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Developing Treatments for Hormone-refractory Prostate Cancer
and stabilization of microtubules, leading to cell-cycle arrest, inhibition of weekly oral formulation of calcitriol, DN-101, which allowed higher
tumor cell proliferation, and programmed cell death.
Epothilones are a concentrations of the active metabolite to be achieved without dose-
novel class of tubulin-targeting agents that demonstrate activity in taxane- limiting toxicities, was developed.
Following the demonstration of in vitro
resistant cell lines and animal models.
Ixabepilone was the first epothilone synergy when calcitriol was combined with cytotoxic drugs,
a series of
to be evaluated in clinical trials and the first to be approved for the treatment clinical trials was initiated.
of metastatic breast cancer.
Antitumor activity was also demonstrated in
phase I and II trials against metastatic prostate cancer. In a phase II trial of In a pilot study of weekly DN-101 with or without docetaxel in patients with
ixabepilone monotherapy in chemotherapy-naïve HRPC patients, a PSA metastatic HRPC, 81% of patients had a PSA decline of >50% after a median
response rate of 33% was reported with a median survival of 18 months.
duration of therapy of 10 months.
There was no increased toxicity in the
In a second phase II trial of ixabepilone with or without estramustine, a PSA combination arm compared with docetaxel alone. A confirmatory
response rate of 48% was observed in patients receiving ixabepilone alone double-blind, randomized, placebo-controlled phase II trial of weekly
compared with a 69% rate in the combination arm.
The results of a docetaxel, prednisone, and DN-101 versus weekly docetaxel and prednisone
randomized phase II trial of ixabepilone or mitoxantrone in the second-line alone (the Androgen-independent Prostate Cancer Study of Calcitriol
setting following progression on a taxane have been reported.
A PSA Enhancing Taxotere [ASCENT] trial) was then conducted in 250 men with
decline of 17% was observed for the ixabepilone arm. A phase I–II trial of HRPC.
The primary end-point of this study was the proportion of men who
ixabepilone in combination with mitoxantrone as second-line therapy for achieved a PSA response within six months of study entry. Although there was
metastatic HRPC is in progress. no statistically significant difference between the two arms in the proportion of
patients achieving a PSA response, there was a benefit in estimated overall
XRP6258 (Sanofi-aventis) is an oral bioavailable semi-synthetic taxoid derivative survival favoring the combination arm (24.5 versus 16.5 months). Based on
that binds to and stabilizes tubulin, resulting in the inhibition of microtubule these results, a phase III placebo-controlled trial (ASCENT II) was initiated to
depolymerization and cell cycle arrest.
Unlike other taxanes, XRP 6258 is a compare weekly docetaxel and prednisone plus DN-101 versus standard
poor substrate for the MDR P-glycoprotein efflux pump, and may therefore be docetaxel and prednisone given every three weeks, with overall survival as the
useful for treating multidrug-resistant tumors. XRP 6258 has shown activity in primary end-point. However, this study was closed to accrual in November
patients with taxane-resistant metastatic breast cancer.
A study of an 2007 after an initial review by the Data and Safety Monitoring Board, and the
intravenous formulation of XRP6258 plus prednisone versus standard status of further development for DN-101 is unclear.
mitoxantrone and prednisone in patients with HRPC after failure of docetaxel-
based chemotherapy is currently under way. Antiangiogenic Therapies
The major mediator of tumor angiogenesis is vascular endothelial growth
Platinum Analogs factor (VEGF), which signals mainly through VEGF receptor 2 (VEGFR-2). This
Satraplatin was the first oral platinum analog to enter clinical trials. Its receptor is over-expressed in tumor endothelial cells engaged in
antitumor activity in pre-clinical models was similar to that of cisplatinum and angiogenesis.
In patients with prostate cancer, high VEGF expression and
carboplatin, with less cross-resistance to these platinum drugs.
In phase I–II increased microvessel density have been associated with angiolymphatic
trials, significant activity against a variety of solid tumors—including prostate invasion, lymph node status, and distant metastasis.
Pre-clinical studies have
cancer—was demonstrated. Based on preliminary results from a randomized suggested several possible mechanisms by which antiangiogenic therapies
phase III trial in which chemotherapy-naïve HRPC patients randomized to a may enhance the efficacy of chemotherapy.
In an early phase II trial of an
combination of satraplatin plus prednisone had a significant improvement in antiangiogenic and cytotoxic agent, 75 patients with metastatic HRPC were
progression-free survival (PFS) compared with prednisone alone,
a large randomized to receive combined thalidomide and docetaxel or docetaxel
multinational phase III trial was conducted. This trial compared satraplatin alone.
Although this study was not powered to detect a statistically
plus prednisone versus placebo plus prednisone in patients with HRPC who significant difference in survival, the median overall survival was doubled
had progressed on first-line therapy.
Its primary end-point was an from 14.7 months in the docetaxel-alone arm to 28.9 months in the
improvement in PFS. The median time to progression for patients who combination arm (p=0.0407). Treatment was well tolerated, but patients in
received satraplatin was 11.1 versus 9.7 weeks for the placebo arm the combination arm required low-molecular-weight heparin to reduce the
(p<0.001). Satraplatin was also superior to prednisone in PSA response, pain risk for venous thromboembolism. Despite the impressive median overall
response, and duration of pain response. However, with longer follow-up, survival achieved with thalidomide and docetaxel, a confirmatory phase II
median survival for both satraplatin and placebo was 61 weeks.
Due to the trial has not been performed to date.
lack of survival data, the US Food and Drug Administration (FDA) did not
recommend approval for satraplatin as a second-line treatment for HRPC. Bevicizumab, a humanized monoclonal antibody that targets vascular
endothelial growth factor, has significant activity in combination with
Differentiation Therapies chemotherapy in metastatic colorectal, lung, and breast cancer.
The most widely studied differentiation agents in prostate cancer inactive as a single agent in HRPC,
the combination of bevacizumab,
treatment have been the vitamin D analogs. The major active metabolite of docetaxel, and estramustine showed substantial activity in a phase II
vitamin D is calcitriol, a naturally occurring hormone that is believed to co-operative group trial.
A PSA decline of >50% was achieved in 81% of
exert its main antineoplastic effects by inhibiting cellular proliferation and patients with HRPC. The median time to progression (9.7 months) and
Early dose-escalation clinical trials of calcitriol in the median survival (21 months) was similar to that seen with previous
treatment of prostate cancer were hampered by the development of docetaxel–etramustine-based studies. A randomized phase III study of
treatment-induced hypercalcemia and hypercalciurea.
Subsequently, a docetaxel and prednisone with or without bevacizumab is currently being
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