Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone

doi:10.1016/j.ejca.2013.08.020

European Journal of Cancer

Volume 50, Issue 1, January 2014, Pages 78-84

https://doi.org/10.1016/j.ejca.2013.08.020 Get rights and content

Abstract

Background

The new generation anti-androgen enzalutamide and the potent CYP17 inhibitor abiraterone have both demonstrated survival benefits in patients with metastatic castration-resistant prostate cancer (CRPC) progressing after docetaxel. Preliminary data on the antitumour activity of abiraterone after enzalutamide have suggested limited activity. The antitumour activity and safety of enzalutamide after abiraterone in metastatic CRPC patients is still unknown.

Patients and Methods

We retrospectively identified patients treated with docetaxel and abiraterone prior to enzalutamide to investigate the activity and safety of enzalutamide in a more advanced setting. Prostate specific antigen (PSA), radiological and clinical assessments were analysed.

Results

39 patients with metastatic CRPC were identified for this analysis (median age 70 years, range: 54–85 years). Overall 16 patients (41%) had a confirmed PSA decline of at least 30%. Confirmed PSA declines of ⩾50% and ⩾90% were achieved in 5/39 (12.8%) and 1/39 (2.5%) respectively. Of the 15 patients who responded to abiraterone, two (13.3%) also had a confirmed ⩾50% PSA decline on subsequent enzalutamide. Among the 22 abiraterone-refractory patients, two (9%) achieved a confirmed ⩾50% PSA decline on enzalutamide.

Conclusion

Our preliminary case series data suggest limited activity of enzalutamide in the post-docetaxel and post-abiraterone patient population.

Introduction

In the last 2 years two novel androgen-targeting agents have shown improved overall survival (OS) and quality of life for men with advanced prostate cancer [1], [2]. The CYP17 inhibitor abiraterone and the novel anti-androgen enzalutamide were approved by the US Food and Drug Administration (FDA) in April 2011 and August 2012 respectively, for men with castration-resistant prostate cancer (CRPC) after docetaxel chemotherapy.

Abiraterone is an irreversible and potent inhibitor of CYP17, a key enzyme for the extragonadal synthesis of androgens and estrogens. In the post-docetaxel Phase III COU-AA-301 study, abiraterone with prednisone demonstrated a 4.6-month increase in OS, with improvements in all secondary end-points, compared to placebo with prednisone [1]. Enzalutamide is a next generation non-steroidal anti-androgen that was compared to placebo in the Phase III AFFIRM trial and demonstrated a 4.8-month improvement in median OS along with superiority in all secondary efficacy measures [2]. On the COU-AA-301 trial prior enzalutamide treatment was excluded and, likewise, on the AFFIRM study prior abiraterone was not allowed. Therefore, although the individual efficacy of abiraterone and enzalutamide after docetaxel is well established, the therapeutic benefit of targeting androgen receptor (AR) signalling by sequential administration of these agents is not clear. We, and others, have reported retrospective data showing that abiraterone has limited activity when used after docetaxel and enzalutamide [3], [4].

Several mechanisms of intrinsic or acquired resistance to abiraterone have been proposed in vitro and in vivo [5]. Furthermore, additional lines of therapy may allow sequential acquisition of mutations and clonal evolution that may impact the activity of subsequent treatments. The aim of this study was to retrospectively analyse the antitumour activity and safety of enzalutamide in patients previously treated with docetaxel and abiraterone.

Section snippets

Eligibility

Patients with metastatic CRPC that started treatment with enzalutamide within an Expanded Access Programme (EAP) at the Royal Marsden (RM) and Guy's and St. Thomas' (GS) NHS Foundation Trusts between June 2012 and February 2013 were retrospectively identified. Clinical data were collected from the electronic patient record. Criteria for inclusion in this study were histological diagnosis of prostate adenocarcinoma, previous docetaxel and abiraterone treatment, ongoing androgen deprivation

Patients characteristics

Between June 2012 and February 2013 a total of 39 patients were identified. The patient characteristics at abiraterone and enzalutamide initiation are described in Tables 1 and 2 respectively. The response and duration of abiraterone treatment are described in Table 3. Of the 38 patients who received abiraterone after docetaxel, 35 received abiraterone within the NHS (National Health System) and three were treated within clinical trials (two patients within the Phase I–II COU-AA-003 trial and

Discussion

With the successful development and approval of cabazitaxel, abiraterone and enzalutamide physicians are facing the difficult task of selecting the optimal sequence for patients with CRPC progressing post-docetaxel. At present, no clinical or biological factors have been shown to predict response to these agents and treatment choices are based on availability, patient and clinician preferences and performance status or comorbidities.

This retrospective study provides for the first time

Conflict of interest statement

Disclosure: Abiraterone acetate was developed at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent.

C.P. received lecture fees from Sanofi-Aventis and travel support from Sanofi-Aventis and Janssen-Cilag. G.A. received consulting fees and travel support from Janssen-Cilag, Veridex, Roche/Ventana and Millennium Pharmaceuticals, lecture fees from Janssen-Cilag, Ipsen, Takeda and Sanofi-Aventis, and grant support from AstraZeneca and

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Taxanes Versus Androgen Receptor Therapy as Second-Line Treatment for Castrate-Resistant Metastatic Prostate Cancer After First-Line Androgen Receptor Therapy
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The optimal therapeutic sequence for metastatic castrate-resistance prostate cancer (mCRPC) is still debated. This study aimed to compare activity of taxanes (TAX) versus that of androgen-receptor therapy (ART) in men with mCRPC treated with first-line ART.
This retrospective study included all consecutive chemo-naive mCRPC patients who have received first-line ART treatment. Progression-free survival (PFS) and overall survival (OS) were compared between patients treated with second-line ART or TAX.
Overall, 175 patients treated with first-line enzalutamide (ENZA, n = 75) or abiraterone (ABI, n = 100) were evaluated. Among them, 69 (39%) and 30 (17%) patients received second-line TAX and ART, respectively, while 76 (43%) patients did not receive further treatment. From the start of first-line therapy, the median PFS and OS were 13 months (95% CI: 11-15) and 34 months (95% CI: 29-39), respectively, without any significant difference between ENZA and ABI. From the start of second-line therapy, the median PFS and OS were 6 months (95% CI: 5-7) and 18 months (95% CI: 14-21), respectively. Compared with ART, docetaxel was associated with significantly higher prostate-specific antigen (PSA, ≥ 50%) (29% vs. 0%, P < .001) and radiological responses (21% vs. 0%, P < .001). PFS was longer in TAX than in ART (6.7 months vs. 4 months, HR: 0.63, 95% CI: 0.41-0.96, P = .034), but there was no significant difference in OS (19 months vs. 12 months, P = .1). After propensity score adjustment, PFS (P = .2) and OS (P = .1) were similar between second-line TAX and ART.
In the second-line setting, TAX provides higher PSA and radiological responses than does ART for mCRPC patients who received first-line ART, but the PFS and OS are similar. This study provides new elements to help deciding the best treatment sequence.
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The treatment landscape of advanced prostate cancer has widely expanded over the past years with androgen receptor signaling inhibitors (ARSIs) and taxane chemotherapy moving to earlier disease stages in the treatment of prostate cancer. With the increasing use of ARSIs in earlier disease stages, cross-resistance between treatments has emerged, which is a dominant impediment in current clinical practice. To overcome cross-resistance in the treatment of prostate cancer, it is of paramount importance to decipher the mechanisms of cross-resistance between ARSIs and between ARSIs and chemotherapy. Here, molecular mechanisms of resistance to the available therapies including androgen receptor (AR) splice variants, AR overexpression, AR mutations and glucocorticoid receptor upregulation are described. Based on these underlying mechanisms, clinical data of cross-resistance between ARSIs and chemotherapy have been reported. Only recently these data have been confirmed in prospective randomized trials. From these studies, it has become clear that sequential ARSI treatment has no place in the treatment of advanced prostate cancer due to emerging drug resistance. In addition, based on prospective evidence, we argue that it is worth considering an early switch to cabazitaxel treatment in case of lack of benefit on docetaxel regimen after an ARSI treatment. Based on these new insights from randomized trials, several recommendations for treatment sequence are proposed.
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To evaluate the impact of the hormonal treatment sequencing including abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) in mCRPC, and determine which sequence provides more benefits for patients.
Studies published in English between 1 January 2013 and 30 September 2017 were identified in PubMed and EMBASE electronic databases. Studies assessing the efficacy of treatment sequences, based on AAP and ENZ, in mCRPC patients, were eligible for analysis.
Seventeen studies met the inclusion criteria. Two assessed both treatment sequences AAP → ENZ and ENZ → AAP; it was found that sequence of AAP → ENZ showed a statistically significantly longer PSA-PFS than the observed in ENZ → AAP (pooled HR: 0,54; 95% CI; 0,36–0,82; p < 0,05). The nine studies analysing Doc → AAP → ENZ sequence, revealed favourable results in terms of PFS. The 5 studies which analysed AAP → ENZ sequence, show a decrease in PSA levels ≥ 50% in 11–41% of patients treated with enzalutamide after previous treatment with AAP. In the two studies that analysed the Doc → ENZ → AAP sequence, PSA response rates were much lower than those reported with Doc → AAP → ENZ, with decreases in PSA ≥ 30 of 3–18% and PSA ≥ 50 of 8–11%.
Significant clinical efficacy of AAP administered as the first-line treatment in mCRPC patients followed by enzalutamide, delaying disease progression, compared with the ENZ → AAP sequence. However, more studies and randomized trials are needed, to validate the best treatment sequencing.
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Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone

Abstract

Background

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Eligibility

Patients characteristics

Discussion

Conflict of interest statement

Ann Oncol

Ann Oncol

Eur J Cancer

Cancer Cell

Abiraterone and increased survival in metastatic prostate cancer

N Eng J Med

Increased survival with enzalutamide in prostate cancer after chemotherapy

N Eng J Med

Molecular pathways: inhibiting steroid biosynthesis in prostate cancer

Clin Cancer Res