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

PurposeThe 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 MethodsPatients 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. ResultsSixty-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%). ConclusionThe 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.

Current treatment strategies for advanced prostate cancer

“…Finally, the TAXYNERGY trial recently reported that patients who did not achieve ≥30% PSA response with taxane after 12 weeks of therapy would benefit from switching to other taxane, which could serve as a prognostic marker for treatment decision-making. 69 Molecular biomarkers for disease prediction and new therapeutic targets As shown in Table 5, AR-V7, a truncated splice variant with no ligand binding domain, has become an attractive biomarker predicting the effect of ASIs. Investigators have sought to develop the methods for the quantitative assessment of this splice isoform from CTCs 59 and PBMCs.…”

Quantitative analysis of taxane drug target engagement of microtubules in circulating tumor cells from metastatic castration resistant prostate cancer patients treated with CRXL301, a nanoparticle of docetaxel

“…In our previous studies, we could not implement quantitative analysis of taxane-induced MT bundling in mCRPC patient CTCs, as MT integrity was not preserved in the CTCs isolated via the PSMA-based microfluidic device [28] . Instead, we quantified nuclear AR as a read-out of taxane clinical efficacy.…”

PARP inhibitors for homologous recombination-deficient prostate cancer

“…[24] A recent first-line chemotherapy trial (FIRSTANA) comparing docetaxel versus cabazitaxel in chemotherapy-untreated CRPC patients failed to show superiority of cabazitaxel in this setting, while a second study suggested that patients who don’t achieve an adequate initial PSA response to docetaxel might fare better if they are immediately switched to cabazitaxel. [25, 26] Thus, cabazitaxel generally remains a second-line chemotherapy option for CRPC at present, while docetaxel is the preferred first-line treatment. In addition, docetaxel added to androgen deprivation has been shown to improve survival in men with metastatic hormone-sensitive prostate cancer with higher initial disease burden, representing a reasonable standard of care for newly-diagnosed metastatic patients who are chemo-fit.…”