Previous Docetaxel Therapy Thwarts Enzalutamide Activity in CRPC

Charles Bankhead

March 2014, Vol 5, No 2 - Prostate Cancer

San Francisco, CA—Men with castration-resistant prostate cancer (CRPC) had inferior time duration to prostate-specific antigen (PSA) progression and of progression-free survival (PFS) if they received the androgen receptor agonist enzalutamide (Xtandi) after the taxane docetaxel (Taxotere) rather than before, according to data from a retrospective study presented at the 2014 Genitourinary Cancers Symposium.

The odds for time to PSA progression and of PFS were reduced by 60% when patients received the taxane before the androgen receptor antagonist compared with receiving enzalutamide before docetaxel.

These findings inform a key issue in the era of expanded treatment options for CRPC—the optimal sequencing of specific agents.

“The effect of enzalutamide pre-docetaxel on time to PSA progression and progression-free survival was maintained after adjusting for baseline prognostic factors,” according to a poster presented by Rosa Nadal, MD, Urologic Oncology Fellow, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, and colleagues. “The lower activity of enzalutamide observed post-docetaxel might be due to taxane-induced androgen receptor signaling changes, supporting the hypothesis of cross-resistance between enzalutamide and docetaxel.”

Enzalutamide is approved by the US Food and Drug Administration for the treatment of patients with CRPC that has proved refractory to docetaxel. However, these agents’ overlapping mechanisms of action and evidence of interaction have raised questions about the most appropriate sequence for the use of these 2 drugs.

Study Details
To examine the effect of sequence on antitumor activity, Dr Nadal and colleagues identified 90 patients with CRPC who were treated with enzalutamide—33 patients had no previous exposure to docetaxel and 57 had received the taxane before initiating treatment with enzalutamide. In addition, 81% of the patients had been treated with abiraterone (Zytiga), and 35.5% with ketoconazole.

PSA response was defined as a ?50% decline from baseline, and PSA progression as a ?25% increase from baseline. Time to PSA progression was defined as the interval from the initiation of treatment with enzalutamide to the first documentation of PSA progression. The investigators defined PFS as the time from the initiation of enzalutamide to the first documentation of PSA progression or death from any cause.

Analysis of prognostic factors associated with time to PSA progression identified baseline alkaline phosphatase, baseline albumin, baseline hemoglobin, no previous hormonal therapy, extent of disease, and previous docetaxel treatment as having significant associations. The same 6 factors were significantly associated with PFS.

By multivariate analysis, previous docetaxel exposure remained significantly and inversely associated with time to PSA progression and PFS duration. Comparison of patients with and without previous docetaxel treatment resulted in hazard ratios of 0.39 for time to PSA progression (P = .021), and 0.41 for PFS (P = .047).

The median follow-up from the initiation of enzalutamide was 6.8 months. The stratification of clinical outcomes by previous docetaxel exposure showed that patients who received enzalutamide before docetaxel had a higher PSA response rate (41.9% vs 25.5%), greater median time to PSA progression (9.0 vs 2.5 months; P <.001), and longer PFS duration (not reached vs 3.2 months; P = .006).