean body mass (kg) 50 57 (7) 36 –4.4 (4) 29 –5.3 (3.7)
Bone turnover biomarkers
Bone alkaline phosphatase (μg/l) 67 11 (6) 53 +12 (32) NA NA
N-telopeptide (nmol/l) 65 334 (177) 52 +62 (120) 39 +36 (90)
N-telopeptide/creatinine (nmol/mol creatinine) 65 28 (13) 52 + 64 (66) 39 +50 (70)

SD = standard deviation; NA = not available.

The most frequently reported treatment-emergent AEs during 2-yr treatment were gynecomastia (49%), fatigue (39%), nipple pain (21%), and hot flushes (21%) (Supplementary Table 2). AEs of decreased libido and loss of libido were reported by one patient (2%). There were 471 AEs reported by 65 patients (97%), of which 229 events (49%) were considered to be related to enzalutamide. Fifteen patients reported 31 serious AEs, of which five were deemed to be drug-related: two incidences of atrial fibrillation, one of arrhythmia, one of tachycardia, and one of chronic fatigue syndrome. Three patients (5%) discontinued because of drug-related AEs: one due to fatigue, one due to dizziness, and one due to asthenia, depression, fatigue, and insomnia.

4. Discussion

This is the first study to investigate the effects of enzalutamide during 2-yr follow-up in noncastrate men (no surgical castration or LHRH analog maintenance) with HNPC, including patients with and without metastases. This analysis builds on previously published results showing that after 25 wk of treatment, enzalutamide provided a level of disease suppression in men with HNPC of varying severity, as measured by large and sustained declines in PSA that were similar to those observed in ADT studies [13] . Enzalutamide monotherapy was associated with large and consistent PSA reductions from week 25 through to week 97 in patients remaining on therapy. Almost three-quarters of patients (73%) still in the study at 97 wk had PSA ≤0.1 ng/ml; 58% had either a complete or partial tumor response. PSA responses were comparable for patients with and without metastases. In patients with measureable disease at study entry, the best overall objective tumor response to enzalutamide monotherapy up to week 97 showed that the majority of patients had either complete or partial responses. Small decreases were observed in total-body BMD and in lean body mass, while there were increases in fat body mass. There were clinically meaningful reductions in sexual functioning, but not sexual activity. A large proportion of patients continued to benefit from enzalutamide and remained in the study at 97 wk.

Our study sample represents a population of prostate cancer patients with a range of baseline disease severity, including patients with localized, locally advanced, and metastatic disease for whom ADT was indicated. Of particular note is the finding that almost all patients remaining on therapy had a PSA reduction of ≥90% at 49 and 97 wk. This compares favorably, albeit indirectly, with other available treatments for prostate cancer. A >90% decrease in geometric mean PSA levels was observed at 12 wk for patients who received bicalutamide ranging from 300 to 600 mg (doses above the approved dose of 150 mg) or who were treated by castration [17] , although, as with other bicalutamide studies, these are short-term results. As an indirect comparison with a contemporary gonadotropin-releasing hormone (GnRH) analog, the GnRH antagonist degarelix resulted in a reduction of PSA to a median level of 0.5 ng/ml after 1 yr [18] , which was maintained at <2 ng/ml during treatment for up to 5 yr [19] . Further comparisons are challenging because of sparse data on the long-term efficacy of primary ADT in terms of PSA response [1] .

The Cochrane Collaboration recently published a systematic review comparing nonsteroidal antiandrogens to ADT and concluded that nonsteroidal antiandrogens were inferior in terms of overall survival and clinical progression [20] . Notably, this conclusion was based on trials using a range of different dosages of bicalutamide, including three trials with bicalutamide 50 mg, a dosage that was found to be ineffective and has not led to subsequent registration of bicalutamide monotherapy. The activity of bicalutamide monotherapy was extensively addressed by the European Medical Agency in 2007 [21] and the recent Cochrane systematic review does not add any new or relevant information for clinicians.

Unlike ADT, which reduces levels of male hormones, enzalutamide acts by inhibiting androgen signaling [9] . This is reflected in the present study by sustained increases across all hormone measures at 49 wk, most notably for luteinizing hormone, testosterone, estradiol, and sex hormone–binding globulin. These findings are consistent with those for other antiandrogens, for which testosterone and estradiol levels generally increase following treatment[17] and [22]. Although increases in hormone levels were observed throughout the first year of treatment in the present study, no AE related to increased hormone levels led to discontinuation. Study withdrawals because of hormone-related AEs, namely gynecomastia and breast pain, have been observed for bicalutamide[3], [23], and [24].

Small decreases in BMD (2–3%) were observed for some body sites, although the changes are smaller than those reported for castration, with decreases in femoral BMD of 7–10%[25] and [26]and lumbar spine of 5% [5] . ADT-related BMD decreases at 1 and 2 yr have been reported for femoral neck (BMD decreases of 4% [27] and 10% [25] ) and at 1 yr for lumbar spine (BMD decrease of 3% [28] ). The relatively stable BMD findings in our study may indicate bone-protective effects due to higher estrogen levels.

Decreases in lean body mass and increases in fat body mass were observed at 49 and 97 wk, indicating a trend towards the development of sarcopenic obesity. The changes observed for enzalutamide suggest that they may be greater than those observed over 1 yr for bicalutamide [29] , and in line with the more potent antiandrogenic effects seen with castration over 1 yr[29] and [30]and 2 yr [5] . These observations are consistent with what is known about muscle and bone biology in relation to the effects of agents targeting the AR.

These results are sufficiently encouraging to consider conducting a larger clinical trial to demonstrate whether enzalutamide may be used not only in addition to ADT but also as an alternative approach to AR signaling suppression, with similar efficacy and a more favorable side-effect profile compared with ADT. There are, however, challenges to address, including identifying the most appropriate clinical setting (locally advanced or metastatic prostate cancer; a single treatment or adjuvant to radical treatment) and, more importantly, establishing registration rules with regulators.

The long-term follow-up and multiple objectively measured outcomes represent major strengths of this study. Although positive, its open-label design, lack of control arm, small sample size, and lack of endocrine, glycemic, and lipid data at week 97 are limitations warranting caution when interpreting the results.

5. Conclusions

In conclusion, in this open-label 2-yr follow-up, enzalutamide monotherapy treatment in men with noncastrate HNPC with or without metastases was associated with large and sustained PSA reductions, signals indicating a favorable tumor response, and a favorable safety/tolerability profile. This was achieved with relatively small negative effects on total-body BMD.


Author contributions:Bertrand Tombal had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design:Baskin-Bey, Hirmand, Ouatas, Perabo, Phung, Smith.

Acquisition of data:Baskin-Bey, Borre, Braeckman, Heidenreich, Heracek, Iversen, Ouatas, Perabo, Rathenborg, Van Poppel, Werbrouck.

Analysis and interpretation of data:Baron, Baskin-Bey, Heidenreich, Hirmand, Iversen, Ouatas, Perabo, Phung, Smith, Tombal, Van Poppel.

Drafting of the manuscript:Baron, Baskin-Bey, Heracek, Ouatas, Perabo, Smith, Tombal.

Critical revision of the manuscript for important intellectual content:Baron, Baskin-Bey, Borre, Heidenreich, Heracek, Hirmand, Iversen, Ouatas, Perabo, Phung, Smith, Tombal, Van Poppel.

Statistical analysis:Baron.

Obtaining funding:Perabo.

Administrative, technical, or material support:Borre.

Supervision:Baskin-Bey, Perabo, Van Poppel.

Other:None.

Financial disclosures:Bertrand Tombal certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Bertrand Tombal has received consultancy fees from Astellas, Medivation, Amgen, and Sanofi; payment for speaker bureaus from Amgen, Sanofi, Ferring, and Bayer (for whom he is also a board member); and travel support from Astellas and Medivation. Michael Borre has received payment for speaker bureaus from Astellas and Janssen; is a member of a Medivation study Steering Committee; and has received consultancy fees from Astellas, Ferring, and Sanofi. Per Rathenborg has received research grant support paid to his institution from Astellas and Medivation. Axel Heidenreich has received consultancy fees and payment for speaker bureaus from Amgen, Jansen, Ipsen, Sanofi, and Takeda (for whom he is also a board member); research and travel support from Astellas; and a research grant from Sanofi. Peter Iversen has received research grant support paid to his institution from Astellas and Medivation; travel support for meetings related to the study from Astellas and Medivation; honoraria for participation in advisory board meetings from Astellas and Medivation; and consultancy fees from Janssen, Ferring, and Sanofi. Jiri Heracek has received payment for speaker bureaus from Amgen and Eli Lilly. Edwina Baskin-Bey, Taoufik Ouatas, and Frank Perabo were employees of Astellas during the study reported here and at the time of manuscript initiation. De Phung and Benoit Baron are employees of Astellas. Mohammad Hirmand is an employee of and owns stock in Medivation. Matthew R. Smith has received consultancy fees from Astellas, Medivation, Janssen, Aragon, and Millenium. Patrick Werbrouck, Hendrik Van Poppel, and Johan Braeckman have nothing to disclose.

Funding/Support and role of the sponsor:Astellas Pharma, Inc. and Medivation, Inc. provided funding and played a role in study design and conduct; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.

Acknowledgments:The authors would like to thank Dr. David McMinn at Complete HealthVizion for assistance with writing and revising the draft manuscript based on detailed discussion and feedback from all the authors. They would also like to thank Lauren Smith at Complete HealthVizion for copy editing the final manuscript. Writing and editorial support was funded by Astellas Pharma, Inc. and Medivation, Inc.

Appendix A. Supplementary data

 

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Footnotes

a Institut de Recherche Clinique, Université Catholique de Louvain, Brussels, Belgium

b Aarhus University Hospital, Aarhus, Denmark

c Herlev Hospital, Herlev, Denmark

d AZ Groeninge Kortrijk, Kortrijk, Belgium

e UZ Leuven, Leuven, Belgium

f Klinik und Poliklinik für Urologie, RWTH University Aachen, Aachen, Germany

g Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

h UZ Brussel, Brussels, Belgium

i Univerzita Karlova v Praze, Prague, Czech Republic

j Astellas Pharma Global Development, Leiden, The Netherlands

k Astellas Pharma Global Development, Northbrook, IL, USA

l Medivation Inc., San Francisco, CA, USA

m Massachusetts General Hospital Cancer Center, Boston, MA, USA

lowast Corresponding author. Institut de Recherche Clinique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium. Tel. +32 2 7645540; Fax: +32 2 7645580.