Elsevier

European Journal of Cancer

Volume 51, Issue 14, September 2015, Pages 1946-1952
European Journal of Cancer

Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer

https://doi.org/10.1016/j.ejca.2015.06.128Get rights and content

Abstract

Background

There is an urgent need for qualified predictive biomarkers of sensitivity for the treatments used in patients with castration-resistant prostate cancer (CRPC). We attempted to identify ready-to-use clinical predictors of improved outcome in metastatic CRPC (mCRPC) patients treated with next generation androgen receptor (AR) axis targeted drugs.

Patients and methods

We reviewed a cohort of patients who received AR axis targeted drugs for CRPC at two major French cancer centres. The predictive role of several clinical, biological and radiological parameters on progression-free survival (PFS) was studied.

Results

The study cohort consisted of 173 patients. Median duration of response to initial androgen deprivation therapy (ADT) (time to castration resistance, TTCRPC) was 17.8 months. The 50% prostate-specific antigen (PSA) response rate to AR axis targeted drugs was 16% (95% confidence interval (CI): 6–27) and 41% (95% CI: 30–47) in patients with TTCRPC of under and over 12 months respectively (p = 0.005). Median PFS was 2.8 months (95% CI: 2.1–3.9) and 5.8 (95% CI: 4.6–7.8; HR: 0.58, p = 0.002). In patients treated with post-docetaxel enzalutamide (n = 57), median PFS was 2.8 months and 8.6 months, (Hazard ratio (HR) = 3.1; 95% CI: 1.6–5.8, p = 0.0016) according to TTCRPC, whereas no difference was observed in placebo-treated patients (n = 27). The 50% PSA response rate to enzalutamide was 8% (95% CI: 0–38) and 58% (95% CI: 42–73) in patients with a TTCRPC of under and over 12 months respectively (p < 0.001).

Conclusion

The previous duration of response to ADT is a predictor of sensitivity to next generation AR axis targeted drugs in patients with mCRPC.

Introduction

Androgen deprivation therapy (ADT) is the main treatment for patients diagnosed with metastatic or relapsed prostate cancer [1]. After an initial response, most patients will eventually progress, leading to the castration-resistant prostate cancer (CRPC) [2]. Docetaxel chemotherapy has been widely used for patients with metastatic CRPC. Androgen signalling remains the main oncogenic driver pathway in CRPC [3] and new strategies to improve its inhibition have successfully developed. Abiraterone acetate, an oral CYP17 inhibitor, improves overall survival (OS) in both chemotherapy-naïve and chemotherapy-pretreated metastatic CRPC (mCRPC) patients [4], [5], [6]. An OS benefit in the same patient profile was demonstrated with enzalutamide, a next-generation androgen receptor (AR) inhibitor [7], [8]. Cabazitaxel, a new taxane compound, improved OS in chemotherapy-pretreated patients [9]. Sipuleucel-T improves OS, mostly in chemotherapy-naïve patients [10], and radium-223 was shown to improve outcome in the pre- and post-docetaxel setting [11]. Finally, the bone-targeting agent denosumab demonstrated a delay in the onset of skeletal-related events in men with symptomatic bone mCRPC [12].

Since not all CRPC patients benefit from these treatments due to primary resistance, there is an urgent need to identify predictive biomarkers of sensitivity to assist decision-making in patients with CRPC and avoid useless side-effects and costs from a poorly performing drug. Intense translational research efforts are ongoing in this direction. We aimed to investigate ready-to-use clinical predictors of improved outcome, notably of PFS, in CRPC patients treated with AR axis targeted drugs.

Section snippets

Patient selection

In this retrospective study we pooled the clinical databases from two comprehensive cancer centres, the Gustave Roussy Institute (IGR) and the Institut Jean Godinot, Reims, France. Patients treated with AR axis targeted drugs for histologically confirmed prostate cancer in the metastatic castration-resistance phase were included. Patients for whom the exact time of ADT initiation and castration resistance was not available were excluded. CRPC was defined as biochemical or radiological disease

Patients and disease characteristics

The study cohort included 173 patients. Data collection was between January 2012 and December 2014 (data of last follow-up). Patient and disease characteristics at diagnosis and at treatment start with the AR axis targeted drug in the CRPC setting are summarised in Table 1. Median TTCRPC was 17.8 months (25th percentile: 11.3 months; 75th percentile: 32 months). Most patients received docetaxel chemotherapy with a median time to progression of 6.7 months (range: 1–17 months). The median pretreatment

Discussion

No strong clinical data exist to provide guidance for the optimal administration of drugs in the CRPC setting. Given the number of existing options in the AR axis targeted drugs, we aimed to identify a reliable cross-cutting predictive factor of efficacy of these therapies. We show that a short duration of response to ADT (TTCRPC < 12 months) is predictive of shorter PFS and lower efficacy (PSA response) in patients treated with next-generation AR axis targeted drugs. Given the heterogeneity of

Conflict of interest statement

Yohann Loriot: honoraria/consultantship from Astellas, Janssen, Sanofi-Aventis. Karim Fizazi: honoraria/consultantship from Astellas, Janssen. Christophe Massard: honoraria/consultantship from Janssen. The other authors do not have any conflict of interest to declare.

Acknowledgements

No specific funding source or writing assistance was used for this article.

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