Randomized, Noncomparative, Phase II Trial of Early Switch From Docetaxel to Cabazitaxel or Vice Versa, With Integrated Biomarker Analysis, in Men With Chemotherapy-Naïve, Metastatic, Castration-Resistant Prostate Cancer

Abstract

Purpose The TAXYNERGY trial ( ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve ≥ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed ≥ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor-targeted therapy. Overall, 35 patients (55.6%) had confirmed ≥ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had ≥ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve ≥ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved ≥ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of ≥ 50% PSA decrease at C4 ( P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.

Fig 1.

(A) Study design. (B) CONSORT diagram. C5, cycle 5; CTC, circulating tumor cell; mCRPC, metastatic castration-resistant prostate cancer; PI, principal investigator; PSA, prostate-specific antigen.

Fig 2.

(A) Progression-free survival (all patients). (B) Overall survival (all patients). NR, not reached.

Fig 3.

Representative high-resolution images of circulating tumor cells captured by geometrically enhanced differential immunocapture with (A) high and (B) low percent androgen receptor (AR) nuclear localization as assessed by quantitative image analysis. Immunofluorescence staining for AR is indicated in green. 4',6-Diamidino-2-phenylindole staining for DNA (nucleus) is indicated in blue (arrow).

Fig 4.

Greatest prostate-specific antigen (PSA) change from baseline at any time on study according to mean percent androgen receptor nuclear localization (%ARNL) at cycle 1 day 8 (C1D8; after 1 week of therapy). (A) Comparison of the lower three quartiles versus the upper quartile of mean %ARNL at C1D8 (n = 31); PSA ≥ 50% decrease from baseline was more common in patients with %ARNL in the lower three quartiles (71%) than in patients with %ARNL in the upper quartile (29%). (B) Comparison of increase versus decrease in %ARNL from cycle 1 day 1 (C1D1) to C1D8 (n = 25); PSA change from baseline was 40% in patients with increased mean %ARNL compared with 67% in patients with decreased mean %ARNL. Thirty-one patients had PSA change and evaluable circulating tumor cells (CTCs) at C1D8; 25 patients had PSA change and evaluable CTCs at both C1D1 and C1D8.