Benefit of docetaxel in castration-sensitive disease

Recently, randomized Phase III trials have validated the impact of docetaxel in metastatic castration-sensitive prostate cancer (mCSPC). The CHAARTED trial (n = 790) demonstrated a relatively large extension of median OS by combining six cycles of docetaxel with ADT (44.0 months vs. 57.6 months; HR: 0.61; P < 0.001).30 Those with extensive metastatic disease (who constituted 65% of all patients), defined as visceral disease or ≥4 bone lesions with ≥1 lesion outside the spine and pelvis, exhibited an even larger increment in median OS, from 32.2 months to 49.2 months. Then, the large STAMPEDE trial comparing 1,184 patients receiving ADT vs. 1,185 patients receiving ADT plus docetaxel demonstrated an increased median OS from 67 months to 77 months by adding six cycles of docetaxel plus prednisolone to ADT (HR: 0.76; P = 0.003).31,32 In contrast, nine cycles of docetaxel combined with ADT did not demonstrate improved OS in the smaller Phase III GETUG-AFU-15 trial, although progression-free survival (PFS) was prolonged.33 Finally, early data indicate a potential benefit for the addition of docetaxel to ADT in patients with high-risk nonmetastatic disease.34,35 The GETUG-12 Phase III trial (n = 413) combined four cycles of docetaxel plus estramustine with ADT plus local therapy and demonstrated improved relapse-free survival (HR: 0.71; P = 0.017). Similarly, the Phase III RTOG-0521 trial (n = 563) demonstrated improved 4-year survival (89% vs. 93%; HR: 0.70; P = 0.04) with the addition of six cycles of docetaxel plus prednisone to ADT plus radiation therapy.35 Overall, the larger increments of OS with docetaxel in CSPC suggest lower intrinsic resistance to docetaxel in this setting compared to the CRPC setting. Furthermore, patients exposed to docetaxel in the castration-sensitive setting may potentially be relatively docetaxel-resistant when the disease progresses to the castration-resistant state, due to the biology of the disease as well as partly due to acquired resistance induced by prior docetaxel exposure.


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CABAZITAXEL

Mechanism of action

Cabazitaxel (Jevtana®; Sanofi-Aventis) is a semisynthetic taxane drug that inhibits micro-tubule disassembly and displays antineoplastic activity in cell lines with p-glycoprotein overexpression, which is also a proposed mechanism for docetaxel resistance.36,37 Moreover, cabazitaxel can penetrate the blood–brain barrier in preclinical systems and can also inhibit nuclear AR transport.38

Clinical evidence for efficacy of cabazitaxel in mCRPC

Activity of cabazitaxel in docetaxel-refractory mCRPC was shown in the Phase III TROPIC trial.19 A total of 755 patients with mCRPC who had progressed, a median of ~4 weeks after the previous cycle of docetaxel, were randomized to prednisone 10 mg with mitoxantrone 12 mg/m2 or cabazitaxel 25 mg/m2 every 3 weeks for a maximum of 10 cycles. The trial showed improvement in median OS of 2.4 months for cabazitaxel over mitoxantrone (15.1 months vs. 12.7 months; HR: 0.70; P = 0.0001). There was also improvement in PFS, PSA response, and time to tumor progression.19 This led to the approval of the drug in 2010 in the postdocetaxel setting. Cabazitaxel was associated with substantial myelosuppression, including toxic deaths in ~5% of patients. Prophylactic granulocyte colony-stimulating factor (G-CSF) support in selected patients at risk for neutropenic sepsis appears to improve the safety of this regimen.39–42 Indeed, with preemptive use of G-CSF when indicated based on performance status, comorbidities, and age, cabazitaxel was well tolerated and associated with quality-of-life benefits, low incidence of neuropathy, and no toxic deaths.

Recently, two postmarketing Phase III studies were reported: FIRSTANA (NCT01308567) compared docetaxel plus prednisone vs. cabazitaxel 25 mg/m2 or 20 mg/m2 plus prednisone as first-line chemotherapy for mCRPC with the objective of demonstrating superiority for OS with cabazitaxel; and PROSELICA (NCT01308580) compared two doses of cabazitaxel (20 mg/m2 vs. 25 mg/m2) as postdocetaxel chemotherapy for mCRPC with the objective of demonstrating noninferiority of the lower dose.43,44 FIRSTANA did not demonstrate superiority of both doses of cabazitaxel over conventional docetaxel, with a median OS of ~2 years for all arms, although objective measurable tumor responses were higher with cabazitaxel 25 mg/m2 compared to docetaxel (41.6% vs. 30.9%, P = 0.0370). There were interesting differences in the toxicity profile: grade 3–4 adverse events occurred in 41.2%, 60.1%, and 46.0% of patients with cabazitaxel 25 mg/m2, cabazitaxel 20 mg/m2, and docetaxel. Neutropenic fevers, diarrhea, and hematuria were more common with cabazitaxel 25 mg/m2, while peripheral neuropathy, peripheral edema, alopecia, and nail disorders were more common with docetaxel. PROSELICA confirmed the noninferiority for OS (~14-month median survival for both doses) of cabazitaxel at a dose of 20 mg/m2 compared to 25 mg/m2. Although PSA and Response Evaluation Criteria in Solid Tumors (RECIST) response rates were higher with cabazitaxel 25 mg/m2, grade 3–4 adverse events were also higher with this dose: 54.5% vs. 39.7%. These data suggest that 20 mg/m2 should be preferred as the more optimal dose in most circumstances, and additionally, this may be hypothesized to be more cost-efficacious. Moreover, TAXYNERGY, a randomized Phase II trial evaluated an early switch in taxane (docetaxel to cabazitaxel or cabazitaxel to docetaxel) in patients with decline in PSA <30% within 3 months.45 Overall, 35 of 63 (55.6%) patients exhibited PSA response, which appeared to exceed the historical response rate of ~45% when using docetaxel.

A phase II trial examined the role of carboplatin in combination with cabazitaxel and granulocyte growth factor support for the “anaplastic” or aggressive variant prostate cancer by clinical criteria defined previously. It showed additional benefit from a platinum–taxane combination.46–48 These previously described anaplastic criteria were exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low PSA levels relative to tumor burden, or short response to prior ADT. The median PFS was 3.8 months with cabazitaxel vs. 5.7 months with the combination of cabazitaxel and carboplatin (P = 0.009).43 PSA and objective response rates also improved with combination therapy. Thus, further investigation of this platinum–taxane chemotherapy doublet may be warranted for the anaplastic variant subgroup.