teaser
Paulina Spiliopoulou MRCP
Simon Chowdhury MD PhD
Department of Medical Oncology,
Guy’s and St Thomas’ Hospital, London, UK
Email: [email protected]
Until recently, men with castration-resistant prostate cancer had limited therapeutic options once they became refractory to docetaxel chemotherapy. Cabazitaxel, a novel tubulin-binding taxane, offers new hope to these patients.
Prostate cancer is the most common cancer in men in the UK, with an estimated 40,841 new cases for the year 2009 and 10,721 deaths in 2010.(1) Despite advances in diagnosis and treatment of localised disease, many men die of prostate cancer. Patients with metastatic disease initially benefit from androgen deprivation but they invariably progress and reach a castration-resistant stage. In 2004, the docetaxel/prednisone regimen was established as first-line treatment for patients with metastatic castration-resistant prostate cancer (CRPC) after two phase III trials – TAX 327 and SWOG 9916 – showed a survival benefit.(2,3) However, until recently, there was an unmet need in the post-docetaxel setting. The first drug to show a survival benefit post-docetaxel was cabazitaxel, and this is the focus of this review.(4)
Evolution of treatment
Systemic treatment of prostate cancer has changed rapidly as our understanding of tumour biology has improved. Pre-clinical data and translational studies have increased our understanding and have led to a new nomenclature for advanced prostate cancer; it is now known as castration-resistant rather than hormone-resistant. The androgen receptor remains an important disease driver, which continues to play a pivotal role even after androgen deprivation. Moreover, it is now appreciated that prostate cancer cells function as both an autocrine and a paracrine organ. Research has led to the development of several novel agents that aim to exploit the fact that CRPC remains susceptible to androgen receptor targeting.(5)
Several agents have been evaluated either in combination with docetaxel or post-docetaxel, including different chemotherapies. Satraplatin, an oral platinum agent, was evaluated in men who progressed after primary chemotherapy and participated in the SPARC trial (satraplatin and prednisone against refractory cancer), including patients who did not receive docetaxel. Although a small improvement in progression-free survival (PFS) was detected, with median PFS of 11.1 weeks (95% CI, 10.3–12.3 weeks) in the satraplatin arm compared with 9.7 weeks (95% CI, 9.3–10.0 weeks) in the placebo arm (log-rank test, p<0.001), there was no difference in overall survival.(6)
Cabazitaxel
Cabazitaxel is a novel taxane that binds and stabilises tubulin, resulting in cell cycle arrest in the G2/M phase and inhibition of cell proliferation. Unlike other taxanes, this agent is a poor substrate for the membrane-associated, multidrug resistance (MDR), P-glycoprotein (P-gp) efflux pump, and this might explain the absence of cross-resistance to docetaxel. Over-expression of P-glycoprotein comprises one of the cellular mechanisms leading to resistance to docetaxel and other tubulin-binding agents. Other known mechanisms of resistance in prostate cancer are altered expression of beta-III tubulin, changes in microtubules, and impaired drug delivery to cancer cells owing to disorganised and leaky vasculature of the tumour.(7)
Clinical trials
Phase I–II
In a phase I study of cabazitaxel in 25 patients with advanced solid tumours, the recommended dose was 20mg/m². Cabazitaxel was administered at four dose levels ranging from 10mg/m² to 25mg/m². The principal dose-limiting toxicity was neutropenia, with one case of febrile neutropenia and two cases of grade 4 neutropenia occurring at a dose of 25mg/m² (in a total of 25 patients). At the recommended dose level – 20mg/m2 –grade 4 neutropenia was observed in only 4% of courses, which compares favourably to other taxanes.
In this study, only patients who had received fewer than two prior chemotherapy regimens for metastatic disease and/or radiotherapy affecting <25% of their haematopoietic reserve were eligible. Neither granulocyte colony-stimulating factor (G-CSF) nor granulocyte–macrophage colony-stimulating factor (GM-CSF) were given as prophylactic treatments.(8)
The most common non-haematological toxicities were gastrointestinal in nature: diarrhoea (56% of patients); nausea (40% of patients); and vomiting (16% of patients). These toxicities were generally grade 1–2 in severity, except for a single patient who experienced grade 3 diarrhoea in the first course at 15mg/m². Cabazitaxel, a much poorer substrate for the P-gp multidrug transporter pump than docetaxel, might accumulate in enterocytes, which constitutively express P-gp, a characteristic that could explain why this toxicity was common compared with other taxanes in clinical use.
Grade 1 neurosensory symptoms were observed in the form of distal paraesthesia and decreased deep tendon reflexes but no grade 3 or 4 neurotoxicity was seen.
Two patients experienced grade 1 hypersensitivity reactions, characterised by flushing, dizziness and chest tightness, which did not re-occur on retreatment in the absence of pre-medication.(8)
A phase II study evaluated cabazitaxel in women with metastatic breast cancer. Patients were treated initially with a dose of 20 mg/m², which was escalated to 25 mg/m² in those who did not incur a significant adverse event during the first cycle of therapy. Despite a median age of 53 years, dose escalation was only possible in 28% of these women. Further studies in metastatic breast cancer have shown that cabazitaxel, when combined with capecitabine, has active antitumour activity in patients who progressed after anthracycline and taxane treatment.(9)
Phase III
The TROPIC trial was undertaken at 146 centres in 26 countries and included 755 patients with documented progression during or after completion of docetaxel treatment. It was a randomised, phase III trial that compared cabazitaxel plus prednisone with mitoxantrone plus prednisone in men with progressive disease after docetaxel-based treatment. A total of 377 men were assigned to the mitoxantrone group and 378 men to the cabazitaxel group. The study showed a significant 2.4-month median overall survival advantage in favour of cabazitaxel. Median survival was 15.1 months in the cabazitaxel group (95% CI 14.1–16.3) vs 12.7 months (11.6–13.7) in the mitoxantrone group. Treatment with 25mg/m² cabazitaxel resulted in a 30% reduction in the risk of death (hazard ratio 0.7; 95% CI: 0.59–0.83, p<0.0001) and an improved median PFS of 2.8 months for cabazitaxel (95% CI 2.4–3.0) and 1.4 months in the mitoxantrone group (95% CI 1.4–1.7 months; Table 1). Time to tumour progression and prostate-specific antigen response were also better than those with mitoxantrone.
Patients who received cabazitaxel had a higher risk of death from toxicity within 30 days of the last drug dose administration, with 4.9% of adverse events leading to death for cabazitaxel (18 deaths) compared with 1.3% for mitoxantrone (five deaths). The rate of febrile neutropenia was 8% with cabazitaxel and 1% with mitoxantrone. It is important to take into consideration that patients in this trial had poor prognosis disease, with 25% having visceral disease and 50% having measurable disease. This was a heavily pre-treated population that was likely to have a degree of bone marrow infiltration. Even for the mitoxantrone arm, the incidence of grade 3–4 neutropenia was 58% compared with 22% of the TAX327 study, where it was given as first-line treatment.(3)
The incidence of neutropenia varied significantly by region; rates of neutropenia in North America exceeded those in Europe. Analyses are currently underway to determine the extent of growth factor use both in the study population at large and within these subgroups (notably, cycle 1 prophylaxis with growth factors was not allowed in the TROPIC protocol).
Until these data are available, the current Food and Drug Administration (FDA) label suggests the use of primary prophylaxis with G-CSF in those patients who are considered high risk(10) (age >65 years, extensive prior radiation, poor nutrition, previous febrile neutropenia, poor performance status and other serious medical co-morbidities).
On the basis of those results, cabazitaxel was approved by the FDA and the European Medicines Agency for men with metastatic CRPC. The TROPIC study was undertaken despite the absence of prior phase II studies assessing cabazitaxel specifically in prostate cancer because the lack of a viable therapeutic option in the post-docetaxel setting generated a substantial area of need.
Future directions
Cabazitaxel is a treatment option in docetaxel-refractory metastatic CRPC; however, unanswered questions and challenges remain. One of the key questions relates to optimal dose.
PROSELICA
PROSELICA is a phase III trial that aims to demonstrate the safety and non-inferiority in term of overall survival of cabazitaxel 20mg/m² vs cabazitaxel 25mg/m² in the post-docetaxel setting.
FIRSTANA
The role of cabazitaxel as first-line chemotherapy is being examined in a phase III study currently recruiting patients (FIRSTANA), which compares two arms of different Cabazitaxel doses (20mg/m² and 25mg/m²) to standard dose docetaxel (75mg/m²). This study will determine the role of cabazitaxel in a chemotherapy-naïve metastatic CRPC.
Another phase III study has been designed to assess if the addition of custirsen to cabazitaxel/prednisone treatment can slow tumour progression and enhance survival outcomes compared with standard cabazitaxel/prednisone treatment. Custirsen inhibits the expression of clusterin, which is a stress-activated cytoprotective chaperone upregulated by a variety of anticancer therapies that confers treatment resistance when over-expressed.(11)
Conclusions
Cabazitaxel significantly improves survival in patients with CRPC post- docetaxel and represents a new treatment option in an area of previously unmet clinical need. Data from the TROPIC study showed significant toxicity, and it should therefore be administered by experienced cancer physicians with close monitoring and proactive management of side-effects, such as febrile neutropenia and diarrhoea. Ongoing studies will help to answer questions on optimal dose, safety and sequencing of cabazitaxel.
Key points
- The therapeutic spectrum in prostate cancer has dramatically changed as a better understanding of the biology of the condition is gained.
- Castration-refractory prostate cancer is sensitive to chemotherapy as well as further hormonal manipulation.
- Cabazitaxel is approved as second-line treatment in docetaxel-refractory cases.
- Further research is currently underway to establish the optimal dose of cabazitaxel as well as its precise role in the metastatic prostate cancer therapeutic algorithm.
References
- Cancer Research UK. CancerStats;Type of cancer; Prostate cancer (updated May 2012).
- Tannock IF et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–12.
- Petrylak DP et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20.
- De Bono JS et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel chemotherapy: A randomised open-label trial. Lancet 2010;376:1147–54.
- De Bono JS et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364(21):1995–2005.
- Sternberg CN et al. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: The SPARC trial. J Clin Oncol 2009; 27:5431–8.
- Seruga B, Tannock IF. Chemotherapy-based treatment for castration-resistant prostate cancer. J Clin Oncol 2011;29:3686–94.
- Mita AC et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 2009;15(2):723–30.
- Villanueva C et al. A multicentre dose-escalating study of cabazitaxel (XRP6258) in combination with capecitabine in patients with metastatic breast cancer progressing after anthracycline and taxane treatment: a phase I/II study. Eur J Cancer 2011;47(7):1037–45.
- Pal SK, Twardowski P, Sartor O. Critical appraisal of cabazitaxel in the management of advanced prostate cancer. Clin Interv Aging 2010;5:395–402.
- International Clinical Trials Registry Platform search portal.
