Combination Androgen Receptor Inhibition and Docetaxel in Metastatic Castration-sensitive Prostate Cancer: The Next Step in First-line Treatment?

Abstract

The addition of docetaxel and abiraterone to androgen deprivation therapy (ADT) heralded a new era in the first-line treatment of metastatic castration-sensitive prostate cancer (mCSPC). Following the success of these combination regimens, 3 new trials presented data on using enzalutamide or apalutamide in men with mCSPC, which showed similar success. These seminal trials collectively established the addition of docetaxel, enzalutamide, apalutamide, or abiraterone to ADT as standards in the upfront treatment of mCSPC. Notably, a subset of patients in these more recent trials were treated with a combination of docetaxel, ADT, and androgen receptor signaling inhibitors or maintenance androgen receptor signaling inhibitors after docetaxel and ADT that provided an initial glimpse into the efficacy of these triplet or maintenance strategies. We discuss the implications of these recent findings and place them in context of the current mCSPC treatment landscape.

Introduction

The addition of docetaxel to androgen deprivation therapy (ADT) heralded a new era in the first-line treatment of metastatic castration-sensitive prostate cancer (mCSPC) based on the positive results of the CHAARTED and STAMPEDE trials.^1,2 In the CHAARTED trial, adding docetaxel to ADT portended a significant survival advantage for patients of 13.6 additional months relative to ADT alone (57.6 vs. 44.0 months; hazard ratio [HR] 0.61; 95% confidence interval [CI], 0.47-0.80; P < .001) Beneficial outcomes were observed only in patients with high-volume metastatic disease.¹ This was similar to the STAMPEDE results, which showed the median overall survival (OS) of patients receiving ADT and docetaxel had a 10-month longer OS than those receiving ADT alone (81 vs. 71 months; HR, 0.78; 95% CI, 0.66-0.93; P = .006).² The outcomes from these trials led to the updated National Comprehensive Cancer Network (NCCN) guidelines recommending docetaxel in the frontline setting of mCSPC.³ Another trial which emphasized similar findings was the phase III LATITUDE trial which demonstrated adding abiraterone to ADT conferred a significantly longer OS, which had not been reached compared with 34.7 months for ADT alone (HR, 0.62; 95% CI, 0.51-0.76; P < .001). As seen in the CHAARTED trial, benefit was more apparent in patients with high-volume disease.⁴

An updated arm of the STAMPEDE trial confirmed the superiority of the androgen receptor signaling inhibitor (ARSI) abiraterone and ADT over ADT alone in docetaxel-naive patients with locally advanced prostate cancer and mCSPC.^4,5 This trial showed that there was a significant survival advantage of adding ARSI to ADT in terms of overall survival (HR, 0.63; 95% CI, 0.52-0.76; P < .001), as well as a longer duration before treatment failure (HR, 0.29; 95% CI, 0.25-0.34; P < .001) that included patients meeting CHAARTED criteria for both high- and low-volume metastatic disease.⁵ These data were the foundation for the NCCN guideline recommendations for using docetaxel or abiraterone in the mCSPC setting.³

Combining ARSIs With Docetaxel in First-line mCSPC

Given the benefits of docetaxel and abiraterone separately when combined with ADT from CHAARTED, STAMPEDE, and LATITUDE, a natural question arises whether the 2 can work together to lead to even greater efficacy. ARSIs, including enzalutamide and abiraterone, comprised the most common utilized therapy beyond progression in CHAARTED, although time to second-line therapy was not reported.^1,6 The docetaxel vs. non-docetaxel arm of the STAMPEDE trial reported that 20% of patients received abiraterone approximately 9 to 10 months from progression after docetaxel + ADT, although median time to abiraterone after progression was not reached at the time of its initial publication.² Data to support combination docetaxel and ARSIs or maintenance ARSI following docetaxel were limited to non-existent until recent large, randomized trials provided the first glimpses into the feasibility of these strategies in mCSPC (Table 1).

Table 1.

Recent Randomized Trials Investigating Androgen Receptor Inhibitors in Metastatic Hormone-sensitive Prostate Cancer

Author	Study	Phase	No. Patients	Experimental Arm	Control Arm	Primary Endpoint	Subset Analysis
Armstrong AJ et al7	ARCHES	III	1150	Enzalutamide 160 mg/ day + ADT (n = 574)	Placebo + ADT (n = 576)	rPFS: NR vs. 19.4 mos (HR, 0.39; 95% CI, 0.30-0.50; P < .0001)	In docetaxel pretreated patients (18% of study population), HR favored enzalutamide arm (HR, 0.53; 95% CI, 0.31-0.92) for rPFS
Chi KN et al8	TITAN	III	1052	Apalutamide 240 mg/day + ADT (n = 525)	Placebo + ADT (n = 527)	rPFS at 24 months: 68.2% vs. 47.5% (HR, 0.48; 95% CI, 0.51-0.89)	In docetaxel pretreated patients (10.7% of study population), HR trended towards improvement with apalutamide (HR, 0.47; 95% CI, 0.22-1.01) for 24-month rPFS
Davis ID et al9	ENZAMET	III	1125	Enzalutamide 160 mg/day + ADT	ADT (continued nonsteroidal antiandrogen)	3-year OS: 80% vs. 72% (HR, 0.67; 95% CI, 0.52-0.86)	In early docetaxel group (45% vs. 44%), HR favored enzalutamide arm (HR, 0.48; 95% CI, 0.36-0.62) for endpoint of PFS

Abbreviations: ADT = Androgen deprivation therapy; CI = confidence interval; HR = hazard ratio; NR = not reached; OS = overall survival; PFS = progression-free survival; rPFS = radiographic progression-free survival.

ARCHES

ARCHES was a multinational, double-blind, phase III trial in which 1150 men with mCSPC were randomized 1:1 to enzalutamide 160 mg/day plus ADT versus placebo plus ADT. Patients were stratified by disease volume and prior docetaxel therapy. Patients were allowed to have received up to 6 cycles of docetaxel prior to treatment with enzalutamide, as long as the last cycle of docetaxel was at least 2 months prior to study treatment, and there was no evidence of disease progression during or after docetaxel therapy.

Treatment with enzalutamide plus ADT was superior to placebo plus ADT for the primary endpoint of radiographic PFS (rPFS) (HR, 0.39; 95% CI, 0.30-0.50; P < .001). Approximately 18% of patients received prior docetaxel chemotherapy in both enzalutamide (n = 103) and placebo (n = 102) arms. In subgroup analysis, treatment with enzalutamide appeared to benefit patients who did not receive prior docetaxel therapy for the primary endpoint of rPFS (HR, 0.37; 95% CI, 0.28-0.49), a result that was largely expected. This benefit also appeared to extend to the subgroup who had received prior docetaxel (HR, 0.52; 95% CI, 0.30-0.89). Additionally, treatment with enzalutamide showed benefit in rPFS both in patients with low-volume (HR, 0.24; 95% CI, 0.13-0.45) and high-volume disease (HR, 0.44; 95% CI, 0.33-0.57). Although a survival benefit has not yet been shown, the currently available data from ARCHES are hypothesis generating for a strategy of enzalutamide “maintenance” following docetaxel therapy in patients with mCSPC can improve clinical outcomes.⁷ However, a definitive conclusion cannot be determined given the small sample of patients included in this subset and the wide CI in the OS analysis may suggest that some patients are even harmed by this approach.

TITAN

The TITAN trial was a double-blind, phase III study of 1052 men with mCSPC randomized 1:1 to treatment with apalutamide 240 mg per day plus ADT versus placebo plus ADT. Patients were stratified by Gleason score, geographic region, and prior docetaxel therapy. At the time of the first interim analysis (median duration of follow-up, 22.7 months), point estimates for 24-month rPFS were 68.2% in the apalutamide group versus 47.5% in the placebo group (HR, 0.48; 95% CI, 0.39-0.60). Additionally, 24-month overall survival was superior for apalutamide (82.4% vs. 73.5%; HR, 0.67; 95% CI, 0.51-0.89). TITAN was the first randomized, controlled trial to show benefit for apalutamide as a frontline treatment option in mCSPC.

Similar to ARCHES, prior to randomization, patients were allowed to have undergone docetaxel therapy for a maximum of 6 cycles as long as there was no evidence of disease progression during or after docetaxel treatment. A total of 113 (10.7% of the study population) patients received prior docetaxel therapy, with 58 patients in the apalutamide arm and 55 in the placebo arm. In this small subgroup, there was a trend toward superior rPFS at 24 months in patients who received apalutamide (not reached [NR] vs. 22.1 months; HR, 0.47; 95% CI, 0.22-1.01). There was no difference in 24-month OS between the arms in the docetaxel-treated subgroup (HR, 1.27; 95% CI, 0.52-3.09) with an actual HR > 1 suggesting harm, although only 11 deaths had occurred within the apalutamide arm and 9 deaths in the placebo arm, limiting the ability to make conclusions at this time.

Treatment with apalutamide was superior for rPFS in both the low-volume and high-volume subgroups. In the high-volume subgroup, apalutamide treatment was associated with superior 24-month OS (HR, 0.68; 95% CI, 0.50-0.92). There was no difference in 24-month survival in the low-volume subgroup (HR, 0.67; 95% CI, 0.34-1.32), although at the time of reporting, only 32 deaths had occurred within this group.⁸

ENZAMET

The initial results of the ENZAMET trial were reported simultaneously with TITAN. ENZAMET was an open-label, randomized, phase III study of 1125 men with mCSPC randomized 1:1 to enzalutamide 160 mg/day or a standard nonsteroidal antiandrogen drug (bicalutamide, nilutamide, or flutamide) plus background testosterone suppression. The role of docetaxel therapy in ENZAMET differed from that of ARCHES and TITAN. Treatment with docetaxel treatment was not initially permitted during the enrollment of the first 88 patients, but following the publication of the initial results of CHAARTED, the study protocol was revised to allow early administration of docetaxel plus testosterone suppression. The decision regarding whether to administer early docetaxel was left to the treating physician. In terms of timing, docetaxel therapy was commenced at least 4 weeks and no later than 6 weeks after randomization and consisted of a standard 6-cycle regimen. Patients who were already receiving docetaxel prior to randomization were allowed to have received up to 2 cycles. Patients therefore received docetaxel concomitantly with enzalutamide and ADT.

Patients were stratified by use of bone anti-resorptive therapy, planned use of early docetaxel, and disease volume. A significant proportion of patients were planned for docetaxel therapy: 45% versus 44% in the enzalutamide and standard care arms, respectively. The full planned 6 cycles of docetaxel was eventually given to 28% vs. 32% of patients in the enzalutamide and standard care arms, respectively. At the time of the first interim analysis, treatment with enzalutamide was superior for the primary endpoint of death (HR, 0.67; 95% CI, 0.52-0.86) with Kaplan-Meier estimates for 3-year survival 80% in the enzalutamide group and 72% in the standard-care group. A prespecified subgroup analysis of PFS was chosen, given the expectation that the number of deaths would be low at the time of the first interim analysis.

With regards to subgroup analysis, PFS was chosen as the primary endpoint, given the expectation that the number of deaths would be low at the time of the first interim analysis. Patients treated with enzalutamide had superior PFS compared with standard-care treatment in all subgroups, including those in whom early docetaxel therapy was planned (HR, 0.48; 95% CI, 0.36-0.62), low-volume disease (HR, 0.30; 95% CI, 0.22-0.43), and high-volume disease (HR, 0.45; 95% CI, 0.36-0.57). For the secondary outcome of OS, treatment with enzalutamide was superior for patients who were not planned for early docetaxel therapy (HR, 0.52; 95% CI, 0.37-0.75), but survival did not differ in the planned early docetaxel subgroup (HR, 0.90; 95% CI, 0.62-1.31). Enzalutamide therapy led to superior survival in patients with low-volume disease (HR, 0.42; 95% CI, 0.27-0.72) but only showed a trend towards superiority for high-volume disease (HR, 0.80; 95% CI, 0.59-1.07).⁹

Discussion

The results from ARCHES, TITAN, and ENZAMET are hypothesis-generating, as they are among the first data from large, prospective trials to highlight the concept of increased intensity of first-line treatment of mCSPC with a strategy of upfront “triple therapy” with ADT, docetaxel, and ARSI or early docetaxel plus ADT with maintenance ARSI. Data from ARCHES and ENZAMET suggest a significant improvement in rPFS and PFS, respectively, in patients who received or were planned to receive docetaxel prior to enzalutamide. Point estimates from TITAN suggested a trend towards benefit in 24-month rPFS for treatment with apalutamide in the docetaxel-treated subgroup. Although the data from the three clinical trials raise curiosity about the use of “triple therapy” for mCSPC, the overall evidence is weak. In both ARCHES AND TITAN, the subset analysis of patients who received docetaxel followed by ARSI vs. those who did not receive docetaxel was not randomized. This creates opportunity for flawed analysis and selection bias. For ARCHES and TITAN, these are retrospective analyses with no statistical support and huge potential for confounding by patient selection. Recognizing such is central to understanding the current data and colors the analysis of all the data presented. Another limitation is the patient subgroups in the trials were relatively small. Although there is suggestion of improvement in rPFS, the trials were not powered to definitively draw any conclusions. Although these data come from relatively small subgroups in trials without power or adequate clinical follow-up to adjudicate the specific question of therapeutic sequencing, they do represent the first evidence that early intensification strategies may be superior to the current standard of care. However, these data need to be cautioned that the OS data, although still immature, clearly suggest no benefit to the triplet combination. Thus, until further follow-up data can be generated, we do not recommend triplet combination at this time. Furthermore, future studies on this topic will be helpful in discerning whether concomitant therapy (triplet therapy upfront) or a maintenance strategy of ARSI following early docetaxel plus ADT would be an optimal approach in mCSPC. These new strategies will have to be compared to the current standard of care which is initiation of an ARSI following progression on chemohormonal therapy in this population. Extrapolating from breast cancer, where hormonal therapy also plays an important role in the systemic treatment paradigm, current guidelines favor a sequential hormonal therapy after chemotherapy approach in the adjuvant setting (cite NCCN breast cancer).¹⁰ However, in the metastatic setting, particularly when patients with breast cancer are candidates for hormonal therapy, proponents have advocated for the use of hormone therapy first, followed by chemotherapy when the tumor becomes resistant to sequential endocrine therapy.¹¹ There is evidence, however, to support benefit in time to progression for maintenance hormonal therapy after chemotherapy in metastatic breast cancer.¹² Future studies in prostate cancer, of ideally prospective design, will be prudent in answering this important question of whether concurrent versus maintenance therapy represents the optimal therapeutic strategy as this has remained an area of controversy in breast cancer.

It is not clear whether disease volume may be important in the selection of patients for early treatment intensification. ARCHES, TITAN, and ENZAMET all showed rPFS or PFS benefit with early ARSI treatment in both low- and high-volume disease. Although ENZAMET did not test the endpoint of OS in these subgroups, ARCHES and TITAN both showed an OS benefit for early ARSI treatment in high-volume disease and a possible trend toward OS benefit in low-volume disease. It is not clear how the even smaller subgroups of patients with high- or low-volume disease and prior or early docetaxel fared. Future studies of “triple” or ARSI maintenance regimens will need to clarify whether there is differential benefit depending on the degree of disease burden.

Future Direction

As triplet and maintenance ARSI strategies potentially move into the frontline setting, the role of treatment of the primary tumor in mCSPC will also have to undergo reassessment. Treatment of the primary tumor via radiotherapy or surgery is now recognized as a viable strategy in M1 mCSPC with low-volume disease and is listed as a treatment option in NCCN guidelines. The best evidence for this strategy comes from a phase III trial within STAMPEDE of 2061 patients with mCSPC randomized 1:1 to radiotherapy to the primary tumor followed by standard therapy versus standard therapy alone. Standard therapy was initially defined as ADT, but was then expanded in December 2015 to include early docetaxel in patients with low-volume disease. Eighteen percent of patients within the study were planned for early docetaxel therapy. Among all patients, no survival benefit was seen with primary RT compared with standard therapy alone (HR, 0.92; 95% CI, 0.80-1.06), but in the subgroup of patients with low-volume disease, survival was superior with radiotherapy (HR, 0.68; 95% CI, 0.52-0.90).¹³ Whether novel treatment combinations in conjunction with treatment of the primary tumor would further improve outcomes in patients with low-volume disease will be an important question for future study.

The primary risk of “triple” therapy would be the increased toxicity of treating a patient with all agents at once as opposed to completing docetaxel treatment prior to moving forward with ARSI maintenance. Future studies will need to determine whether men with mCSPC will be willing or able to tolerate such aggressive upfront treatment.

Work is already underway to assess whether upfront “triple” and maintenance ARSI strategies in mCSPC can improve outcomes. ARASENS is a phase III, placebo-controlled trial of men with mCSPC who are randomized 1:1 to ADT plus docetaxel and darolutamide versus ADT plus docetaxel alone. Also underway is the phase III PEACE1 trial (NCT01957436), which is randomizing men with mCSPC 1:1:1:1 to treatment with ADT plus docetaxel with or without RT and with or without abiraterone acetate plus prednisone. ARASENS and PEACE1 may offer insights into the benefit of triple therapy in mCSPC, whereas PEACE1 could further extend our understanding of the role of RT in combination with these therapies.

Conclusions

In summary, ADT is the cornerstone for treatment of mCSPC; however, over the past few years, the treatment paradigm of prostate cancer has been evolving. Combination therapies with docetaxel and ARSI as well as early docetaxel with maintenance ARSI have shown promising results. Growing the current understanding of the role of upfront combination versus sequential treatment strategies are still uncharted territory for mCSPC. Ongoing trials to answer this question are needed to better evaluate clinical benefit and cumulative toxicity.