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Study Overview
Objective: To evaluate whether the addition of the potent androgen-receptor inhibitor (ARA) darolutamide to the standard doublet androgen-deprivation therapy (ADT) and docetaxel in metastatic, hormone-sensitive prostate cancer (mHSPC) would increase survival.
Design: A randomized, double-blind, placebo-controlled, multicenter, phase 3 study. The results reported in this publication are from the prespecified interim analysis.
Intervention: Patients with mHSPC were randomly assigned to receive either darolutamide 600 mg twice daily or placebo. All patients received standard ADT with 6 cycles of docetaxel 75 mg/m2 on day 1 every 21 days along with prednisone given within 6 weeks after randomization. Patients receiving luteinizing hormone–releasing hormone (LHRH) agonists as ADT were bridged with at least 4 weeks of first-generation antiandrogen therapy, which was discontinued before randomization. Treatments were continued until symptomatic disease progression, a change in neoplastic therapy, unacceptable toxicity, patient or physician decision, death, or nonadherence.
Setting and participants: Eligible patients included those newly diagnosed with mHSPC with metastases detected on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and bone scan. Patients were excluded if they had regional lymph node–only involvement or if they had received more than 12 weeks of ADT before randomization. Between November 2016 and June 2018, 1306 patients (651 in the darolutamide group and 655 in the placebo group) were randomized in a 1:1 manner to receive darolutamide 600 mg twice daily or placebo in addition to ADT and docetaxel. Randomization was stratified based on the TNM staging system (M1a—nonregional lymph node–only metastasis, M1b—bone metastasis with or without lymph node, or M1c—bone metastases) as well as baseline alkaline phosphatase levels.
Main outcome measures: The primary end point for the study was overall survival. Other meaningful secondary end points included time to castration resistance, time to pain progression, time to first symptomatic skeletal event, symptomatic skeletal event-free survival, time to subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms, initiation of opioid therapy for ≥7 days, and safety.
Results: The baseline and demographic characteristics were well balanced between the 2 groups. Median age was 67 years. Nearly 80% of patients had bone metastasis, and approximately 17% had visceral metastasis. At the data cutoff date for the primary analysis, the median duration of therapy was 41 months for darolutamide compared with 16.7 months in the placebo group; 45.9% in the darolutamide group and 19.1% in the placebo group were receiving the allotted trial therapy at the time of the analysis. Six cycles of docetaxel were completed in approximately 85% of patients in both arms. Median overall survival follow-up was 43.7 months (darolutamide) and 42.4 months (placebo). A significant improvement in overall survival was observed in the darolutamide group. The risk of death was 32.5% lower in the darolutamide cohort than in the placebo cohort (hazard ratio [HR], 0.68; 95% CI, 0.57-0.80; P < .001). The overall survival at 4 years was 62.7% (95% CI, 58.7-66.7) in the darolutamide arm and 50.4% (95% CI, 46.3-54.6) in the placebo arm. The overall survival results remained favorable across most subgroups.
Darolutamide was associated with improvement in all key secondary endpoints. Time to castration-resistance was significantly longer in the darolutamide group (HR, 0.36; 95% CI, 0.30-0.42; P < .001). Time to pain progression was also significantly longer in the darolutamide group (HR, 0.79; 95% CI, 0.66-0.95; P = .01). Time to first symptomatic skeletal events (HR, 0.71; 95% CI, 0.54-0.94; P = .02) and time to initiation of subsequent systemic therapy (HR, 0.39; 95% CI, 0.33-0.46; P < .001) were also found to be longer in the darolutamide group.
Safety: The risk of grade 3 or higher adverse events was similar across the 2 groups. Most common adverse events were known toxic effects of docetaxel therapy and were highest during the initial period when both groups received this therapy. These side effects progressively decreased after the initial period. The most common grade 3 or 4 adverse event was neutropenia, and its frequency was similar between the darolutamide and placebo groups (33.7% and 34.2%, respectively). The most frequently reported adverse events were alopecia, neutropenia, fatigue, and anemia and were similar between the groups. Adverse events of special significance, including fatigue, falls, fractures, and cardiovascular events, were also similar between the 2 groups. Adverse events causing deaths in each arm were low and similar (4.1% in the darolutamide group and 4.0% in the placebo group). The rates of discontinuation of darolutamide or placebo were similar (13.5% and 10.6%, respectively).
Conclusion: Among patients with mHSPC, overall survival was significantly longer among patients who received darolutamide plus ADT and docetaxel than among those who received ADT and docetaxel alone. This was observed despite a high percentage of patients in the placebo group receiving subsequent systemic therapy at the time of progression. The survival benefit of darolutamide was maintained across most subgroups. An improvement was also observed in the darolutamide arm in terms of key secondary end points. The adverse events were similar across the groups and were consistent with known safety profiles of ADT and docetaxel, and no new safety signals were identified in this trial.
Commentary
The results of the current study add to the body of literature supporting multi-agent systemic therapy in newly diagnosed mHSPC. Prior phase 3 trials of combination therapy using androgen-receptor pathway inhibitors, ADT, and docetaxel have shown conflicting results. The results from the previously reported PEACE-1 study showed improved overall survival among patients who received abiraterone with ADT and docetaxel as compared with those who received ADT and docetaxel alone.1 However, as noted by the authors, the subgroup of patients in the ENZAMET trial who received docetaxel, enzalutamide, and ADT did not appear to have a survival advantage compared with those who received ADT and docetaxel alone.2 The results from the current ARASENS trial provide compelling evidence in a population of prospectively randomized patients that combination therapy with darolutamide, docetaxel, and ADT improves overall survival in men with mHSPC. The survival advantage was maintained across subgroups analyzed in this study. Improvements were observed in regards to several key secondary end points with use of darolutamide. This benefit was maintained despite many patients receiving subsequent therapy at the time of progression. Importantly, there did not appear to be a significant increase in toxicity with triplet therapy. However, it is important to note that this cohort of patients appeared largely asymptomatic at the time of enrollment, with 70% of patients having an Eastern Cooperative Oncology Group performance status of 0.
Additionally, the average age in this study was 67 years, with only about 15% of the population being older than 75 years. In the reported subgroup analysis, those older than 75 years appeared to derive a similar benefit in overall survival, however. Whether triplet therapy should be universally adopted in all patients remains unclear. For example, there is a subset of patients with mHSPC with favorable- risk disease (ie, those with recurrent metastatic disease, node-only disease). In this population, the risk-benefit analysis is less clear, and whether these patients should receive this combination is not certain. Nevertheless, the results of this well-designed study are compelling and certainly represent a potential new standard treatment option for men with mHSPC. One of the strengths of this study was its large sample size that allowed for vigorous statistical analysis to evaluate the efficacy of darolutamide in combination with ADT and docetaxel.
Application for Clinical Practice
The ARASENS study provides convincing evidence that in men with mHSPC, the addition of darolutamide to docetaxel and ADT improves overall survival. This combination appeared to be well tolerated, with no evidence of increased toxicity noted. Certainly, this combination represents a potential new standard treatment option in this population; however, further understanding of which subgroups of men benefit from enhanced therapy is needed to aid in proper patient selection.
—Santosh Kagathur, MD, and Daniel Isaac, DO, MS
Michigan State University, East Lansing, MI
1. Fizazi K, Carles Galceran J, Foulon S, et al. LBA5 A phase III trial with a 2x2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: overall survival with abiraterone acetate plus prednisone in PEACE-1. Ann Oncol. 2021;32:Suppl 5:S1299. doi:10.1016/j.annonc.2021.08.2099
2. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381:121-131. doi:10.1056/NEJMoa1903835
Study Overview
Objective: To evaluate whether the addition of the potent androgen-receptor inhibitor (ARA) darolutamide to the standard doublet androgen-deprivation therapy (ADT) and docetaxel in metastatic, hormone-sensitive prostate cancer (mHSPC) would increase survival.
Design: A randomized, double-blind, placebo-controlled, multicenter, phase 3 study. The results reported in this publication are from the prespecified interim analysis.
Intervention: Patients with mHSPC were randomly assigned to receive either darolutamide 600 mg twice daily or placebo. All patients received standard ADT with 6 cycles of docetaxel 75 mg/m2 on day 1 every 21 days along with prednisone given within 6 weeks after randomization. Patients receiving luteinizing hormone–releasing hormone (LHRH) agonists as ADT were bridged with at least 4 weeks of first-generation antiandrogen therapy, which was discontinued before randomization. Treatments were continued until symptomatic disease progression, a change in neoplastic therapy, unacceptable toxicity, patient or physician decision, death, or nonadherence.
Setting and participants: Eligible patients included those newly diagnosed with mHSPC with metastases detected on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and bone scan. Patients were excluded if they had regional lymph node–only involvement or if they had received more than 12 weeks of ADT before randomization. Between November 2016 and June 2018, 1306 patients (651 in the darolutamide group and 655 in the placebo group) were randomized in a 1:1 manner to receive darolutamide 600 mg twice daily or placebo in addition to ADT and docetaxel. Randomization was stratified based on the TNM staging system (M1a—nonregional lymph node–only metastasis, M1b—bone metastasis with or without lymph node, or M1c—bone metastases) as well as baseline alkaline phosphatase levels.
Main outcome measures: The primary end point for the study was overall survival. Other meaningful secondary end points included time to castration resistance, time to pain progression, time to first symptomatic skeletal event, symptomatic skeletal event-free survival, time to subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms, initiation of opioid therapy for ≥7 days, and safety.
Results: The baseline and demographic characteristics were well balanced between the 2 groups. Median age was 67 years. Nearly 80% of patients had bone metastasis, and approximately 17% had visceral metastasis. At the data cutoff date for the primary analysis, the median duration of therapy was 41 months for darolutamide compared with 16.7 months in the placebo group; 45.9% in the darolutamide group and 19.1% in the placebo group were receiving the allotted trial therapy at the time of the analysis. Six cycles of docetaxel were completed in approximately 85% of patients in both arms. Median overall survival follow-up was 43.7 months (darolutamide) and 42.4 months (placebo). A significant improvement in overall survival was observed in the darolutamide group. The risk of death was 32.5% lower in the darolutamide cohort than in the placebo cohort (hazard ratio [HR], 0.68; 95% CI, 0.57-0.80; P < .001). The overall survival at 4 years was 62.7% (95% CI, 58.7-66.7) in the darolutamide arm and 50.4% (95% CI, 46.3-54.6) in the placebo arm. The overall survival results remained favorable across most subgroups.
Darolutamide was associated with improvement in all key secondary endpoints. Time to castration-resistance was significantly longer in the darolutamide group (HR, 0.36; 95% CI, 0.30-0.42; P < .001). Time to pain progression was also significantly longer in the darolutamide group (HR, 0.79; 95% CI, 0.66-0.95; P = .01). Time to first symptomatic skeletal events (HR, 0.71; 95% CI, 0.54-0.94; P = .02) and time to initiation of subsequent systemic therapy (HR, 0.39; 95% CI, 0.33-0.46; P < .001) were also found to be longer in the darolutamide group.
Safety: The risk of grade 3 or higher adverse events was similar across the 2 groups. Most common adverse events were known toxic effects of docetaxel therapy and were highest during the initial period when both groups received this therapy. These side effects progressively decreased after the initial period. The most common grade 3 or 4 adverse event was neutropenia, and its frequency was similar between the darolutamide and placebo groups (33.7% and 34.2%, respectively). The most frequently reported adverse events were alopecia, neutropenia, fatigue, and anemia and were similar between the groups. Adverse events of special significance, including fatigue, falls, fractures, and cardiovascular events, were also similar between the 2 groups. Adverse events causing deaths in each arm were low and similar (4.1% in the darolutamide group and 4.0% in the placebo group). The rates of discontinuation of darolutamide or placebo were similar (13.5% and 10.6%, respectively).
Conclusion: Among patients with mHSPC, overall survival was significantly longer among patients who received darolutamide plus ADT and docetaxel than among those who received ADT and docetaxel alone. This was observed despite a high percentage of patients in the placebo group receiving subsequent systemic therapy at the time of progression. The survival benefit of darolutamide was maintained across most subgroups. An improvement was also observed in the darolutamide arm in terms of key secondary end points. The adverse events were similar across the groups and were consistent with known safety profiles of ADT and docetaxel, and no new safety signals were identified in this trial.
Commentary
The results of the current study add to the body of literature supporting multi-agent systemic therapy in newly diagnosed mHSPC. Prior phase 3 trials of combination therapy using androgen-receptor pathway inhibitors, ADT, and docetaxel have shown conflicting results. The results from the previously reported PEACE-1 study showed improved overall survival among patients who received abiraterone with ADT and docetaxel as compared with those who received ADT and docetaxel alone.1 However, as noted by the authors, the subgroup of patients in the ENZAMET trial who received docetaxel, enzalutamide, and ADT did not appear to have a survival advantage compared with those who received ADT and docetaxel alone.2 The results from the current ARASENS trial provide compelling evidence in a population of prospectively randomized patients that combination therapy with darolutamide, docetaxel, and ADT improves overall survival in men with mHSPC. The survival advantage was maintained across subgroups analyzed in this study. Improvements were observed in regards to several key secondary end points with use of darolutamide. This benefit was maintained despite many patients receiving subsequent therapy at the time of progression. Importantly, there did not appear to be a significant increase in toxicity with triplet therapy. However, it is important to note that this cohort of patients appeared largely asymptomatic at the time of enrollment, with 70% of patients having an Eastern Cooperative Oncology Group performance status of 0.
Additionally, the average age in this study was 67 years, with only about 15% of the population being older than 75 years. In the reported subgroup analysis, those older than 75 years appeared to derive a similar benefit in overall survival, however. Whether triplet therapy should be universally adopted in all patients remains unclear. For example, there is a subset of patients with mHSPC with favorable- risk disease (ie, those with recurrent metastatic disease, node-only disease). In this population, the risk-benefit analysis is less clear, and whether these patients should receive this combination is not certain. Nevertheless, the results of this well-designed study are compelling and certainly represent a potential new standard treatment option for men with mHSPC. One of the strengths of this study was its large sample size that allowed for vigorous statistical analysis to evaluate the efficacy of darolutamide in combination with ADT and docetaxel.
Application for Clinical Practice
The ARASENS study provides convincing evidence that in men with mHSPC, the addition of darolutamide to docetaxel and ADT improves overall survival. This combination appeared to be well tolerated, with no evidence of increased toxicity noted. Certainly, this combination represents a potential new standard treatment option in this population; however, further understanding of which subgroups of men benefit from enhanced therapy is needed to aid in proper patient selection.
—Santosh Kagathur, MD, and Daniel Isaac, DO, MS
Michigan State University, East Lansing, MI
Study Overview
Objective: To evaluate whether the addition of the potent androgen-receptor inhibitor (ARA) darolutamide to the standard doublet androgen-deprivation therapy (ADT) and docetaxel in metastatic, hormone-sensitive prostate cancer (mHSPC) would increase survival.
Design: A randomized, double-blind, placebo-controlled, multicenter, phase 3 study. The results reported in this publication are from the prespecified interim analysis.
Intervention: Patients with mHSPC were randomly assigned to receive either darolutamide 600 mg twice daily or placebo. All patients received standard ADT with 6 cycles of docetaxel 75 mg/m2 on day 1 every 21 days along with prednisone given within 6 weeks after randomization. Patients receiving luteinizing hormone–releasing hormone (LHRH) agonists as ADT were bridged with at least 4 weeks of first-generation antiandrogen therapy, which was discontinued before randomization. Treatments were continued until symptomatic disease progression, a change in neoplastic therapy, unacceptable toxicity, patient or physician decision, death, or nonadherence.
Setting and participants: Eligible patients included those newly diagnosed with mHSPC with metastases detected on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and bone scan. Patients were excluded if they had regional lymph node–only involvement or if they had received more than 12 weeks of ADT before randomization. Between November 2016 and June 2018, 1306 patients (651 in the darolutamide group and 655 in the placebo group) were randomized in a 1:1 manner to receive darolutamide 600 mg twice daily or placebo in addition to ADT and docetaxel. Randomization was stratified based on the TNM staging system (M1a—nonregional lymph node–only metastasis, M1b—bone metastasis with or without lymph node, or M1c—bone metastases) as well as baseline alkaline phosphatase levels.
Main outcome measures: The primary end point for the study was overall survival. Other meaningful secondary end points included time to castration resistance, time to pain progression, time to first symptomatic skeletal event, symptomatic skeletal event-free survival, time to subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms, initiation of opioid therapy for ≥7 days, and safety.
Results: The baseline and demographic characteristics were well balanced between the 2 groups. Median age was 67 years. Nearly 80% of patients had bone metastasis, and approximately 17% had visceral metastasis. At the data cutoff date for the primary analysis, the median duration of therapy was 41 months for darolutamide compared with 16.7 months in the placebo group; 45.9% in the darolutamide group and 19.1% in the placebo group were receiving the allotted trial therapy at the time of the analysis. Six cycles of docetaxel were completed in approximately 85% of patients in both arms. Median overall survival follow-up was 43.7 months (darolutamide) and 42.4 months (placebo). A significant improvement in overall survival was observed in the darolutamide group. The risk of death was 32.5% lower in the darolutamide cohort than in the placebo cohort (hazard ratio [HR], 0.68; 95% CI, 0.57-0.80; P < .001). The overall survival at 4 years was 62.7% (95% CI, 58.7-66.7) in the darolutamide arm and 50.4% (95% CI, 46.3-54.6) in the placebo arm. The overall survival results remained favorable across most subgroups.
Darolutamide was associated with improvement in all key secondary endpoints. Time to castration-resistance was significantly longer in the darolutamide group (HR, 0.36; 95% CI, 0.30-0.42; P < .001). Time to pain progression was also significantly longer in the darolutamide group (HR, 0.79; 95% CI, 0.66-0.95; P = .01). Time to first symptomatic skeletal events (HR, 0.71; 95% CI, 0.54-0.94; P = .02) and time to initiation of subsequent systemic therapy (HR, 0.39; 95% CI, 0.33-0.46; P < .001) were also found to be longer in the darolutamide group.
Safety: The risk of grade 3 or higher adverse events was similar across the 2 groups. Most common adverse events were known toxic effects of docetaxel therapy and were highest during the initial period when both groups received this therapy. These side effects progressively decreased after the initial period. The most common grade 3 or 4 adverse event was neutropenia, and its frequency was similar between the darolutamide and placebo groups (33.7% and 34.2%, respectively). The most frequently reported adverse events were alopecia, neutropenia, fatigue, and anemia and were similar between the groups. Adverse events of special significance, including fatigue, falls, fractures, and cardiovascular events, were also similar between the 2 groups. Adverse events causing deaths in each arm were low and similar (4.1% in the darolutamide group and 4.0% in the placebo group). The rates of discontinuation of darolutamide or placebo were similar (13.5% and 10.6%, respectively).
Conclusion: Among patients with mHSPC, overall survival was significantly longer among patients who received darolutamide plus ADT and docetaxel than among those who received ADT and docetaxel alone. This was observed despite a high percentage of patients in the placebo group receiving subsequent systemic therapy at the time of progression. The survival benefit of darolutamide was maintained across most subgroups. An improvement was also observed in the darolutamide arm in terms of key secondary end points. The adverse events were similar across the groups and were consistent with known safety profiles of ADT and docetaxel, and no new safety signals were identified in this trial.
Commentary
The results of the current study add to the body of literature supporting multi-agent systemic therapy in newly diagnosed mHSPC. Prior phase 3 trials of combination therapy using androgen-receptor pathway inhibitors, ADT, and docetaxel have shown conflicting results. The results from the previously reported PEACE-1 study showed improved overall survival among patients who received abiraterone with ADT and docetaxel as compared with those who received ADT and docetaxel alone.1 However, as noted by the authors, the subgroup of patients in the ENZAMET trial who received docetaxel, enzalutamide, and ADT did not appear to have a survival advantage compared with those who received ADT and docetaxel alone.2 The results from the current ARASENS trial provide compelling evidence in a population of prospectively randomized patients that combination therapy with darolutamide, docetaxel, and ADT improves overall survival in men with mHSPC. The survival advantage was maintained across subgroups analyzed in this study. Improvements were observed in regards to several key secondary end points with use of darolutamide. This benefit was maintained despite many patients receiving subsequent therapy at the time of progression. Importantly, there did not appear to be a significant increase in toxicity with triplet therapy. However, it is important to note that this cohort of patients appeared largely asymptomatic at the time of enrollment, with 70% of patients having an Eastern Cooperative Oncology Group performance status of 0.
Additionally, the average age in this study was 67 years, with only about 15% of the population being older than 75 years. In the reported subgroup analysis, those older than 75 years appeared to derive a similar benefit in overall survival, however. Whether triplet therapy should be universally adopted in all patients remains unclear. For example, there is a subset of patients with mHSPC with favorable- risk disease (ie, those with recurrent metastatic disease, node-only disease). In this population, the risk-benefit analysis is less clear, and whether these patients should receive this combination is not certain. Nevertheless, the results of this well-designed study are compelling and certainly represent a potential new standard treatment option for men with mHSPC. One of the strengths of this study was its large sample size that allowed for vigorous statistical analysis to evaluate the efficacy of darolutamide in combination with ADT and docetaxel.
Application for Clinical Practice
The ARASENS study provides convincing evidence that in men with mHSPC, the addition of darolutamide to docetaxel and ADT improves overall survival. This combination appeared to be well tolerated, with no evidence of increased toxicity noted. Certainly, this combination represents a potential new standard treatment option in this population; however, further understanding of which subgroups of men benefit from enhanced therapy is needed to aid in proper patient selection.
—Santosh Kagathur, MD, and Daniel Isaac, DO, MS
Michigan State University, East Lansing, MI
1. Fizazi K, Carles Galceran J, Foulon S, et al. LBA5 A phase III trial with a 2x2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: overall survival with abiraterone acetate plus prednisone in PEACE-1. Ann Oncol. 2021;32:Suppl 5:S1299. doi:10.1016/j.annonc.2021.08.2099
2. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381:121-131. doi:10.1056/NEJMoa1903835
1. Fizazi K, Carles Galceran J, Foulon S, et al. LBA5 A phase III trial with a 2x2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: overall survival with abiraterone acetate plus prednisone in PEACE-1. Ann Oncol. 2021;32:Suppl 5:S1299. doi:10.1016/j.annonc.2021.08.2099
2. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381:121-131. doi:10.1056/NEJMoa1903835