ARASENS is an international phase III trial demonstrating the beneficial role of darolutamide, a novel antiandrogen, when added to docetaxel and androgen deprivation therapy (ADT), with improvement in overall survival in men with metastatic castration-sensitive or hormone-sensitive prostate cancer. Darolutamide is a nonsteroidal androgen receptor antagonist that has been previously shown to improve metastasis-free survival in nonmetastatic castration-resistant prostate cancer. ARASENS showed that the risk of death was 32.5% lower in those who received additional darolutamide compared to ADT and docetaxel alone. Darolutamide also improved other secondary endpoints including time to castrate-resistant disease, time to pain progression, time to first skeletal-related event, and subsequent initiation of therapy. ARASENS, therefore, shows that darolutamide, in addition to ADT and docetaxel, as a form of upfront systemic intensification of “triplet” therapy for patients deemed chemotherapy-fit, represents a new standard of care for men with metastatic hormone-sensitive or castrate-sensitive prostate cancer and is anticipated to further change the landscape of treatment for this population of patients.
Prostate cancer remains the most common solid tumor among American men,1 with the incidence of de novo metastatic hormone-sensitive prostate cancer rising about 6% per year. Treatment for metastatic prostate cancer has changed rapidly over the recent several years. While androgen deprivation therapy (ADT) has remained the backbone of treatment for decades,2 further upfront intensification of systemic therapy has proven beneficial and additive effects in overall survival have resulted in rapid revolutionary adoption with additional therapy (Table 1) as seen with docetaxel chemotherapy in the CHAARTED trial,3 or abiraterone in the LATITUDE trial, especially for high-risk or high-volume disease,4 or apalutamide in the TITAN trial,5 or enzalutamide in the ARCHES trial,6 and ENZAMET study,7 that have all led credence to this approach.
More recent data suggest that triplet therapy, in the setting of added abiraterone to ADT and docetaxel, based on the PEACE-1 trial, also led to longer overall survival compared to ADT and docetaxel alone, with an 18% improvement overall or a one-year improvement in the overall population of 5.7 years compared to 4.7 years in the ADT with docetaxel alone arm (hazard ratio [HR] = 0.82; 95% confidence interval [CI]: 0.69 to 0.98; P = 0.030).8 Indeed, the addition of darolutamide, a novel antiandrogen, in the ARASENS trial shows a very similar trend in terms of survival benefit.9
ARASENS is a phase III trial with randomization of 1:1 that was conducted internationally in 23 countries with the primary objective of evaluating the overall survival difference between the de facto standard of care with ADT and docetaxel with placebo compared to ADT plus docetaxel plus darolutamide, with the latter oral antiandrogen given at the standard dose of 600 mg twice daily with food (2 pills of 300 mg). Randomization was stratified according to patients’ metastatic stage via Tumor, Node, Metastasis (TNM) staging with nonregional metastases (M1a), which made up a minority of patients at 3.5%, with the majority at 79.5% having bone metastases (metastatic stage M1b) and 17.5% having visceral metastases (metastatic stage M1c). Other stratification included the alkaline phosphatase level though the true definition of high-volume or low-volume disease was not well defined in the study. Patients continued to receive darolutamide or placebo until symptomatic disease progression or excessive toxicity occurred, although docetaxel was given at the standard dose of 75 mg per m2 intravenously every 3 weeks for six cycles.
The primary endpoint was overall survival, which was defined as the time from randomization to death from any cause. Other secondary endpoints that were evaluated included time to development of castration-resistant disease, skeletal event-free survival, symptomatic skeletal event, initiation of subsequent antineoplastic treatment and worsening of disease-related symptoms, or initiation of opioid therapy. Patients were assessed using conventional computed tomography (CT) scan and technetium-99 bone scan within 30 days of finishing docetaxel and yearly thereafter. They also filled out questionnaires for quality of life brief pain inventory and the National Comprehensive Cancer Network (NCCN) symptom index.
The trial was designed to detect a 25% decreased risk in death in the darolutamide group compared to placebo with a two-sided alpha level of 0.05 and with a power of 90% with calculations utilizing the Cox proportional-hazards model for the HR comparisons and CI calculations between darolutamide and placebo. The secondary endpoints were meant to be tested in a hierarchical gatekeeping procedure which would be tested only if the primary endpoint and each preceding secondary endpoint achieved statistical significance. The Kaplan–Meier method was used to estimate the time to specific events in the secondary endpoints.
The results showed similar demographic characteristics between the two groups with a median age of 67 years, most patients with ECOG performance status of 0, and majority at 78.2% with Gleason score of 8 or higher as well as de novo metastatic at presentation in 86.1% of patients, suggesting a more aggressive course of prostate cancer, which was used as one of the definitions in an aforementioned LATITUDE trial for higher-risk prostate cancer. While all patients had metastatic disease at baseline, 17.5% had visceral metastases and 79.5% had bone metastases.
Majority of patients (87.6% in the darolutamide group compared to 85.5% in the placebo group) were able to complete the standard six cycles of docetaxel. The primary endpoint of overall survival was met with overall survival at 4 years of 62.7% in the darolutamide group compared to 50.4% in the placebo group, and a median overall survival of not evaluable (NE) for darolutamide compared to 48.9% in the placebo arm, translating to a 32.5% reduction in the risk of death in the darolutamide arm compared to that in the placebo group (HR = 0.68; 95% CI: 0.57 to 0.80; P < 0.001). All the secondary endpoints tested, including time to castration-resistant disease, are also improved in the darolutamide arm, being not evaluable in the darolutamide compared to 19.1 months for placebo (HR = 0.36; 95% CI: 0.30 to 0.42; P < 0.001). Other secondary endpoints, including time to pain progression, were also longer in the darolutamide arm, at nonevaluable compared to 27.5 months with placebo (HR = 0.79; 95% CI: 0.66 to 0.95; P = 0.01), as well as time to symptomatic skeletal event-free survival and first symptomatic skeletal event and initiation of subsequent systemic antineoplastic therapy. The safety profile seen in both arms also appeared to be similar, with grade 3 to 5 events occurring in about 66.1% of patients in the darolutamide group and 63.5% in the placebo group, while patients with grade 5 events occurred similarly in 4.1% in the darolutamide and 4% in the placebo group and the incidence of neutropenia and febrile neutropenia was also similar across both arms.
ARASENS is one of the two pivotal trials, in addition to PEACE-1,8 that heralded the benefit of triplet therapy. Men who present with metastatic prostate cancer can either arise de novo versus recurrent or primary progressive, with the former showing a much more aggressive disease profile.10 In addition, the benefit from upfront chemotherapy has historically been deemed driven mostly by men who have the high-volume disease as defined in the CHAARTED trial, that is the presence of visceral metastases or greater than/equal to four bone metastases with at least one outside of the vertebral column and pelvis.11 The updated results from CHAARTED showed that men with the low-volume disease did not have overall survival benefit compared to those who had high-volume disease treated with ADT with docetaxel, with a median overall survival of 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR = 0.63; 95% CI: 0.50 to 0.79; P < 0.001).11
Further analyses of ARASENS showed that the median overall survival seen in the darolutamide arm far exceeds that of the comparator placebo arm, which consisted of ADT with docetaxel with a median overall survival of 48.9 months. Similar to the PEACE-1 dataset, which showed a remarkable median overall survival of 61 months for the ADT with docetaxel and abiraterone arm, the era of triplet therapy shows impressive outcomes that far exceeds the survival outcomes achieved from ADT with docetaxel alone. In addition, despite majority of patients in the PEACE-1 trial (81%) receiving subsequent next-generation androgen-signaling agents in the ADT plus docetaxel SOC arm, early intensification with triplet therapy still resulted in improvement in radiographic progression-free survival and overall survival compared to sequential therapy. While these registrational trials do show fairly tolerable risks and equivalent safety profiles with majority of patients completing all six cycles of docetaxel, it has yet to be seen if all patients, regardless of volume or risk of disease, benefit equally. For instance, in the PEACE-1 dataset, while the beneficial effect was seen across almost all subgroup population of patients including those who were considered to have high-volume disease (HR = 0.72, 95% CI: 0.55 to 0.95) and low-volume disease (HR = 0.83, 95% CI: 0.50 to 1.38), the overall survival data were considered immature for the low-volume patients due to a small number of events. In contrast, ARASENS does not have granular detail on the breakdown of high- versus low-volume disease, clinical node-positive only disease, or de novo metastatic prostate cancer versus the recurrent or progressive metastatic prostate cancer. While the study also predominantly enrolled men who had a median age of 67 years and had good performance status, it is unclear how real-world adoption would be given usual multiple concomitant comorbidities in many men who are diagnosed with metastatic prostate cancer and their inherent ability to tolerate triplet therapy combination. Regardless, despite the multitude of patients with 75.6% receiving further life-prolonging therapies after progression in the placebo arm, ARASENS was still able to definitively show a survival benefit. While triplet therapy does appear to enhance the overall response, effects and survival in the first-line upfront metastatic hormone-sensitive setting, it remains to be seen if this is simply a “triplet therapy” effect versus a specific androgen-signaling drug effect, especially since there was no comparator arm of ADT and darolutamide alone. A previously reported phase III trial that utilized enzalutamide in the ENZAMET study did include a subset of men who received early docetaxel and the overall effect of enzalutamide on overall survival appeared to be less robust in the early docetaxel subgroup, although ENZAMET was admittedly not designed nor powered to reliably analyze the results of the triplet therapy subgroup.7 In addition, whether the potential drug–drug interactions with the use of enzalutamide and docetaxel as previously reported in a small phase Ib trial,12 could have impacted the outcomes of ENZAMET with ensuing higher toxicity rates seen in the early docetaxel arm could have dampened down the benefits, remain unknown.
Taken together, these datasets add to the current existing literature that suggests that upfront early intensification of systemic triplet therapy, which constitutes combined ADT with docetaxel and additional androgen signaling agents, results in vast improvement in overall survival compared to usual sequential therapy, and represents a new standard of care for those who are eligible or qualified or fit for such intensified treatment.
JBAC serves on the Speakers’ Bureau of BMS and Astellas/Seattle Genetics; and JBAC previously served on the Advisory Board for Pfizer/Myovant, Astellas and Bayer.
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