Original StudyComparative 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
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.
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French AFU Cancer Committee Guidelines - Update 2022-2024: prostate cancer - Management of metastatic disease and castration resistance
2022, Progres en UrologieCitation Excerpt :If the initial treatment at the hormone-sensitive stage was ADT ± NHA Due to cross-resistance between NHAs (Table 11), docetaxel chemotherapy is advisable [120–124]. If initial treatment at the hormone-sensitive stage was ADT ± docetaxel
Systematic Review of Efficacy and Health Economic Implications of Real-world Treatment Sequencing in Prostate Cancer: Where Do the Newer Agents Enzalutamide and Abiraterone Fit in?
2021, European Urology FocusCitation Excerpt :Abiraterone and enzalutamide work along the same androgen receptor signalling pathway that suggests a similar mechanism of action and therefore the possibility of cross-resistance [12]. Evidence of cross-resistance was documented in some real-world studies [30–33,35]. In de bono et al’s [35] study, which sequenced AA → ENZ, second-line therapy showed antitumour activity in some patients who had previously progressed after >24 wk of abiraterone.
Cross-resistance and drug sequence in prostate cancer
2021, Drug Resistance UpdatesFrench ccAFU guidelines – update 2020–2022: prostate cancer
2020, Progres en Urologie