Original Study
Comparative Assessment of Efficacies Between 2 Alternative Therapeutic Sequences With Novel Androgen Receptor-Axis-Targeted Agents in Patients With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer

https://doi.org/10.1016/j.clgc.2016.12.015Get rights and content

Abstract

Background

The objective of this study was to compare the efficacies of sequential therapies with novel androgen receptor-axis-targeted (ARAT) agents in patients with docetaxel-naïve metastatic castration-resistant prostate cancer (mCRPC).

Patients and Methods

This study included 108 consecutive patients with mCRPC who sequentially received abiraterone acetate (AA) and enzalutamide (Enz), in either order, without prior treatment with docetaxel. The combined prostate-specific antigen (PSA) progression-free survival (PFS) was defined as the sum of PFS1 and PFS2, representing PSA PFSs on the first and second ARAT agents, respectively.

Results

Of these patients, 49 and 59 received ARAT therapy with the AA-to-Enz sequence (AA-to-Enz group) and with the reverse sequence (Enz-to-AA group), respectively. No significant differences in the baseline characteristics were noted between the 2 groups. In the overall patient population, the PSA response rate to the second-line ARAT agent (21.3%) was significantly lower than that of the first-line ARAT agent (58.3%). The combined PSA PFS in the AA-to-Enz group (median, 18.4 months) was significantly superior to that of the Enz-to-AA group (median, 12.8 months). Furthermore, multivariate analysis identified the treatment sequence (ie, AA-to-Enz vs. Enz-to-AA group) in addition to performance status as an independent predictor of combined PSA PFS in these patients. However, there was no significant difference in overall survival (OS) between the 2 groups.

Conclusions

Although cross-resistance between ARAT agents is a common phenomenon in docetaxel-naïve patients with mCRPC, different efficacies were observed favoring the AA-to-Enz rather than Enz-to-AA sequence in this series with respect to combined PSA PFS but not OS.

Introduction

It has been well documented that the androgen receptor (AR) axis remains a key factor driving the disease progression of prostate cancer (PC), even after the acquisition of a castration-resistant phenotype.1 In fact, 2 recently developed novel AR-axis-targeted (ARAT) agents, the androgen biosynthesis inhibitor abiraterone acetate (AA) and the second-generation antiandrogen enzalutamide (Enz), were demonstrated to significantly improve overall survival (OS) in pivotal randomized clinical trials (RCTs) targeting both docetaxel-naïve and -pretreated patients with metastatic castration-resistant prostate cancer (mCRPC),2, 3, 4, 5 resulting in the markedly elevated proportion of patients with mCRPC treated with these new agents. However, these RCTs were restricted to patients without a prior history of treatment with novel ARAT agents,2, 3, 4, 5 indicating that the efficacies of sequential treatment in patients with mCRPC with AA and Enz have not been prospectively evaluated.

To date, there have been small retrospective studies analyzing the outcomes of second-line ARAT therapy for patients with mCRPC following the failure of first-line therapy, and the sequential treatment with AA and Enz in either order has been shown to generally exhibit limited activity in these patients.6, 7, 8, 9, 10, 11, 12, 13, 14 For example, Noonan et al7 assessed the data from 27 docetaxel-refractory patients with mCRPC who were treated with AA following progression on Enz, and reported that prostate-specific antigen (PSA) decline ≥ 50% and the median time to disease progression were 3.7% and 15.4 weeks, respectively. Although these findings suggest that there may be shared mechanisms mediating cross-resistance between AA and Enz, such as the emergence of AR splice variants and activating AR mutations, sequential ARAT therapies with AA and Enz are commonly provided for patients with mCRPC in routine clinical practice.15, 16 Furthermore, there has been a strong trend toward the movement of novel ARAT therapies into the front line for mCRPC treatment before the introduction of docetaxel within the past few years, due to the favorable tolerability of ARAT agents compared with taxanes6; however, most of the studies investigating the efficacies of sequential therapies with novel ARAT agents have focused on patients with mCRPC who previously showed docetaxel failure.

Considering these findings, it is still important to determine the optimal sequencing order of novel ARAT agents for patients with mCRPC, particularly those without a history of treatment with docetaxel. In this study, therefore, we conducted a retrospective evaluation of the data from a total of 108 consecutive Japanese docetaxel-naïve patients with mCRPC who sequentially received AA and Enz, in either order, to compare the clinical efficacies between ARAT therapy with the AA-to-Enz sequence (AA-to-Enz group) and that with the reverse sequence (Enz-to-AA group).

Section snippets

Patients and Methods

This was a retrospective study performed by reviewing clinicopathological data from a total of 108 consecutive Japanese patients with mCRPC who sequentially received AA and Enz without prior treatment with docetaxel at our institutions between August 2014 and May 2016 in a routine clinical setting. All the patients included in this series had been histologically confirmed as having adenocarcinoma of the prostate, and then received androgen deprivation therapy (ADT) with medical or surgical

Patient Characteristics

The clinicopathological characteristics of the 108 patients with mCRPC included in this study are presented in Table 1. Of these 108 patients, 49 (45.4%) and 59 (54.6%) were treated with ARAT therapy according to the AA-to-Enz sequence (AA-to-Enz group) and reverse sequence (Enz-to-AA group), respectively. No significant differences in the major clinicopathological parameters were noted between these 2 groups.

Response to ARAT Therapy

Figure 1 shows the maximum reduction of the serum PSA values during treatment with

Discussion

For patients with mCRPC following progression on primary ADT, the introduction of a novel ARAT agent, either AA or Enz, before docetaxel therapy, has become a preferred option for most of these patients, whereas for patients treated with an ARAT agent as first-line therapy for mCRPC, accumulated data strongly suggest the limited activity of sequential ARAT therapy with another agent.6 In real-world clinical practice, however, the sequential introduction of an alternative ARAT agent is

Disclosure

The authors have stated that they have no conflicts of interest.

References (18)

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