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Giuseppe di Lorenzo
Researcher in Molecular and Medical Oncology
Department of Clinical and Molecular Oncology
Federico II University
The mainstay of treatment for metastatic prostate cancer is androgen deprivation. Unfortunately, the response to this therapy is short (median duration 18-24 months). Most men eventually become resistant to hormonal manipulation, developing what can be defined as hormone-refractory prostate cancer (HRPC).(1)
In 2004, two pivotal trials of docetaxel-based chemotherapy (TAX 327 and SWOG99-16) were reported: for the first time a survival benefit was observed for chemotherapy in HRPC. Results from the two studies have changed the expectations of treatment outcome in these patients from palliative to improved survival, representing a significant milestone in treating the disease.(2,3)
In the TAX 327 trial, docetaxel (two schedules, every three weeks and weekly) was used with steroid only, with the comparator being mitoxantrone and prednisone, the previously accepted standard care. In total, 1,006 patients were randomised to one of the three arms, and it is noteworthy that the vast majority had a good performance status prior to treatment.
Compared with men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95% confidence interval (CI) 0.62-0.94; p=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95% CI, 0.75-1.11; p=0.36).(2)
Based on these results, the most effective treatment was the three-weekly regimen, which produced a significant improvement of 24% in overall patient survival. This equated to an actual median survival improvement of 2.4 months in comparison with the control arm (18.9 months docetaxel vs 16.5 months control). No significant difference in terms of survival was observed between weekly docetaxel and mitoxantrone.
The second study, SWOG 99-16, randomised 770 patients to three-weekly docetaxel at a slightly lower dose (60mg/mq) than in the TAX 327 in combination with estramustine, compared with mitoxantrone and steroid.(3) In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs 15.6 months, p=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95% CI, 0.67-0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (p<0.001).
Although there has been clarification relating to which current chemotherapeutic regimen is most effective in HRPC, several questions remain.
In fact, the drug’s efficacy is not universal in all patients. The taxane combinations are clearly advantageous but only about one-third of patients respond and the survival benefit is marginal (median of 2.4 months).
Improving the standard: new docetaxel-based combinations
The demonstration of survival benefits observed with docetaxel-based chemotherapy in HRPC has aroused new interest among investigators. Recently reported and ongoing clinical trials have built on the success of docetaxel. Combination therapy with docetaxel represents the most exciting investigational area for treatment of HRPC.
In addition to traditional chemotherapeutic modalities, newer combinations utilising novel and existing agents are being tested in HRPC. Among these drugs, high-dose calcitriol (HDC) merits detailed discussion.
HDC has both antiproliferative and proapoptotic effects in prostate cancer. DN-101 is a novel formulation of calcitriol designed for investigation as anticancer therapy. A phase II trial of oral HDC with docetaxel in HRPC yielded high response rates.(4) In this trial 37 men with metastatic HRPC were treated with calcitriol (0.5-3g/kg) on day one followed by docetaxel (36mg/m2) on day 2, repeated weekly for six weeks of an eight-week cycle. Of those patients, 81% achieved a prostate-specific antigen (PSA) response and 22% had a >75% reduction in serum PSA level. Median time to progression and overall survival time were 11.4 and 19.5 months, respectively. Tolerability was similar to that with single-agent weekly docetaxel. These initial results formed the basis for the Androgen-independent prostate cancer Study of Calcitriol Enhancing Taxotere (ASCENT) trial – a randomised double-blinded placebo-controlled trial evaluating the combination of docetaxel with the proprietary HDC formulation DN-101. A total of 250 patients with chemotherapy-naive HRPC were randomised to treatment with docetaxel (36mg/m2) for three consecutive weeks of a four-week cycle with
DN-101 or placebo. The primary objective of the study, PSA response rate at six months, was better with the addition of DN-101, but did not meet statistical significance (63% vs 52%). However, median survival, a secondary endpoint, was significantly longer with DN-101 (23.5 months estimated with docetaxel plus DN-101 vs 16.4 months observed with docetaxel plus placebo). Treatment was well tolerated, with incidences and types of adverse events similar in the two groups. With the weekly docetaxel regimen, incidence of grade 3-4 haematological events was relatively low for both the docetaxel/DN-101 and docetaxel/placebo group.(5)
Behind the taxanes: second-line chemotherapeutic options
Although the taxanes represent the most active chemotherapeutic agents for the first-line treatment of metastatic HRPC and have large phase III trial clinical data to support their use, most patients eventually progress while on taxane-based treatments. Of interest are several agents under investigation for HRPC.
Satraplatin is an oral third-generation platinum analogue with structural similarities to cisplatin. It acts by binding to DNA, forming interstrand crosslinks, resulting in cell-cycle arrest and apoptosis.
In a phase II trial of satraplatin, 39 chemotherapy-naive patients with progressive HRPC were treated with satraplatin in combination with prednisone vs prednisone alone. Seven (32%) of 22 assessable patients had a PSA response compared with prednisone alone (33% vs 9%; p=0.046) and improvement in progression-free survival (5.2 vs 2.5 months; p=0.023) compared with prednisone alone.(6)
These results led the European Organisation for Research and Treatment of Cancer (EORTC) to Âinitiate a phase III trial of satraplatin plus prednisone vs prednisone alone for first-line treatment of HRPC.(7)
Although target accrual was 380 patients, only 50 patients were enrolled when the study was terminated early by the sponsoring company.
A phase III trial known as SPARC (Satraplatin and Prednisone Against Refractory Cancer) was a multinational double-blind placebo-controlled trial, initiated in 2003, that compared satraplatin plus prednisone with prednisone alone for second-line treatment of patients with HRPC.
Primary endpoint was time to progression; secondary trial endpoints were overall survival and time to pain progression. Target accrual is completed.
Recent results show that the results for progression-free survival (PFS) are highly statistically significant (p<0.00001) using the protocol-specified log-rank test. PFS is the primary endpoint for submission for accelerated approval in the USA and will also serve as the primary basis for a marketing authorisation application in Europe. The most common adverse reactions were myelosuppression (bone marrow functions, such as lowered platelet count or lowered white blood cell count) and gastro-intestinal events, such as nausea, vomiting and diarrhoea. These adverse reactions were mostly mild to moderate in severity. It is expected that European marketing application will be filed in the second half of 2007.
Novel options in HRPC management: targeted therapy
The mechanism behind angiogenesis inhibitors is inhibition of factors promoting tumour blood supply. Currently, dozens of compounds that interfere with different steps of the angiogenic cascade are in preclinical and clinical development. Some of these agents have exhibited promising antitumour activity in HRPC.(8)
Thalidomide has recently resurfaced, with the aim of suppressing angiogenesis in prostate cancer. The highest median survival reported in any phase II trial in HRPC was seen in the one comparing weekly docetaxel plus thalidomide with docetaxel alone in 75 patients with chemotherapy-naive HRPC. In this study, median survival was 29 months in the docetaxel-thalidomide group; 69% of patients in the combination arm vs 42% receiving docetaxel alone were alive at 18 months. However, venous thromboembolism was observed with greater frequency in the combination group.(9)
This humanised monoclonal antibody targeting vascular endothelial growth factor (VEGF) is also under investigation in combination with docetaxel. Initial results from the Cancer and Leukemia Group B (CALGB) 90006 trial, a single-arm phase II trial, demonstrate encouraging activity for a combination of bevacizumab, docetaxel and estramustine in chemotherapy-naive men with progressive HRPC. PSA progression occurred in 29 of 75 treated patients, for a PSA response rate of 77%. Median time to PSA progression was 10.3 months.(10) The US National Cancer Institute is currently conducting a phase II study of a four-drug combination consisting of docetaxel, prednisone, thalidomide and bevacizumab in men with chemotherapy-naive progressive HRPC and the CALGB is coordinating a phase III double-blinded placebo-controlled trial of docetaxel plus prednisone with or without bevacizumab.(11)
Endothelin-1 receptor antagonists
Endothelin-1 (ET-1) is implicated in the progression of prostate cancer as well as in the development of the painful osteoblastic bone lesions that characterise metastatic disease. ET-1 mediates these effects through the ETAR, which is overexpressed in advanced prostate cancer. Interference with the ET-1/ETAR pathway with the use of the ETAR antagonist atrasentan significantly delayed clinical progression in men with asymptomatic HRPC in a randomised, placebo-controlled phase II trial.(12)
A meta-analysis of data from 1,002 patients treated with atrasentan (10mg/day orally) or placebo in phase II and phase III clinical trials revealed that atrasentan therapy resulted in significantly longer time to progression, time to onset of bone pain and time to biochemical progression relative to placebo.(13) Recently, atrasentan has been combined with docetaxel in a phase I/II study. Determination of the maximum tolerated dose (MTD) and pharmacokinetic profile were primary aims of the trial. Docetaxel dose escalation was begun at 60mg/m2, and atrasentan (10mg/day) was started on day three of the first cycle. Initial results suggest there is no significant pharmacokinetic interaction and that the combination is generally well tolerated up to a docetaxel dose of 75mg/m2. Completion of the trial is necessary to determine the MTD.(14) Additional trials of the combination are in development or under way, such as SWOG S0421 – a randomised, placebo-controlled phase III trial designed to compare docetaxel, prednisone and atrasentan with docetaxel plus prednisone alone in men with advanced HRPC.
Ixabepilone and patupilone
The epothilones A and B form a new class of cytotoxic agents, derived from the fermentation broth of the myxobacterium Sorangium cellulosum.
Ixabepilone is an epothilone B analogue that works in a manner similar to that of taxanes. In a multi-institutional randomised phase II trial, 92 patients with progressive HRPC were randomised to receive ixabepilone with or without estramustine. PSA response was achieved in 21 of 44 patients (48%) in the ixabepilone arm and 31 (69%) of 45 patients in the ixabepilone + estramustine arm. Time to PSA progression was 4.4 months and 5.2 months, respectively.(15)
To understand the activity of this class of agents in patients with HRPC for whom first-line docetaxel therapy has failed, Rosenberg et al conducted a double crossover randomised phase II study comparing the outcomes of ixabepilone as a single agent versus mitoxantrone. To qualify for this trial, patients had to have metastatic HRPC and progressive disease during or within 60 days of stopping docetaxel-based therapy. Preliminary results in 82 patients showed that neuropathy was greater in the ixabepilone arm, and grade 3/4 neutropenia was seen in 41% and 54% patients treated with ixabepilone and mitoxantrone, respectively. Fifty percent of post-therapy PSA value declines were seen in 17% of patients treated with ixabepilone and 20% of patients who received mitoxantrone. Median survival for both arms was similar (12.5 and 13 months).(16)
Immunotherapy for prostate cancer: the next step
Several immunotherapeutic strategies have moved forward into clinical development.
APC8015 (Provenge®) is an autologous vaccine derived from CD54+ dendritic cells (DCs), the major antigen-presenting cells, which are pheresed from individuals and processed with the recombinant fusion protein PAP and the cytokine
GM-CSF. Recently, a randomised phase III trial was conducted involving 127 patients with metastatic HRPC treated with APC8015.(17) Although early data suggested that the vaccine delayed disease progression and improved survival only in hormone-refractory disease patients with a Gleason score of 7 or less, a more recent update suggests that advantages in progression-free and overall survival have been observed across all grades after three years follow-up. Currently, a phase III trial is under way in all Gleason scores.
GVAX consists of two inactivated allogeneic prostate carcinoma cell lines (PC-3 and LNCaP) that have been genetically modified to secrete GM-CSF. In a phase II study involving 34 patients with metastatic HRPC, GVAX has been demonstrated to lower serum PSA transiently or reduce PSA progression in some patients, as well as extending time to clinical progression. Median survival in this trial was 26 months, historically very favourable.(18) Also ongoing are another phase II study of 80 patients with metastatic HRPC treated at higher doses, as well as two phase III trials (one comparing GVAX with docetaxel/prednisone, and one comparing GVAX/docetaxel with docetaxel/prednisone) in men with metastatic HRPC.
A promising future: ongoing trials
The most important ongoing phase III are summarised in Table 1. Among these, the ASCENT-2 trial is particularly notable. This phase III trial will evaluate the effect of DN-101 in combination with docetaxel (ASCENT regimen) on survival in HRPC.
1. Scher HI, Steineck G, Kelly WK. Hormone-refractory (D3) prostate cancer: refining the concept. Urology 1995;46:142.
2. Tannock IF, de Wit R, Berry W, 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. Beer TM, Eilers KM, Garzotto M et al. Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 2003;21:123-8.
5. Berry W, Eisenberger M. Achieving treatment goals for hormone-refractory prostate cancer with chemotherapy. Oncologist 2005;10(suppl 3):30-9.
6. Latif T, Wood L, Connell C, et al. Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) given daily x 5 in hormone refractory prostate cancer (HRPC). Invest New Drugs 2005;23:79-84.
7. Sternberg CN, Whelan P, Hetherington J, et al. Phase III trial of satraplatin, an oral platinum plus prednisone vs prednisone alone in patients with hormone-refractory prostate cancer. Oncology 2005;68;1:2-9.
8. Lara PN, Twardowski P, Quinn DJ. Angiogenesis targeted therapies in prostate cancer. Clin Prostate Cancer 2004;3(3):165-73.
9. Dahut WL, Gulley JL, Arlen PM, et al. Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol 2004;22:2532-7.
10. Picus J, Halabi S, Rini B, et al. The use of bevacizumab with docetaxel and estramustine in hormone-refractory prostate cancer: initial results of CALGB 900006. Proc Am Soc Clin Oncol 2003;22:393;Abstract 1578.
11. Berry W, Eisenberger M. Achieving treatment goals for hormone-refractory prostate cancer with chemotherapy. Oncologist 2005;10 Suppl 3:30-9.
12. Carducci M, Padley RJ, Breul, et al. Effect of endothelin-A receptor blockade with atrasetan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol 2003;4:679.
13. Vogelzang NJ, Nelson JB, Schulman CC, et al. Meta-analysis of clinical trials of atrasentan 10mg in metastatic hormone-refractory prostate cancer. J Clin Oncol 2005;23:393s.
14. George DJ, Gockerman JP, Petros W, et al. A phase I/II study of docetaxel and atrasentan in men with metastatic hormone-refractory prostate cancer (HRPC). J Clin Oncol 2005;23:419s.
15. Hussain M, Tangen CM, Lara PN, et al. Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: a Southwest Oncology Group trial S0111. J Clin Oncol 2005;23(34):8724-9.
16. Rosenberg JE, Weinberg VK, Kelly WK, et al. Randomized phase II study of ixabepilone or mitoxantrone and prednisone in patients with taxane-resistant hormone-refractory prostate cancer. Paper presented at 2006 Prostate Cancer Symposium, 17-19 February 2005, Orlando FL;abstract 253.
17. Small EJ, Schellammer PF, Higano CS, et al. Placebo-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(19):3089-94.
18. Simons J, Higano C, Corman J. A phase I/II trial of high-dose allogeneic GM-CSF gene-transduced prostate cancer cell line vaccine in patients with metastatic hormone-refractory prostate cancer. Proc Am Soc Clin Oncol 2003;22:166; Abstract 667.