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European UrologyVolume 62, issue 6, pages e95-e106, December 2012
Letters to the Editor NOT referring to a recent journal article
Treatment Decisions for Metastatic Castration-resistant Prostate Cancer Progressing After Docetaxel Chemotherapy: The Role of Cabazitaxel in the Continuum of Care
Published online 30 August 2012, pages 1201 - 1204
Many patients with metastatic, castration-resistant prostate cancer (mCRPC) experience disease progression during or following first-line docetaxel therapy; until recently, second-line treatment approaches have been limited. Within the last 2 yr, novel therapies able to prolong survival in the postdocetaxel setting have emerged, including the novel semisynthetic taxane cabazitaxel. Cabazitaxel has the ability to overcome taxane resistance in vitro and in vivo and has demonstrated activity in docetaxel-sensitive and docetaxel-resistant cell lines and tumor models . In addition, unlike docetaxel and paclitaxel, cabazitaxel has demonstrated the ability to cross the blood–brain barrier and may be effective in patients with cerebral or spinal cord metastases.
The randomized, multinational, phase 3 Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated with a Taxotere-containing Regimen (TROPIC) trial compared cabazitaxel with mitoxantrone in patients with mCRPC previously treated with a docetaxel-containing regimen . A total of 755 patients were randomized to cabazitaxel (25 mg/m2; n = 378) plus prednisone (10 mg/d), or mitoxantrone (12 mg/m2; n = 377) plus prednisone, every 3 wk. Approximately three-fourths of the patient population experienced disease progression during or within 3 mo of completion of docetaxel, suggesting the patient population was primarily docetaxel refractory. Cabazitaxel significantly improved median overall survival (OS) compared to mitoxantrone (15.1 mo vs 12.7 mo; hazard ratio [HR]: 0.70; p < 0.0001), representing a 30% reduction in the risk of death (Fig. 1). At 2 yr, 28% of patients in the cabazitaxel group were alive compared to 17% of patients in the mitoxantrone group .
Progression-free survival (PFS) was doubled in the cabazitaxel arm compared to mitoxantrone (2.8 mo vs 1.4 mo; HR 0.74; p < 0.0001) . The observed PFS is somewhat shorter than what has been reported in the phase 3 COU-AA-301 trial comparing the CYP17 inhibitor abiraterone acetate with placebo in docetaxel-pretreated mCRPC (PFS: 5.6 mo vs 3.6 mo; p < 0.001) . A contributing factor to this difference is the definition for PFS, which, in the COU-AA-301 trial, was a composite end point defined as time to disease progression including radiographic progression plus symptomatic/clinical progression plus prostate-specific antigen (PSA) progression . In the TROPIC trial, PFS was defined as time from randomization to either PSA progression, or tumor progression, or pain progression, or death . PSA elevation alone often predates clinical tumor progression by 3–4 mo; thus, such a definition may result in a shorter PFS. In the TROPIC trial, cabazitaxel also significantly improved the objective response rate (14.4% vs 4.4%; p = 0.0005) and the PSA response rate (39.2% vs 17.8%; p = 0.0002).
In the TROPIC trial, the percentage of patients who discontinued treatment due to adverse events (AEs) was 18% in the cabazitaxel group compared to 8% in the mitoxantrone group . Grade ≥3 AEs in both treatment arms were primarily hematologic, with neutropenia (82% vs 58%), leucopenia (68% vs 42%), and febrile neutropenia (8% vs 1%) being higher with cabazitaxel compared to mitoxantrone (Table 1). The most common grade ≥3 nonhematologic AEs with cabazitaxel compared to mitoxantrone were diarrhea (6% vs <1%), fatigue (5% vs 3%), and asthenia (5% vs 2%). The rate of mortality within 30 d of last drug infusion was 5% in the cabazitaxel arm, compared with 2% in the mitoxantrone arm. However, close examination of the study data show that most of the mortality related to AEs occurred early in the trial and may be due, in part, to the inexperience of the participating centers regarding proactive management of neutropenia, neutropenic fever, diarrhea, and other AEs. The importance of adequate patient care to optimize treatment benefits was highlighted by a subanalysis limited to TROPIC centers in France and Germany  and . With proactive management of side effects, the discontinuation rate due to AEs was lower with cabazitaxel than in the global study population (11% vs 18%) and there was no toxic death, resulting in a greater survival benefit versus mitoxantrone (+3.7 mo vs +2.4 mo) .
|Selected adverse events b||MP (n = 371)||CBZP (n = 371)|
|All grades||Grade ≥3||All grades||Grade ≥3|
|Neutropenia||325 (88)||215 (58)||347 (94)||303 (82)|
|Leukopenia||343 (92)||157 (42)||355 (96)||253 (68)|
|Anemia||302 (81)||18 (5)||361 (97)||39 (11)|
|Febrile neutropenia||–||5 (1)||–||28 (8)|
|Diarrhea||39 (11)||1 (<1)||173 (47)||23 (6)|
|Fatigue||102 (27)||11 (3)||136 (37)||18 (5)|
|Asthenia||46 (12)||9 (2)||76 (20)||17 (5)|
|Back pain||45 (12)||11 (3)||60 (16)||14 (4)|
|Nausea||85 (23)||1 (<1)||127 (34)||7 (2)|
|Vomiting||38 (10)||0||84 (23)||7 (2)|
|Hematuria||14 (4)||2 (1)||62 (17)||7 (2)|
|Abdominal pain||13 (4)||0||43 (12)||7 (2)|
a Data presented as number (percentage).
b Sorted by decreasing frequency of grade ≥3 events in the CBZP arm.
CBZP = cabazitaxel plus prednisone; MP = mitoxantrone plus prednisone.
To examine the tolerability of cabazitaxel in daily clinical use, a German Compassionate Use Program (CUP) was implemented and enrolled patients with mCRPC who would have met the eligibility criteria for the TROPIC trial . Patients received prednisone plus cabazitaxel until disease progression, death, unacceptable toxicity, or physician's decision. Prophylactic granulocyte-colony stimulating factor was recommended, per American Society of Clinical Oncology guidelines, in patients with preexisting risk factors for neutropenia. An awareness program focused on proactive management of AEs related to cabazitaxel was also implemented. While the types of AEs observed in the German CUP were similar to those seen in the TROPIC trial, the percentage of patients who discontinued treatment due to AEs was only 8% in the CUP compared to 18% in the TROPIC trial  and . The frequency of grade ≥3 hematologic AEs in the CUP was also lower than that observed in the TROPIC trial, including leucopenia (11%), neutropenia (7%), and febrile neutropenia (4%) (Table 2) . These results reinforce the importance of implementation of prophylactic and therapeutic strategies to address AEs and prevent therapy discontinuation.
|Grade ≥3 toxicities, no. (%)||All patients, no. (%) (N = 111)|
|Febrile neutropenia||4 (3.6)|
|General health deterioration||1 (0.9)|
|Renal failure||1 (0.9)|
|Pulmonary embolism||1 (0.9)|
In addition to cabazitaxel, abiraterone acetate is also approved for the postdocetaxel setting, based on the phase 3 COU-AA-301 trial demonstrating a significant OS benefit (14.8 mo vs 10.9 mo; HR: 0.65; p < 0.0001) for abiraterone acetate compared to placebo in docetaxel-pretreated mCRPC . There are currently limited data on the optimal sequencing of these agents in mCRPC, but the aggressiveness of the disease, predictors of poor response to hormonal therapies, patient characteristics, and comorbidities have to be considered.
The importance of disease characteristics in therapy selection was illustrated by the French Abiraterone compassionate use study that showed a Gleason score of 8–10 was associated with a poor response . In addition, a retrospective analysis of patients with mCRPC enrolled in clinical trials demonstrated that patients who progressed to mCRPC quickly after primary androgen-deprivation therapy (ADT) (<16 mo) had a poor PSA response and a short PFS with secondary hormonal therapies such as abiraterone, estrogens, or MDV3100 (enzalutamide) . The magnitude of response to prior docetaxel is also important when considering second-line therapy. In a study of 44 patients with mCRPC treated with first-line docetaxel followed by abiraterone, none of the seven patients who discontinued docetaxel due to disease progression (those considered to have docetaxel-refractory disease) demonstrated a PSA, radiologic, or clinical response to abiraterone . In contrast, a recent post hoc analysis of the TROPIC trial showed that the OS benefit associated with cabazitaxel was consistent in the 63% of patients (n = 239) who discontinued prior docetaxel due to disease progression when compared to the overall patient cohort (median OS: 13.8 mo vs 10.9 mo for mitoxantrone; HR: 0.70; 95% confidence interval, 0.57–0.87) (Fig. 2) .
When selecting second-line therapy, the potential for cross resistance should also be considered. In vitro studies suggest that one mechanism of action for taxanes is inhibition of microtubule-dependent, androgen-receptor (AR) translocation to the nucleus, impairing AR signaling and reducing PSA expression . Abiraterone impairs AR signaling by reducing CYP17-dependent androgen production, as well as directly binding to AR and reducing AR signaling in a dose-dependent manner . This raises concerns regarding the potential for cross resistance between microtubule inhibitors and hormonal therapies such as abiraterone, based on the hypothesis that use of AR-signaling inhibitors may impair the ability of taxanes to subsequently inhibit this pathway. In a phase 1/2 trial of 54 patients with abiraterone-pretreated CRPC, 35 patients who received subsequent docetaxel at disease progression demonstrated a median OS of 12.5 mo . In contrast, a median OS of 18.9 mo was observed for docetaxel administered every 3 wk in the phase 3 TAX327 trial . Additionally, patients receiving cabazitaxel in the TROPIC trial achieved a median OS of 29.4 mo from the first dose of docetaxel . This issue is further complicated by recently presented interim results from the phase 3 COU-AA-302 trial comparing abiraterone to placebo in patients with asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC . Abiraterone significantly improved radiographic PFS (not reached vs 8.3 mo; HR: 0.43; p < 0.0001), but demonstrated only a trend in OS (HR: 0.75; p = 0.0097). Further analyses of the trial are needed to clarify this issue.
In summary, selection of second-line therapy beyond docetaxel and sequencing of therapies in patients with progressive mCRPC should be based on careful evaluation of disease characteristics. In patients likely to poorly respond to abiraterone (eg, high Gleason score, rapid progression to CRPC with primary ADT, or progression during docetaxel therapy), cabazitaxel might be the first option in the second-line setting. For patients with less-aggressive mCRPC, cabazitaxel and abiraterone are reasonable treatment options. In addition to these newer agents, rechallenge with docetaxel may still have a place in the second-line treatment for patients with mCRPC who have a very good response to first-line docetaxel and relapse >6 mo after having stopped docetaxel  and . Further research and clinical trials are needed to identify the optimal sequencing of therapies, patient-selection strategies, and potential biomarkers for mCRPC. Results from these studies will continue to shape the way we make treatment recommendations and improve individualization of therapy.
Conflicts of interest
Axel Heidenreich has received honoraria or served as a member of advisory boards for the following companies: AMGEN, Astellas, Bayer AG, Dendreon, GlaxoSmithKline, IPSEN, Jansen Cilag, Pfizer, Sanofi Aventis, and Takeda. David Pfister has received honoraria or served as a member of advisory boards for the following companies: Astellas, IPSEN, and Jansen Cilag.
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Department of Urology, Oncological Urology, Pediatric Urology and Renal Transplantation, RWTH University Aachen, Aachen, Germany
© 2012 European Association of Urology, Published by Elsevier B.V.
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