CLINICAL EVIDENCE OF RESISTANCE AND CROSS-RESISTANCE WITH DOCETAXEL AND CABAZITAXEL

Although newer chemotherapeutic agents have shown some survival benefit, the improvement is modest at best.13,19 The issue of acquired resistance or de novo resistance to chemotherapeutics has posed a challenge. Cross-resistance can also occur between docetaxel and cabazitaxel, between taxanes and androgen-targeting agents, and between androgen-targeting agents.

The PSA response rate is only ~25% for abiraterone acetate following enzalutamide or the reverse sequence, and radiographic responses are rare. In a retrospective study of patients receiving enzalutamide after abiraterone, PSA response rate (22% vs. 26%; P = 0.8), median time to radiologic/clinical progression (4.6 months vs. 6.6 months; P = 0.6), and median OS (10.6 months vs. 8.6 months; P = 0.2) did not differ significantly between docetaxel-treated and docetaxel-naive patients.49 Enzalutamide also induced modest PSA responses and median survival of only 8.3 months in patients progressing following both chemotherapy and abiraterone.50 In another report, treatment with either enzalutamide or docetaxel following abiraterone produced modest PSA responses and median PFS of only ~4.5 months.51,52 The activity of abiraterone acetate following enzalutamide and docetaxel also is modest.53,54


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Interestingly, cabazitaxel appeared to retain moderate activity following docetaxel and novel antiandrogen drugs in one retrospective study.55 In this retrospective study, 79 patients who had progressive mCRPC after docetaxel and abiraterone acetate displayed benefit from cabazitaxel. PSA decline ≥30% occurred in 48 patients (62%), and the median PFS and OS were 4.4 months and 10.9 months, respectively. In another study, cabazitaxel appeared active when given after both abiraterone and/or enzalutamide.56 In this retrospective study of 41 patients, ≥50% PSA declines were seen in 16 of 41 (39%) patients, and objective radiologic responses occurred in three of 22 (14%) evaluable patients.

MECHANISMS OF RESISTANCE TO CHMOTHERAPY

Resistance to chemotherapy can be attributed to specific mechanisms intrinsic to prostate cancer biology or general mechanisms common to different tumor types or drug pharmacokinetics (Figure 1).57

(To view a larger version of Figure 1, click here.)

Continued androgen–AR signalling

Activation of AR by androgens not only stimulates proliferation but also inhibits apoptosis of prostate cancer cells, leading to tumor growth and progression. Increased AR expression, AR gene amplification, mutations, alterations in coregulators, and continuous production of androgens within the tumor tissue and adrenal glands owing to the activity of cytochrome P450 (CYP)-17, among other enzymes, may engender continued activity of the androgen axis despite castrate serum testosterone levels, which may fuel tumor growth and resistance.58–60 Additionally, nonandrogen molecules, such as estrogens, progestin, and other oncogenic signaling molecules, may bind the promiscuous altered AR.61,62 Signal transduction pathways, cross talk between AR and human epidermal growth factor receptor (HER)-2/3 receptors, SRC family of kinases, transforming growth factor (TGF)-β are all implicated in the activation of AR even in the absence of androgens.57 AR, when present in cytoplasm, is bound to heat shock proteins (HSPs) such as HSP-90 in both normal and prostate cancer cells. Testosterone is converted to dihydrotestosterone, which causes conformational change by dimerization and phosphorylation of the receptor, which dissociates AR from HSP. This change causes trafficking of AR to the nucleus, mediated by dynein, where it binds along with the coactivators and corepressors such as FOXO1 to the androgen response elements of DNA in the gene promoter and enhancer regions and induces transcriptional activation of the target growth-promoting genes.3,21–23 Indeed, the survival increments conferred by enzalutamide and abiraterone acetate following docetaxel exposure attest to the continued relevance of signaling via the androgen–AR axis in the late postdocetaxel phase of the disease.

Interestingly, recent retrospective studies suggest that the AR splice variant, AR-v7 and circulating free (cf)-DNA alterations of AR are associated with resistance to both abiraterone acetate and enzalutamide.63 In contrast, hypothesis-generating studies suggest that tumors harboring AR-v7 may continue to respond to taxanes, while the TMPRSS2-ERG translocation may be associated with poor response to taxanes.64–66 One retrospective study showed that taxanes are associated with improved survival vs. antiandrogen drugs in AR-v7-expressing patients.67 Additionally, conversion of AR-v7–positive to AR-v7–negative status appears to occur more frequently with taxanes than with antiandrogen drugs.68