Abiraterone, an androgen synthesis inhibitor, has been successfully used in the treatment of castration-resistant prostate cancer (CRPC) for 2 yr. Enzalutamide is a second-generation nonsteroidal antiandrogen that has recently been approved for the same indication.
Objective
This is the first study to evaluate the effectiveness of enzalutamide after failure of abiraterone.
Design, setting, and participants
Thirty-five patients were identified as having received sequential therapy with abiraterone followed by enzalutamide. All patients had undergone prior docetaxel chemotherapy, and no patient had received ketoconazole.
Outcome measurements and statistical analysis
Posttreatment changes in prostate-specific antigen (PSA) were used to determine the activity of enzalutamide in patients who had received prior abiraterone.
Results and limitations
The median duration of abiraterone treatment was 9.0 mo (range: 2.0–19.0 mo). Of the 35 patients, 16 (45.7%) achieved a >50% decline in PSA, and 14 (40%) had a rising PSA as the best response. The median duration of subsequent enzalutamide treatment was 4.9 mo (Kaplan-Meier estimate; 95% confidence interval [CI], 2.4–7.4). Seven of 16 CRPC patients who were initially abiraterone-sensitive (43.8%) and 3 of 19 CRPC patients who were initially abiraterone-insensitive (15.8%) showed a >50% PSA decline while taking enzalutamide. Of the 35 patients, 17 (48.6%) were primarily enzalutamide-resistant and showed a rising PSA as the best response. Median time to progression was 4.0 mo (95% CI, 2.0–6.0) for 18 of 35 patients with at least one declining PSA value while taking enzalutamide (51.4%). Of the 17 patients who were assessable radiologically, only 1 (2.9%) attained a confirmed partial response. Small sample size was the major limitation.
Conclusions
Enzalutamide treatment achieved only a modest response rate in patients progressing after abiraterone. Although cross-resistance between abiraterone and enzalutamide was a common phenomenon, it was not inevitable, and a small but significant number of patients showed significant benefit from sequential treatment.
Introduction
Almost all prostate cancer (PCa) patients in the Western world who die of their disease have received androgen-deprivation therapy (ADT). Although the majority of PCa responds to initial ADT, PCa cells usually acquire the ability to survive and grow under low levels of circulating testosterone (<50 ng/dl) within 12–48 mo of treatment. This state of the disease, also known as castration-resistant prostate cancer (CRPC), is almost invariably fatal [1].
Until recently, taxanes such as docetaxel and cabazitaxel were the only antineoplastic agents with significant activity against CRPC [2], [3]. Consequently, there was an urgent need for additional new therapeutic approaches.
In contrast to previous beliefs, the progression from androgen-sensitive PCa to CRPC is rarely due to the loss of the androgen receptor (AR); in fact, in CRPC, the cells’ AR signaling remains active even under castration levels of serum testosterone [4]. Two novel drugs (abiraterone and enzalutamide) targeting the AR-signaling pathway have shown efficacy with mild toxicity in CRPC patients: Abiraterone is an oral CYP17A1 inhibitor that is able to block intracellular androgen synthesis in CRPC tissue (Fig. 1), thereby blocking a major mechanism of resistance to first-line ADT [5], [6], [7]. Enzalutamide is a nonsteroidal antiandrogen that binds to the ligand-binding domain (LBD) of the AR with 8–10 times higher affinity than bicalutamide [8]. On binding to the LBD, enzalutamide diminishes AR nuclear translocation, DNA binding, and recruitment of AR coactivators [8], [9]. Because of their efficacy and favorable toxicity profiles, these drugs have become a standard treatment of CRPC.
Unfortunately, the clinical effectiveness of both compounds is limited. Phase 3 trials including docetaxel-refractory CRPC patients described a median time to prostate-specific antigen (PSA) progression of only 8.5 mo for abiraterone and 8.3 mo for enzalutamide [6], [10].
To date, there is only limited information regarding the sequential use of both drugs. Two small studies showed only a limited efficacy of a sequential enzalutamide–abiraterone treatment [11], [12]. To assess the potency of an enzalutamide treatment in abiraterone-refractory CRPC, we performed a pilot study analyzing biochemical response during sequential abiraterone–enzalutamide treatment.
Section snippets
Patients
Since June 2012, 35 consecutive CRPC patients have been included in the MDV3100 (enzalutamide [Xtandi]) compassionate use program at three German university medical centers (Ulm, n = 11; Muenster, n = 19; Homburg/Saar, n = 5); at the time of their inclusion, these patients showed disease progression after or during treatment with docetaxel (Taxotere) and abiraterone (Zytiga). Implementation of the compassionate use program was approved by the respective local ethics commissions; all patients gave
Patient-specific characteristics
The study included 35 CRPC patients treated sequentially with docetaxel, abiraterone, and enzalutamide. Patient- and tumor-specific characteristics are listed in Table 1.
Response to the different lines of androgen-deprivation therapy
Of the 35 patients, 33 (94.3%) showed a significant initial biochemical response to primary ADT (PSA decline >50%) (Table 2). Only two PCa patients were primarily refractory to conventional ADT.
At least one decline in PSA (5–99%) was observed in 21 of 35 patients who subsequently received abiraterone in the state of castration
Discussion
Despite high initial response rates, the benefits from primary ADT are only transitory because of the emergence of CRPC cells in which AR reactivation occurs and tumor cells grow despite subphysiologic levels of circulating testosterone [4], [13]. In 2001, Feldman and Feldman [4] defined several potential pathways to independence from circulating androgens: AR signaling in CRPC cells was characterized by combinations of AR gene amplification, enhanced sensitivity through upregulation of
Conclusions
Treatment with enzalutamide was associated with a low response rate in patients progressing after abiraterone treatment. Various experimental findings suggest that the expression of AR-LBD mutants or ARΔLBD in CRPC might be responsible for the failure of both abiraterone and enzalutamide. Although cross-resistance between abiraterone and enzalutamide is a common phenomenon, it is not inevitable, and a small but significant number of patients can benefit from sequential treatment. Therefore, a
