Management of Metastatic Castration-resistant Prostate Cancer
with docetaxel-pre-treated ketoconazole-naïve CRPC to MDV3100 160 mg daily (n=780) or placebo (n=390), has now completed accrual. A second randomised Phase III trial (A safety and efficacy study of oral MDV3100 in chemotherapy-naive patients with progressive metastatic prostate cancer; PREVAIL), investigating the same treatment arms in men with chemotherapy-naïve CRPC, is currently under way (see Table 2). One advantage of MDV3100 over agents such as abiraterone or orteronel is the lack of requirement for concurrent corticosteroid administration. However, the optimal sequencing of this agent, if approved, with immunotherapies and other emerging hormonal therapies will need to be defined through future clinical trials. Finally, newer AR antagonists (e.g. ARN-509 and others) have also entered early-phase clinical trials.
Ipilimumab – Immune Checkpoint Blockade Due to on-going host immunological pressures on evolving tumours, cancers have developed mechanisms to escape immune surveillance, effectively inducing a state of immune tolerance.36
One way to inhibit
immunological evasion by tumour cells is through blockade of the immune checkpoint molecule cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), thus preventing the normal attenuation of antitumour T-cell responses.37
In murine prostate cancer models,
CTLA-4 inhibition has been shown to potentiate T-cell effects and induce tumour rejection.
Several clinical trials using the monoclonal anti-CTLA-4 antibody, ipilimumab, have been conducted in men with metastatic CRPC. These include Phase I and II studies of ipilimumab monotherapy or in combination with radiation,38 ipilimumab with GM-CSF.39
Conclusions
as well as a Phase I study combining Encouragingly, ≥50 % PSA reductions have
Ipilimumab is now in placebo-controlled Phase III testing in the post-docetaxel setting in men with CRPC following a palliative and perhaps immune-stimulatory dose of radiation to a metastatic site, with the intent to demonstrate a survival advantage over radiation alone. A second pre-docetaxel placebo-controlled study is also under way (see Table 2).
1. Jemal A, Siegel R, Xu J, Ward E, Cancer statistics, 2010, CA Cancer J Clin, 2010;60:277–300.
2. Tannock IF, de Wit R, Berry WR, et al., Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer, N Engl J Med, 2004;351:1502–12.
3. Petrylak DP, Tangen CM, Hussain MH, et al., Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer, N Engl J Med, 2004;351:1513–20.
4. Tannock IF, Osoba D, Stockler MR, et al., Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points, J Clin Oncol, 1996;14:1756–64.
5. Antonarakis ES, Drake CG, Current status of immunological therapies for prostate cancer, Curr Opin Urol, 2010;20:241–6.
6. Small EJ, Fratesi P, Reese DM, et al., Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells, J Clin Oncol, 2000;18:3894–903.
7. Small EJ, Schellhammer PF, Higano CS, et al., Placebo-
been observed in about 20 % of patients, and radiological tumour responses were seen in about 5 % of men, which is particularly noteworthy given that PSA and tumour responses were rarely reported in the immunotherapy trials with sipuleucel-T or other therapeutic vaccines. Common side effects of ipilimumab include fatigue (42 %), nausea (35 %), pruritus (24 %), constipation (21 %) and rash (19 %). In addition, because CTLA-4 normally serves to attenuate autoimmunity, immunological toxicities resulting from an unchecked immune response may occur. Such immune-related adverse events include colitis (8 %), adrenal insufficiency (2 %), hepatitis (1 %) and even hypophysitis (1 %).40
With more drugs at our fingertips for the treatment of metastatic CRPC than ever before, and an increasing number of novel therapeutic targets being discovered every day, we are still left with several challenges and unanswered questions. First, we must determine how these approved and experimental therapies should ideally be sequenced in individual patients with CRPC. For example, should sipuleucel-T routinely be given prior to chemotherapy or abiraterone with prednisone? Should abiraterone be reserved only for docetaxel-resistant patients? How should we treat cabazitaxel-refractory patients? Second, we will need to develop strategies to optimally combine these drugs in a rational manner, taking advantage of our understanding of negative feedback loops and alternative pathway activation to overcome resistance to monotherapies. Ultimately, only prospective trials incorporating biomarker-driven hypotheses will be able to address these key clinical questions. Thus, the collection of tumour specimens or correlative samples may be essential in identifying novel targets or developing enrichment strategies for future study of these agents. Third, we must design smarter trials with the goal of quickly yet reliably identifying agents that do not hold promise, while enabling those that do to move swiftly to registrational studies. For example, in the clinical development of MDV3100 and cabazitaxel, pivotal Phase III trials were designed directly following the initial Phase I/II studies that demonstrated significant drug activity in men with CRPC. Finally, we must select our patients more carefully based on clinical or molecular characteristics, in order to identify the subset most likely to benefit from a particular therapy. For example, in men with significant pain, perhaps sipuleucel-T is not appropriate systemic therapy given the prolonged onset of action and lack of palliative benefits; additionally, immune-based biomarkers may shed light on which men may obtain a greater degree of benefit from immunotherapies.
In conclusion, cabazitaxel was the first agent to be approved by the FDA for men with metastatic CRPC who have progressed after docetaxel chemotherapy, and abiraterone acetate was the second FDA-approved drug in this same patient population. In addition, sipuleucel-T has been FDA approved for patients with asymptomatic or minimally symptomatic metastatic CRPC, and may be best utilised in men without visceral metastases. In addition, denosumab gained FDA approval for the prophylaxis of SREs in men with castration-resistant bone metastases, and may have some advantages over zoledronate. In addition, palliative radiation or radiopharmaceuticals (e.g. samarium, strontium or investigational radium) may play a significant role in the management of men with symptomatic disease, both before or after systemic therapies. Several additional active agents are currently in Phase III development, and some of these therapies are also likely to further expand our therapeutic arsenal for men with metastatic CRPC in the near future. n
controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer, J Clin Oncol, 2006;24:3089–94.
8. Higano CS, Schellhammer PF, Small EJ, et al., Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer, Cancer, 2009;115:3670–9.
9. Kantoff PW, Higano CS, Shore ND, et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer, N Engl J Med, 2010;363:411–22.
10. Kantoff PW, Schuetz TJ, Blumenstein BA, et al., Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer, J Clin Oncol, 2010;28:1099–105.
11. Hoos A, Eggermont AM, Janetzki S, et al., Improved endpoints for cancer immunotherapy trials, J Natl Cancer Inst, 2010;102:1388–97.
12. Paller CJ, Antonarakis ES, Cabazitaxel: a novel second-line
treatment for metastatic castration-resistant prostate cancer, Drug Des Devel Ther, 2011;5:117–24.
13. Attard G, Greystoke A, Kaye S, de Bono J, Update on tubulin- binding agents, Pathol Biol, 2006;54:72–84.
14. Mita AC, Denis LJ, Rowinsky EK, 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;15:723–30.
15. de Bono JS, Oudard S, Ozguroglu M, et al., Prednisone plus cabazitaxel or mitoxantrone for metastatic castration- resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial, Lancet, 2010;376:1147–54.
16. Mohler J, Bahnson RR, Boston B, et al., NCCN clinical practice guidelines in oncology: prostate cancer, J Natl Compr Canc Netw, 2010;8:162–200.
17. O’Donnell A, Judson I, Dowsett M, et al., Hormonal impact of
the 17α-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer, Br J Cancer,
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