Original Study
Sequential Use of Androgen Receptor Axis-targeted Agents in Chemotherapy-naive Castration-resistant Prostate Cancer: A Multicenter Retrospective Analysis With 3-Year Follow-up

https://doi.org/10.1016/j.clgc.2019.09.011Get rights and content

Abstract

Background

There has been no established clinical evidence for using sequential treatment in castration-resistant prostate cancer (CRPC). Despite evident cross-resistance, androgen receptor axis-targeted agents (ARTAs), namely abiraterone (ABI) and enzalutamide (ENZ), are often used sequentially owing to less toxicity compared with chemotherapy.

Patients and Methods

A multicenter retrospective review of chemotherapy-naive patients with CRPC who had received ABI followed by ENZ (ABI-to-ENZ) or ENZ followed by ABI (ENZ-to-ABI) was conducted. Combined progression-free survival (PFS), overall survival (OS), and prostate-specific antigen (PSA) response (≥ 50% PSA decline) to each drug were compared between the 2 groups at the median follow-up of 36.0 months.

Results

There were no significant differences in combined PFS (12.4 vs. 10.9 months; hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.72-1.23; P = .6594) or OS (28.3 vs 29.3 months; HR, 0.96; 95% CI, 0.66-1.38; P = .8314) between the ABI-to-ENZ and ENZ-to-ABI groups. PSA response rate was not significantly different in first-line ARTAs (48.9% vs. 58.4%; P = .153) but significantly higher in ENZ as a second-line ARTA (40.4% vs. 13.7%; P < .0001). Although multivariate analysis revealed that the ABI-to-ENZ sequence was associated with favorable PFS on second-line ARTA (HR, 0.65; 95% CI, 0.49-0.85; P = .0019), it was not associated with an increased combined PFS or OS.

Conclusion

With relatively longer follow-up, ARTA sequence did not affect clinical outcomes of CRPC treatment except for PSA response and PFS on a second-line ARTA. These findings will be useful information in clinical decision-making, particularly in chemotherapy-unfit patients with CRPC.

Introduction

Androgen receptor axis-targeted agents (ARTAs), namely abiraterone acetate (ABI) and enzalutamide (ENZ), are one of the standard treatments for men with castration-resistant prostate cancer (CRPC). Use of ARTAs, irrespective of pre- or post-docetaxel therapy, has been shown to prolong survival of patients with metastatic CRPC.1, 2, 3, 4 However, it was reported that men who developed ARTA-refractory progression often showed cross-resistance to another ARTA,5 and therefore, docetaxel is recommended for those patients. However, men with ARTA-refractory CRPC are often rejective or unfit for chemotherapy. Then use of a different ARTA is a treatment option in first-line ARTA-refractory patients.

There have been several retrospective studies on the sequential use of ARTAs.6, 7, 8, 9 These studies showed a tendency for better progression-free survival (PFS) in patients treated with abiraterone followed by enzalutamide (ABI-to-ENZ) versus those treated with enzalutamide followed by abiraterone (ENZ-to-ABI) (hazard ratio [HR] range, 0.29-0.78), but there was no statistically significant difference in overall survival (OS) (HR range, 0.79-0.98). Recently, interim results of a prospective randomized phase II trial on the crossover use of ABI and ENZ was reported. Patients treated with the ABI-to-ENZ sequence showed a tendency towards a better PFS, similar to those in the previous retrospective studies, but the difference was not statistically significant (HR, 0.75; 95% confidence interval [CI], 0.53-1.06). The median overall survival (OS) was not reached at 24.3 months (HR, 0.82; 95% CI, 0.53-1.27).10,11 However, this prospective trial did not have the statistical power to detect the difference in OS because the primary endpoint was prostate-specific antigen (PSA) response to a second-line ARTA.

It is not clear whether the discrepancy between the results from those retrospective studies and the results from the prospective study reflected differences between real-world and clinical trial settings or if it was because of the small sample size, imbalanced background, or insufficient follow-up period of each study. Herein, we have performed a multicenter retrospective study based on further follow-up of patients, most of whom were analyzed in the previous 3 retrospective studies based on real-world data.7, 8, 9

Section snippets

Patients and Methods

We retrospectively retrieved and analyzed the data of 255 men with metastatic (mCRPC) and non-metastatic CRPC (nmCRPC) who received sequential treatment with ABI-to-ENZ or ENZ-to-ABI (sequential ARTAs) as the primary treatment for CRPC refractory to androgen deprivation (ADT) alone or ADT plus a first-generation antiandrogen (bicalutamide or flutamide) (Table 1). The 255 men initiated sequential ARTA treatment between 2012 and 2018 in one of 22 study institutions (see the Appendix) under

Results

Of the 255 study patients, 94 received sequential ABI-to-ENZ and the remaining 161 received sequential ENZ-to-ABI treatment. Patient characteristics are shown in Table 1, and no significant differences were observed between treatment groups. Maximum PSA changes during each treatment regimen are depicted in waterfall plot charts (Figure 1). In first-line treatment, PSA responses (≥ 50% PSA decline) were observed in 48.9% of patients in the ABI-to-ENZ group (Figure 1A, top) and 58.4% in the

Discussion

The present multicenter retrospective analysis demonstrated that combined PFS and PFS in patients on a first-line ARTA were not significantly different regarding the sequence of ARTAs, which is consistent with prospective randomized studies.10,11 Previous retrospective studies showed generally similar tendencies in terms of combined PFS that were favorable for sequential ABI-to-ENZ, which was also observed in the prospective randomized study, although the difference was not statistically

Conclusions

Our study demonstrated that the sequence of administered ARTAs did not affect the combined PFS or OS in chemotherapy-naive patients with CRPC. However, we showed that several factors had a significant impact on cancer outcomes, including the number of subsequently used OS-prolonging agents. The findings of the present study could be informative in clinical decision-making in real-world daily practice at least until the final results of the prospective randomized trial are made available.

Disclosure

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

Acknowledgments

The authors thank Mark Abramovitz, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

References (18)

There are more references available in the full text version of this article.

Cited by (0)

View full text