Efficacy and Safety of Enzalutamide vs Bicalutamide
Efficacy and Safety of Enzalutamide vs Bicalutamide in Younger and Older Patients with Metastatic Castration Resistant Prostate Cancer in the TERRAIN Trial
The Journal of Urology
D. Robert Siemens, Laurence Klotz,Axel Heidenreich, Simon Chowdhury, Arnauld Villers, Benoit Baron, Steve van Os, Nahla Hasabou, Fong Wang, Ping Lin and Neal D. Shore
Purpose: Enzalutamide significantly prolonged median progression-free survival vs bicalutamide in chemotherapy naïve men with metastatic castration resistant prostate cancer in the TERRAIN (Enzalutamide versus Bicalutamide in Castrate Men with Metastatic Prostate Cancer) trial. In this post hoc analysis we investigated the influence of age on the efficacy and safety of enzalutamide vs bicalutamide in this population.
Materials and Methods: Patients were randomized 1:1 to enzalutamide 160 mg per day or bicalutamide 50 mg per day. Progression-free survival, time to prostate specific antigen progression and safety were analyzed post hoc in younger (age less than 75 years) and older (age 75 years or greater) subgroups.
Results: Enzalutamide significantly reduced the risk of disease progression or death vs bicalutamide in patients younger than 75 years (HR 0.38, 95% CI 0.27–0.52, p <0.0001) and 75 years old or older (HR 0.59, 95% CI 0.37–0.92, p = 0.018). Time to prostate specific antigen progression was also significantly prolonged with enzalutamide vs bicalutamide in each subgroup. The adverse event distribution between treatments was similar in each subgroup except for more (5% or greater difference between subgroups) atrial fibrillation, urinary tract infections, falls and decreased appetite as well as less extremity pain and hot flushing in enzalutamide treated patients 75 years old or older, and less back pain and hot flushing in bicalutamide treated patients 75 years old or older. Grade 3 or greater cardiac events were more frequent in enzalutamide treated and bicalutamide treated patients who were 75 years old or older vs younger than 75 years. Fatigue was more frequent in enzalutamide treated patients with a similar distribution in each age subgroup
Conclusions: Enzalutamide improved clinical outcomes vs bicalutamide irrespective of age. Increased falls and cardiac events suggest caution when prescribing to older patients (age 75 years or greater) with significant comorbidity.
Metastatic castration resistant prostate cancer is primarily a disease of older men. 1As older patients show reduced tolerability toward chemotherapy due to an increased risk of serious toxicity, 2myelosuppression and sepsis in particular, 3they are less likely to receive chemotherapy during routine clinical practice. Therefore, it is important to find effective and tolerable nonchemotherapeutic treatments for older patients with mCRPC, especially given the higher burden of comorbidities in this population. 1
Second line treatment with bicalutamide, a nonsteroidal antiandrogen, was previously recommended in patients with mCRPC despite a lack of meaningful clinical benefit observed in phase 3 clinical trials. 4However, the introduction of new therapeutic options in this setting, particularly the androgen receptor inhibitor enzalutamide, has led to a shift in second line therapeutic options. 1Enzalutamide improved radiographic PFS and overall survival vs placebo in chemotherapy naïve and post-chemotherapy men with mCRPC in PREVAIL 5and AFFIRM, 6respectively.
TERRAIN demonstrated significant improvements in median PFS, radiographic PFS, TTPP, a 50% or greater PSA response and quality of life maintenance in patients with mCRPC who received enzalutamide compared with bicalutamide. 7,8Although some common AEs occurred more frequently in patients receiving enzalutamide, they were consistent with its known safety profile. 7Most grade 3 or greater AEs occurred at a similar frequency in the treatment arms except hypertension and back pain, which were more frequently reported by enzalutamide treated patients. 7Prespecified subgroup analyses of PFS, including age (less than 65, 65 to 75 and greater than 75 years), revealed that treatment effects were consistent for enzalutamide and bicalutamide. 7
The aim of this post hoc analysis was to evaluate the efficacy and safety of enzalutamide vs bicalutamide in younger (age less than 75 years) and older (age 75 years or greater) chemotherapy naïve patients with mCRPC.
Materials and Methods
TERRAIN was a multinational, double-blind, randomized, phase 2 trial of enzalutamide vs bicalutamide. The study design, patient population and conduct of TERRAIN have been described previously. 7Briefly, 184 and 191 chemotherapy naïve patients with mCRPC were randomized 1:1 to enzalutamide 160 mg per day or bicalutamide 50 mg per day, respectively, until central confirmation of radiographic disease progression, a skeletal related event, initiation of a new antineoplastic therapy, patient withdrawal or an AE by which discontinuation of the study drug was deemed necessary by the investigator. Previous antiandrogen use was prohibited if patients had progressed while on such therapy, or if treatment was administered within 6 weeks before randomization. Review boards at participating institutions approved the study protocol and the trial was performed in accordance with the Declaration of Helsinki.
The primary analysis cutoff date was October 19, 2014. Subgroup analyses were performed to determine whether the treatment effect was concordant among age groups, with an emphasis on efficacy, differences in therapy duration, AEs and reasons for study drug discontinuation. The age categories (less than 75 and 75 years or greater), which differed from those specified in the trial protocol in the original publication (less than 65, 65 to 75 and greater than 75 years), 7were selected post hoc in accordance with United States Food and Drug Administration guidelines on defining a geriatric population in clinical trials. 9
TERRAIN outcomes for enzalutamide vs bicalutamide were assessed by age group. Assessment included 1) PFS, by which a progression event is defined as centrally determined radiographic disease progression, occurrence of a skeletal related event, initiation of a new antineoplastic therapy or death from any cause, whichever occurred first; 2) TTPP, by which a progression event is defined as a 25% or greater increase and an absolute increase of 2 ng/ml or greater above the nadir (or above baseline in patients who did not have a decrease in post-baseline PSA), as confirmed by a second consecutive PSA assessment at least 3 weeks later; and 3) time to FACT-P progression and safety.
All efficacy end points were analyzed in all randomized patients. Treatment comparisons of PFS, TTPP and time to FACT-P progression were assessed using the 2-sided unstratified log rank test, a Cox proportional hazards model and the Kaplan-Meier method. Safety analyses were performed for all patients who had received 1 or more doses of study drug and were summarized descriptively by treatment and age groups. All data processing, summarization and analyses were performed with SAS®, version 9.2 or later.
Baseline Demographics and Disease Characteristics
TERRAIN enrolled and randomized 375 patients, including 184 who received enzalutamide and 191 who received bicalutamide, from March 22, 2011 to July 11, 2013. Of these men 58 (31.5%) in the enzalutamide arm and 72 (37.7%) in the bicalutamide arm were 75 years old or older ( supplementary table 1, http://jurology.com/). The safety analysis set of 372 of the 375 patients (99%), included 183 who were enzalutamide treated and 189 who were bicalutamide treated.
Baseline demographics and disease characteristics were generally well balanced between treatments and age groups ( supplementary table 1, http://jurology.com/). However, there was a higher proportion of history of cardiac disorders among enzalutamide treated patients who were 75 years old or older, including 33 (56.9%) on enzalutamide vs 30 (41.7%) on bicalutamide ( table 1). Patients 75 years old or older in the 2 treatment arms had a longer prostate cancer history, higher serum PSA and higher ECOG (Eastern Cooperative Oncology Group) performance scores than patients younger than 75 years.
Exposure and Discontinuation
Median time on the study drug was longer for enzalutamide than for bicalutamide in patients in each age group, including 12.5 (Q1-Q3, 7.1-20.9) vs 6 months (Q1-Q3, 3-11.4) in those younger than 75 years and 10 (Q1-Q3, 3.65-18.2) vs 5 months (Q1-Q3, 3.1-12.4) in those 75 years old or older. Treatment with enzalutamide vs bicalutamide was discontinued in 81 (64.3%) vs 107 patients (89.9%) who were younger than 75 years and in 45 (77.6%) vs 63 (87.5%) who were 75 years old or older.
The main reasons for study discontinuation by patients younger than 75 years were progressive disease in 54 (42.9%) on enzalutamide vs 71 (59.7%) on bicalutamide, withdrawal from study in 7 (5.6%) vs 10 (8.4%) and AEs in 6 (4.8%) vs 5 (4.2%), respectively. Similarly the main reasons for discontinuation by patients 75 years old or older were progressive disease in 21 (36.2%) on enzalutamide vs 34 (47.2%) on bicalutamide, withdrawal from study in 3 (5.2%) vs 10 (13.9%), AEs in 8 (13.8%) vs 7 (9.7%) and death in 4 (6.9%) vs 1 (1.4%), respectively.
Fewer enzalutamide than bicalutamide treated patients in the 2 age groups received subsequent treatment during the study period, including 39 (31.0%) vs 61 (51.3%) who were younger than 75 years and 21 (36.2%) vs 31 (43.1%) who were 75 years old or older. Abiraterone acetate was the most common subsequent treatment in enzalutamide treated patients in each age group and in bicalutamide treated patients who were 75 years old or older. Docetaxel was most common in bicalutamide treated patients who were younger than 75 years ( supplementary table 2, http://jurology.com/).
Enzalutamide significantly improved PFS compared with bicalutamide in patients younger than 75 years (HR 0.38, 95% CI 0.27–0.52, p <0.0001) and 75 years old or older (HR 0.59, 95% CI 0.37–0.92, p = 0.018, fig. 1). Median PFS in patients younger than 75 years was 16.6 (95% CI 11.5–25.6) and 5.8 months (95% CI 4.2–8.1) in the enzalutamide and bicalutamide groups, respectively. Median PFS in patients 75 years old or older was 13.8 (95% CI 8.6–18.7) and 6.4 months (95% CI 4.0–11.2), respectively ( supplementary figure, http://jurology.com/).
Prostate Specific Antigen Progression
In the enzalutamide arm patients in each age subgroup experienced delayed PSA progression compared with those in the bicalutamide arm. However, patients younger than 75 years in each treatment arm had significantly longer TTPP than patients 75 years old or older. In patients younger than 75 years median TTPP was 22.1 months in the enzalutamide arm (95% CI 16.8–33.2) vs 8.2 months (95% CI 5.6–8.3) in the bicalutamide arm (HR 0.27, 95% CI 0.18–0.40, p <0.0001, fig. 2). In patients 75 years old or older median TTPP was 16.6 (95% CI 11.1–23.1) vs 5.8 months (95% CI 5.6–8.3) in the enzalutamide vs bicalutamide arms (HR 0.33, 95% CI 0.19–0.57, p <0.0001). Median TTPP exceeded median PFS because some patients experienced progression events in the absence of a PSA increase.
Functional Assessment of Cancer Therapy-Prostate Progression
Median time to FACT-P progression in patients younger than 75 years was 14.0 (95% CI 11.1–not yet reached) and 8.3 months (95% CI 5.7–11.3) for enzalutamide and bicalutamide, respectively. Although median time to FACT-P progression in patients 75 years old or older was 8.5 (95% CI 8.1–19.8) vs 10.9 months (95% CI 5.6–14.2), the difference was not statistically significant, probably due to the limited sample size and the small number of events.
The safety profile of enzalutamide and bicalutamide was generally similar in the 2 age groups ( table 2). The incidence of atrial fibrillation (0.8% vs 12.1%), urinary tract infection (2.4% vs 20.7%), falls (4.0% vs 12.1%) and decreased appetite (6.4% vs 15.5%) was higher (5% or greater difference) in patients on enzalutamide who were 75 years old or older vs younger than 75 years. The incidence of extremity pain (13.6% vs 5.2%) and hot flushes (17.6% vs 8.6%) was lower in patients on enzalutamide who were 75 years old or older vs younger than 75 years. The incidence of back pain (20.3% vs 14.1%) and hot flushes (13.6% vs 7.0%) was lower in patients on bicalutamide who were 75 years old or older vs younger than 75 years ( table 2).
A grade 3 or greater AE was experienced by 44 (35.2%) and 29 patients (50.0%) on enzalutamide who were younger than 75 years or 75 years old or older, and by 48 (40.7%) and 24 (33.8%) on bicalutamide who were younger than 75 or 75 years old or older, respectively. Overall the rate of grade 3 or greater AEs was low with hypertension predominant across each age group and treatment. Of the most common grade 3 or greater AEs only back pain occurred in a higher proportion (5% or greater difference) of enzalutamide treated patients who were 75 years old or older vs younger than 75 years (6.9% vs 0.8%). The corresponding incidence of grade 3 or greater AEs was broadly similar in bicalutamide treated patients who were 75 years old or older vs younger than 75 years ( table 2). A lower incidence of grade 3 or greater cardiac AEs was noted in enzalutamide and bicalutamide treated patients who were younger than 75 years (2.4% and 0.8%) vs 75 years old or older (12.1% and 4.2%, respectively, table 1).
In the enzalutamide arm 8 patients, including 2 younger than 75 years and 6 who were 75 years old or older, reported a total of 10 grade 3 or greater cardiac AEs. One of the 2 enzalutamide treated patients who were younger than 75 years experienced myocardial infarction, which was diagnosed based on elevated serum creatine phosphokinase in the context of traumatic rib fractures after a motor vehicle accident. The other patient, who had a history of atrial fibrillation and hypertension, experienced cardiac failure and atrial fibrillation.
Two of the 6 enzalutamide treated patients who were 75 years old or older experienced multiple events. One man with a history of cardiac failure and atrial fibrillation experienced myocardial infarction and cardiac failure. The other with a history of hypertension experienced myocardial infarction and atrial fibrillation. The other 4 enzalutamide treated patients who were 75 years old or older experienced a single event of myocardial infarction or cardiac failure. They reported a history of rheumatoid arthritis and chronic obstructive pulmonary disease, atrial fibrillation, cardiac failure and hypertension, hypertension and cardiac failure, and hypertension, respectively. Table 1 summarizes the grade 3 or greater cardiac AEs stratified by age and treatment, including medical history and treatment duration. An increased incidence of grade 3 or greater cardiac AEs occurred in enzalutamide treated patients who were 75 years old or older vs those younger than 75 years (12.1% vs 2.4%).
Drug related AEs led to treatment discontinuation in 7 (5.6%) and 7 patients (12.1%) younger than 75 years and 75 years old or older who were receiving enzalutamide, and 5 (4.2%) and 5 (7.0%), respectively, who were receiving bicalutamide ( table 3). Similar rates of fatigue and depression were reported as enzalutamide related in patients younger than 75 years and 75 years old or older, including fatigue in 27.2% vs 29.3% and depression in 4.0% vs 1.7%.
One enzalutamide treated patient in each age group experienced a seizure and neither event was reported to be treatment related. One of the 2 patients had a previously undisclosed history of seizures and experienced the event after a traumatic head injury. The other patient was subsequently diagnosed with a brain tumor. A hypoglycemic seizure was reported in 1 bicalutamide treated patient who was younger than 75 years. One enzalutamide treated patient in each age group experienced a fall which was reported to be treatment related.
There were 9 deaths in the enzalutamide arm, including 1 reported to be treatment related (systemic inflammatory response syndrome) in a patient younger than 75 years. None of the 3 deaths in the bicalutamide arm was treatment related.
In this age subgroup analysis of the TERRAIN study PFS and TTPP were comparable in younger and older (age less than 75 and 75 years or greater, respectively) chemotherapy naïve patients with mCRPC treated with enzalutamide and bicalutamide. PFS and TTPP in the enzalutamide arm were improved vs bicalutamide in each age subgroup. Enzalutamide treatment resulted in prolonged quality of life maintenance vs bicalutamide with longer time to FACT-P progression across the 2 age groups. However, the small number of events did not allow definitive conclusions to be drawn in the older patient group.
Treatment duration was longer for enzalutamide and similar in the age subgroups. The increased enzalutamide treatment duration did not appear to affect the safety profile compared with bicalutamide. In each age group enzalutamide showed safety consistent with its known safety profile 5,6with no increased rate of most AEs observed in older patients 75 years or older. A higher proportion of enzalutamide treated patients 75 years old or older reported grade 3 or greater cardiac AEs vs those younger than 75 years (12.1% vs 2.4%). This may have been due to the greater number of older patients with a history of cardiac disorders at baseline, including 18 (31.1%) vs 12 (9.6%) for enzalutamide and 19 (26.4%) vs 6 (5.0%) for bicalutamide.
The results of this analysis are concordant with those of similar analyses performed for AFFIRM (post-chemotherapy patients with mCRPC) 10and PREVAIL (chemotherapy naïve patients with mCRPC). 11These analyses also showed that all efficacy outcomes were independent of age with comparable AEs except for fatigue (AFFIRM and PREVAIL) and falls (PREVAIL).
These data suggest that the favorable risk-to-benefit ratio of enzalutamide compared with bicalutamide is maintained across the age spectrum, supporting the idea that treatment decisions should depend on the overall health of the individual and the treatment benefit received rather than on age. 1,12,13These findings suggest that enzalutamide may be a preferred treatment option in older patients in whom frailty precludes chemotherapy. 2
The greater number of older patients with a history of cardiac disorders at baseline in the current study confounded the interpretation of cardiac event data. Nonetheless, attention to such a history may be prudent when prescribing enzalutamide to elderly patients.
Limitations of the TERRAIN study, which were fully described in the original publication, 7include the chosen 50 mg per day dose of bicalutamide, which was selected based on regional practices and most international guidelines. This dose is only used in combination with gonadotrophin releasing hormone modulator therapy in certain regions. Therefore, the results are not generalizable to patient populations receiving treatment in all geographic areas where a different bicalutamide dose is used in combination with gonadotrophin releasing hormone modulator therapy or in a monotherapy (noncastrate) setting.
Furthermore, although the primary end point of PFS included death, overall survival alone was not investigated due to the large number of life extending therapies that became available.
The beneficial effect of enzalutamide vs bicalutamide was independent of age, with enzalutamide demonstrating prolonged PFS and TTPP. An increased frequency of falls and cardiac events in older patients who also had a significant history of cardiovascular disorders warrants caution in this patient subset. With appropriate physician-patient shared decision making, enzalutamide is an effective treatment option across the age spectrum of patients with mCRPC.
Stephanie Rippon and Lauren Smith, Complete HealthVizion, assisted with manuscript writing and editing.
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