Recent Progress in the Treatment of Advanced Prostate Cancer With Intermittent Dose-Intense Calcitriol (DN-101)

Treatment Update

RIU0313_02-13.qxd 2/14/07 6:06 PM Page 1 TREATMENT UPDATE Recent Progress in the Treatment of Advanced Prostate Cancer With Intermittent Dose-Intense Calcitriol (DN-101) Michael K. Brawer, MD Northwest Prostate Institute, Northwest Hospital, Seattle, WA Docetaxel is becoming standard therapy for androgen-independent prostate cancer (AIPC), and investigational agents are being added to docetaxel to assess potential additive effects and synergy. Although one of these agents, calcitriol, has repeatedly demonstrated antiproliferative properties against cancer of the prostate, breast, colon, and lung, the antineoplastic activity of calcitriol requires superphysiologic levels. Unfortunately, chronic exposure to superphysiologic levels of calcitriol causes hypercalcemia and resulting toxicity. Therefore, a host of analogues of calcitriol have been investigated for antineoplastic function, including intermittent dose-intense calcitriol, or DN-101. Because of encouraging results from phase II studies of DN-101 combined with docetaxel, the ASCENT (AIPC Study of Calcitriol Enhancement of Taxotere) phase II trial investigated docetaxel plus DN-101 versus docetaxel plus placebo in 250 men with metastatic AIPC and an abnormal baseline prostate-specific antigen (PSA) level. Although the ASCENT trial did not achieve its primary endpoint for increased PSA response, there was a significant trend in PSA response rate in the DN-101 arm. DN-101 in combination with docetaxel seems to improve overall survival and, interestingly, has a favorable safety profile compared with docetaxel alone. The DN-101/docetaxel combination is currently being studied in a much larger international trial, ASCENT-2. [Rev Urol. 2007;9(1):1-8] © 2007 MedReviews, LLC Key words: Calcitriol • DN-101 • Docetaxel • Prostate cancer • Vitamin D he management of hormone-refractory prostatic carcinoma (HRPC) continues to evolve. One of the confounding factors for our patients treated for advanced prostate cancer is that the majority experience or derive major beneficial effects with androgen deprivation, with improvement in bone pain, T VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY 1 RIU0313_02-13.qxd 2/14/07 6:06 PM Page 2 Intermittent DN-101 in Advanced Prostate Cancer continued regression of soft tissue metastasis, and decrease in serum prostatespecific antigen (PSA) levels. Unfortunately, historically none of the therapies utilized for managing men progressing to androgen-independent prostate cancer has provided survival of more than approximately 2 years. Approaches such as secondary hormonal therapy, mitoxantrone and prednisone, salvage radiation therapy, and the use of systemic radioisotopes may be construed only as palliative. Recent progress has been demonstrated in small nondefinitive clinical trials with a number of agents, and it is hoped that before too long, that will significantly lessen the mortality in most men with late-stage prostate cancer. Recent Advances in Chemotherapy Treatment of Late-Stage Prostate Cancer In 2004, the Southwest Oncology Group (SWOG) 99-16 clinical trial demonstrated a survival benefit of 20% with docetaxel/estramustine therapy compared with mitoxantrone and prednisone.1 This finding has served as the beginning of a change in the paradigm for the management of advanced prostate cancer. In another phase III trial reported in 2004, TAX327, patients received either docetaxel with prednisone or mitoxantrone plus prednisone.2 Again, in this study, improved survival in the group receiving docetaxel was observed in patients receiving an every3-week regimen but not in those on the weekly regimen. The median survivals were 18.9 months in the every3-week docetaxel group, 17.4 months in the weekly docetaxel group, and 16.9 months in patients receiving mitoxantrone and prednisone. SWOG 99-16 and TAX327 led to the registration of every-3-week docetaxel and prednisone as an approved treatment regimen for men with metasta- 2 VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY tic androgen-independent prostate cancer (AIPC) or HRPC. Antiangiogenesis Treatment in Late-Stage Prostate Cancer Angiogenesis is one of the primary pathophysiologic mechanisms in the development of prostatic carcinoma, and numerous trials have addressed the potential effect of agents that inhibit angiogenesis to affect the course of the disease. Thalidomide has seen the most clinical investigation in prostate cancer. In a study by Figg and colleagues,3 a greater than 50% decline in PSA was noted in 14% of patients, but, unfortunately, improvement in median survival was not greater compared with historical controls. Docetaxel with thalidomide has been investigated and there was a significant survival advantage in the combination cohort.4 Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF), a known angiogenesis factor in prostate cancer. Picus and associates5 treated men with HRPC with a combination of docetaxel, estramustine, and bevacizumab. Their nonrandomized study demonstrated a significant decrease in progression as well as survival benefits in patients treated with estramustine/docetaxel-based regimens. As is routine in the development of novel combination chemotherapy regimens, docetaxel is becoming standard therapy for AIPC, and investigational agents are being added to docetaxel to assess potential additive effects and synergy. Other Agents for the Treatment of Late-Stage Prostate Cancer In addition to docetaxel chemotherapy, a number of studies are under way looking at new drugs for the management of men with HRPC. Bone-specific targeted therapy is being addressed with endothelinbased agents. Endothelins affect bone matrix synthesis and enhance apoptosis. Atrasentan, a specific endothelin1A receptor antagonist that inhibits metastasis and angiogenesis, was evaluated in a phase III trial of HRPC.6 Among 131 men, a significant decrease in time to progression and survival was observed in evaluated patients who received astrasentan compared with those who received placebo. However, in intent-to-treat analysis, the survival benefit was not observed. Meta-analysis of all atrasentan studies does show a time to disease progression in favor of atrasentan.7 Unfortunately, despite these encouraging results, atrasentan approval was recently declined by the US Food and Drug Administration (FDA). Calcitriol and Vitamin D Synthesis Vitamin D is a general term for a group of substances characterized as antirachitic (ie, curing or preventing rickets). In humans, vitamin D3 is synthesized in the skin in response to ultraviolet radiation. Under the activity of ultraviolet light, dietary 7dehydrocholesterol is converted to vitamin D3. In the liver, the 25-position is hydroxylated to produce 25hydroxyvitamin D3, the most abundant form of vitamin D3 in the blood and body. Subsequently, the kidneys perform a second hydroxylation at the 1
position, leading to the potent and biologically active 1,25-dihydroxyvitamin D3 or 1,25-dihydroxycholecalciferol (calcitriol). Calcitriol is the most potent metabolite of vitamin D in humans, affording 1000 times the receptor affinity of 25-hydroxyvitamin D3 or 1,000,000 times the receptor affinity of the vitamin D3 obtained commercially as vitamin D supplements. In reality, it is more accurate to consider vitamin D3 an ultraviolet light–activated hormone rather than a RIU0313_02-13.qxd 2/14/07 6:06 PM Page 3 Intermittent DN-101 in Advanced Prostate Cancer vitamin. Dietary sources of vitamin D substances that can substitute for vitamin D3 exist in foods such as fish and certain vegetables. The primary activity of calcitriol is to regulate serum calcium and phosphorus levels. Regulation of the renal synthesis of calcitriol is modulated by parathyroid hormone levels. Calcitriol is the ligand for the vitamin D nuclear receptor. It is well known that there are vitamin D receptors (VDRs) that participate in the absorption and release of calcium in, for example, the gastrointestinal (GI) tissues, bones, and kidneys. However, VDRs are also present in a Epidemiology of Sunlight and Vitamin D in Prostate Cancer The relationships among sunlight exposure, blood levels of 25-hydroxyvitamin D, and calcium on the incidence of prostate cancer have been repeatedly studied over the past few decades. It has been established that geographic differences in prostate cancer incidence are significantly correlated with sun exposure (ultraviolet light wavelength B) and resulting vitamin D synthesis. The incidence of prostate cancer in the northern latitudes of the United States is higher than it is in the southern regions. Sunlight provides ultraviolet light, The antiproliferative actions of calcitriol and its analogues have repeatedly been demonstrated in human carcinomas of the prostate, breast, colon, and lung. host of tissues not involved with calcium metabolism, where these receptors exhibit numerous biologic functions. Many anticancer agents are known to work directly or indirectly through interactions with nuclear receptors, including glucocorticoids, selective estrogen response modulators, gonadotropin-releasing hormone agonists and antagonists, antiandrogens, and retinoids. Abe and associates8 demonstrated that mouse myeloid leukemia cells have vitamin D receptors and that exposure to potent forms of vitamin D results in terminal differentiation. Calcitriol also has potent antiproliferative effects on human prostate cancer cells, as described by Peehl and others.9 The antiproliferative actions of calcitriol and its analogues have repeatedly been demonstrated in human carcinomas of the prostate, breast, colon, and lung. The action of calcitriol in human prostate cancer has been reviewed by Moreno and colleagues.10 which is required for synthesis of vitamin D3 in the skin. Hanchette and Schwartz11 postulated that the decreased sun exposure in the northern latitudes may affect prostate cancer in this regard. Polymorphisms of the vitamin D receptor are also associated with risk and progression of prostate cancer, as reported by Habuchi and colleagues.12 Schwartz and Hulka13 described other potential relationships between vitamin D and prostate cancer, including the fact that vitamin D synthesis in the sun decreases with age as the incidence of prostate cancer increases. In addition, elderly patients have less sun exposure. Melanin in the skin of African Americans may inhibit vitamin D synthesis; the highest incidence of prostate cancer in the world is in African Americans. There is a high concentration of vitamin D in the Asian diet, and this may contribute to the lower incidence of prostate cancer in men from these countries. Calcium has been associ- ated with increased incidence of prostate cancer, and it is known that increased dietary calcium results in lower vitamin D levels. In addition, Corder and associates14 demonstrated lower levels of the active form of vitamin D in men with palpable tumors but not in those with stage T1c disease. Unfortunately, although serum levels of vitamin D3 correlate with actual exposure, they are not predictive of prostate cancer in individual men because of the wide variation in concentration that confuses the situation. The serum level of calcitriol is far more a reflection of serum calcium and phosphate concentration than is dietary consumption, making geographic and dietary studies difficult to interpret. For example, increased calcium ingestion results in a reduction of 1,25-vitamin D owing to the activity of the parathyroid gland. Seasons and Sunlight Exposure Are Correlated With Treatment Outcome at the Time of Diagnosis Not only does the incidence of prostate cancer correlate with vitamin D sunlight exposure, but the malignant potential of numerous tumors, including prostate, also reflects the amount of sunlight at the time of diagnosis.15 Robsahm and associates16 showed that among 115,096 patients with breast, colon, or prostate cancer, the prognosis was significantly better in patients diagnosed during summer and fall (when the greatest level of vitamin D3 occurs in the skin, leading to the highest levels of 25-hydroxyvitamin D3 in the blood). Zhou and colleagues,15 independently showed that patients who had surgery for non–small cell lung cancer in the summer had better recurrence-free survival. Similar findings have been reported by Lim and coworkers17 and Porojnicu and colleagues.18 VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY 3 RIU0313_02-13.qxd 2/14/07 6:06 PM Page 4 Intermittent DN-101 in Advanced Prostate Cancer continued In Vitro Laboratory Studies of Calcitriol and Prostate Cancer Multiple preclinical studies from many different groups provide the evidence of the potential influence of vitamin D on prostate cancer. Some researchers have noted that vitamin D receptors are present on cell lines of prostate cancer, including the well-established LNCaP cell line. Schwartz and associates19 demonstrated that supraphysio- dose-limiting hypercalcemia was noted in the majority of the 14 patients despite the modest increase in the daily dose of calcitriol. However, 2 patients did demonstrate significant decreases in PSA. Gross and colleagues22 used calcitriol in an adjuvant setting for rising PSA after definitive local therapy. Six of 7 men had a reduction in the rate of PSA rise; however, again, doselimiting hypercalcemia ensued. Owing to the overwhelming preclinical, environmental, and epidemiologic data, there has been great interest in using calcitriol or potent analogues in prostate cancer therapy. Human Clinical Trials of Calcitriol and Vitamin D Analogues in Prostate Cancer Calcitriol has been investigated in human prostate cancer trials. Osborn and associates21 carried out an investigation of calcitriol up to 1.5 g/d in men with HRPC. Unfortunately, 4 VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY Intermittent Dose-Intense Calcitriol or High-Dose Pulse Administration of Calcitriol Beer and associates23 initiated a series of investigations at the Oregon Health Sciences University on the role of calcitriol in advanced malignancy using intermittent dose-intense calcitriol or high-dose pulse administration. The novelty of their strategy was to increase the interval between calcitriol administrations with the hypothesis that an increased dosing interval Figure 1. Preclinical studies suggest that nanomolar concentrations of calcitriol are required for antitumor effects. Image courtesy of Novacea, Inc. Anti-Cancer Dose Range Blood Calcitriol Level logic concentrations of 1,25 (OH) D3 (calcitriol) in the nanomolar and above ranges inhibited these cells in culture. Owing to the overwhelming preclinical, environmental, and epidemiologic data, there has been great interest in using calcitriol or potent analogues in prostate cancer therapy. The antineoplastic activity of calcitriol requires superphysiologic levels. For example, in prostate cancer cell lines, significantly higher than physiologic concentration is required for growth inhibition. Unfortunately, chronic exposure to superphysiologic levels of calcitriol results in hypercalcemia and resulting toxicity; therefore, a host of analogues of calcitriol have been investigated for antineoplastic function.20 Hypercalcemia continues to cause doselimiting toxicity, and none of these agents has been approved for human malignancy. would allow one to achieve supraphysiologic levels of calcitriol (those needed to achieve a therapeutic benefit in in vitro laboratory studies) while avoiding the incidence of doselimiting hypercalcemia and its resulting toxicities (Figure 1). An intermittent dose-intense regimen theoretically has the potential for a prolonged cancer effect because of sustained activity of VDR-induced transcription and translation of tumor-inhibiting proteins. In the intermittent doseintense trial utilizing a weekly dosing schema, the investigators were able to demonstrate escalation to 2.8 g/kg (100  the daily replacement dose of 0.25 g total dose) with no grade 3 toxicities. Importantly, hypercalcemia was not a clinically significant problem, and the most significant grade hypercalcemia-related toxicity was grade 1. There was no requirement for dose reduction or treatment for hypercalcemia. Unfortunately, utilizing the existing formulations of calcitriol required patients to ingest up to 100 capsules for each dose, and beyond this number, the calcitriol absorption was limited by bioavailability through the GI absorption. The large number 1.0 nmol/L DN-101 Physiological Calcitriol Levels Daily Calcitriol Dosing Hypercalcemia Stop Dosing! Days RIU0313_02-13.qxd 2/15/07 2:35 AM Page 5 Intermittent DN-101 in Advanced Prostate Cancer of capsules was associated with variable interpatient absorption in addition to a ceiling for bioavailability. In a subsequent study,24 22 patients with recurrent, hormone-naïve prostate cancer were investigated following local therapy. They were treated with calcitriol, 0.5
g/kg/wk; the median duration of treatment was 10 months. Again, no hypercalcemia or resulting toxicity was observed, and no grade 3 toxicity for any cause was found. Three patients had sustained PSA reductions, and the PSA doubling time for the entire group increased from 7.8 to 10.3 months (P  .03). This study demonstrated that chronic administration of calcitriol in this population was well tolerated. The problem of systemic absorption of the calcitriol was raised, and the question was posed regarding leagues,25 37 men with advanced HRPC who had not had other chemotherapy were treated with calcitriol, 0.5
g/kg, on day 1 followed by docetaxel 36 mg/m2 on day 2. The rationale for starting the calcitriol earlier than docetaxel was to allow time for the vitamin to induce proapoptotic proteins before exposure of the prostate cancer cells to docetaxel. Dosing continued for 6 consecutive weeks and was repeated on an 8-week cycle. The study was designed to demonstrate a 20% or greater improvement in PSA response compared with the historical control of 40% with docetaxel alone. The toxicity observed was primarily related to that known to be associated with taxane therapy. Clinically insignificant grade 1 hypercalcemia was observed in 2 patients and grade 2 Because of the beneficial effect of docetaxel in the treatment of prostatic carcinoma, studies of the combination of docetaxel with calcitriol are an obvious extension. whether an improved formulation allowing greater levels of calcitriol in the serum and, more importantly, at the site of persistent carcinoma may be beneficial. Intermittent Dose-Intense Calcitriol and Docetaxel Because of the beneficial effect of docetaxel in the treatment of prostatic carcinoma, studies of the combination of docetaxel with calcitriol are an obvious extension. The combinations are also supported by studies in preclinical models in which it was demonstrated that calcitriol is synergistic with taxanes in their antineoplastic activity. Importantly, there is no overlap in toxicity between calcitriol and docetaxel. In a single-center open-label phase II trial conducted by Beer and col- hypercalcemia in 1 patient, who had erroneously ingested 2 full doses of the calcitriol. The PSA response criteria ( 50% reduction) was achieved in 30 of 37 patients (81%), and 9% had a greater than 75% reduction in PSA. PSA progression–free survival was 11.4 months in the combination arm, compared with a mean of 5 months in historical controls (range, 4.6–5.1 months). In evaluating measurable disease, tumor response was achieved in 53% compared with 28% historically (range, 17%–40%). Median survival was 19.5 months in the calcitriol with docetaxel cohort compared with a historical rate of 9.2 (range, 9%–9.4%). The investigators observed no effects on the single-drug pharmacokinetics of docetaxel from the combination of agents.25 These encouraging phase II results stimulated the investigators and others to pursue further trials of docetaxel and calcitriol. As noted earlier, there are many limitations pertaining to the various existing oral and intravenous formulations of calcitriol, most importantly the large number of capsules patients would need to take for an oral dose of 45
g, which approximates the maximally bioavailable dose of 0.5
g/kg. Additionally, small bowel absorption is suboptimal with the currently available oral formulations. On the basis of the preliminary studies by Beer and colleagues,25 Novacea Corporation (South San Francisco, CA) has developed Asentar, or DN-101, specifically for the intermittent doseintense calcitriol treatment of patients with cancer. Initially, 15-
g capsules of calcitriol in a novel formulation were used for the phase I and phase II studies, with the final configuration being 45
g in a single capsule, which is being used in a phase III trial and will be commercially available after registration. DN-101 is being investigated in clinical trials studying a number of malignancies. In addition to a higher dose, this formulation allows much higher peak levels (Cmax) of calcitriol. Because of the encouraging phase II results of intermittent dose-intense calcitriol in conjunction with docetaxel in the studies by Beer and colleagues,25 a phase II trial known as the ASCENT (AIPC Study of Calcitriol Enhancement of Taxotere) trial investigated docetaxel plus DN-101 versus docetaxel plus placebo in 250 men with metastatic AIPC and an abnormal baseline PSA level and was carried out under the sponsorship of Novacea. The patients were randomized in Canada and the United States between September 2002 and January 2004. Subjects received either DN-101, 45
g PO, plus docetaxel, 36 mg/m2 VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY 5 RIU0313_02-13.qxd 2/14/07 6:06 PM Page 6 Intermittent DN-101 in Advanced Prostate Cancer continued Patients with metastatic AIPC (n = 250) R A N D O M I Z E DN-101 45 g PO  docetaxel 36 mg/m2 IV weekly 3 of 4 wks Placebo PO  docetaxel 36 mg/m2 IV weekly 3 of 4 wks P R O G R E S S I O N Continuous therapy if PSA  4 ng/mL Intermittent therapy if PSA  4 ng/mL Figure 2. ASCENT (Androgen Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere): randomized double-blind study design. AIPC, androgen-independent prostate cancer; PSA, prostate-specific antigen. Data from Beer TM et al.25 IV weekly for 3 out of 4 weeks or placebo PO plus the same docetaxel schedule. The randomization scheme is shown in Figure 2. Patients received continuous therapy if the PSA level was greater than 4.0 ng/mL or were offered intermittent therapy if the PSA level fell into the normal range of less than 4.0 ng/mL. The primary endpoint was a 50% reduction in baseline PSA with a second confirmation of PSA reduction 4 weeks after meeting the 50% or greater reduction by 6 months. The study was powered at the 85% level for an increase in PSA response rate from 45% to 65% (based on historical data). Prespecified secondary endpoints included overall survival, skeletal morbidity–free survival, tumor response rate in patients with measurable disease, and time to PSA response. Safety and tolerability were monitored as well, in accordance with good clinical practice. Patients were required to have metastatic AIPC that was progressive, that is, 3 rising PSA measurements or a new metastatic lesion. Their PSA level needed to be greater than 5.0 ng/mL, and patients had to be chemotherapy naïve. 6 VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY At the time of final data analysis, the median follow-up was 18.3 months. Two hundred twenty-nine patients (92%) were off study, and there were 122 deaths (49%). All analyses were conducted by intent to treat. The randomization was well balanced. The treatment response of the primary endpoint of PSA response by 6 months was achieved in 49% of patients by 6 months in the placebo group and in 58% of those receiving DN-101 (P  .16). Overall PSA response (PSA response at any time) was 52% in the placebo cohort and 63% in the group receiving DN-101 (P  .073). The observed median survival is 16.4 months in the placebo arm, and the estimated median survival in the DN-101 arm is 23.5 months. There seemed to be a strong trend toward survival advantage. Although the unadjusted hazard ratio did not achieve significance (P  .070), the prespecified multivariate Cox regression hazard ratio (HR) demonstrated statistically significant survival advantage (P  .035). Skeletal-related events (SREs), including pathologic bone fracture, spinal cord compression, surgery for bone lesions, and radiation therapy, were evaluated. The definition of skeletal morbidity–free survival was the time from randomization to SRE or death due to all causes. There was no statistically significant advantage to the DN-101 arm, although there was a strong trend in favor of DN-101 treatment (HR  .78; P  .13). Serious adverse events (SAEs) as defined by the FDA occurred in 41% of patients in the placebo arm and, intriguingly, only 27% in patients receiving DN-101 plus docetaxel. Grade 3 or 4 adverse events also favored the combination arm at 58% versus 70% in the patients on placebo. Twentyeight percent of patients in the placebo arm discontinued treatment owing to adverse events, as opposed to 22% in the combination arm. The decreased incidence of adverse events in the DN-101 arm is certainly unusual in combination chemotherapy trials. It is reminiscent of the improved outcome seen with the addition of corticosteroids (another nuclear receptor ligand) to a number of chemotherapy regimens, which has been the subject of significant investigation. As is rarely apparent, there were fewer significant adverse events, as well as other adverse events, in the DN-101 group. Specific attention was focused on renal- and calcium-related adverse events. As expected, there was a greater incidence of hypercalcemia (grade 1 only) in the DN-101 arm; however, no grade 2, 3, or 4 toxicity was observed. The conclusions of ASCENT were that the trial did not achieve its primary endpoint for increased PSA response; however, there was certainly a trend in PSA response rate in the DN-101 arm. DN-101 in combination with docetaxel seems to improve overall survival and, intriguingly, there was a favorable safety profile compared with docetaxel alone. RIU0313_02-13.qxd 2/14/07 6:06 PM Page 7 Intermittent DN-101 in Advanced Prostate Cancer A more careful analysis of the adverse events seen in this study was reported at the 2005 European Cancer Conference. Exploratory analyses were performed for the significant differences in SAEs favoring the combination arm. The investigators examined the number of patients reporting at least one SAE as well as for the subgroups of patients reporting an SAE involving the GI tract and those reporting thromboembolic events. A thromboembolic event is defined as a clinical thrombosis of the venous system (deep vein thrombophlebitis or pulmonary embolism of the arterial system [eg, myocardial infarction, cerebrovascular accident, arterial thrombus]). The decrease in SAEs involving GI toxicity in the combination arm was significant (P  .017). Cantorna and colleagues26 showed that DN-101 may reduce proliferation of GI-epithelial cells. Reducing the epithelial cell proliferation rate before exposure to docetaxel may lessen the overall cell toxicity. The apparent prophylaxis for significant thromboembolic events has several potential targets. Of great interest are the up-regulation of thrombomodulin, a natural antithromboembolic substance that modulates the activation of thrombin on the vascular wall,27 and down-regulation of tissue factor, the most common cancerassociated procoagulant that activates factor VII. A more detailed analysis of thromboembolic events was performed.28 Overall, thromboembolic events were, as noted above, statistically fewer in the combination arm. Grades 3 and 4 thromboembolic events occurred in 8% of the patients on placebo but in 1.6% of those in the DN-101 arm (P  .02). All thromboembolic events occurred in 8.8% of those in the placebo arm but in 1.6% of those receiving DN-101 (P  .01). Of the 13 thromboembolic events observed among the 250 patients, there were 11 in the placebo-treated patients and 2 in the arm receiving DN-101 (P  .01). This difference remains statistically significant after adjustments for risk factors such as history of thrombosis, atrial fibrillation, and use of antithrombotic agents. Unfortunately, the primary endpoint—PSA response—was not met in the ASCENT trial; however, both the overall survival and the incidence of SAEs showed differences that were statistically different, although these were not the designated primary endpoint making the statistical comparisons descriptive. The safety profile and analyses suggest that there is an advantage in the sparing of significant toxicity of docetaxel when combined with DN-101. DN-101 is currently undergoing additional study with docetaxel in a much larger international trial (ASCENT-2), which will recruit 900 patients with metastatic AIPC with a primary endpoint of overall survival. This important study is actively seeking patients throughout the United States. Summary Although significant strides in the management of HRPC have been achieved and numerous investigations are on the way, there is clearly an ever-present need for novel agents and approaches. Calcitriol, particularly in its newer formulation, DN101, seems to offer promise in this regard. This orally available, natural hormone demonstrates an unusual, perhaps unique, profile of improving tumor inhibition and overall survival while decreasing the toxicity of concomitant drugs. The synergy of calcitriol with docetaxel and potentially other agents should expand the therapeutic index for current standard treatments for cancer. We eagerly await the results of phase III trials of Main Points • Docetaxel is becoming standard therapy for androgen-independent prostate cancer (AIPC), and investigational agents are being added to docetaxel to assess potential additive effects and synergy. • The antiproliferative actions of calcitriol and its analogues have repeatedly been demonstrated in human carcinomas of the prostate, breast, colon, and lung. • The antineoplastic activity of calcitriol requires superphysiologic levels. Unfortunately, chronic exposure to superphysiologic levels of calcitriol causes hypercalcemia and resulting toxicity. Therefore, a host of analogues of calcitriol have been investigated for antineoplastic function. • Because of the encouraging phase II results of intermittent dose-intense calcitriol in conjunction with docetaxel, the phase III ASCENT (AIPC Study of Calcitriol Enhancement of Taxotere) trial investigated docetaxel plus DN-101 versus docetaxel plus placebo in 250 men with metastatic AIPC and an abnormal baseline prostate-specific antigen (PSA). • Although the ASCENT trial did not achieve its primary endpoint for increased PSA response, there was certainly a trend in PSA response rate in the DN-101 arm. DN-101 in combination with docetaxel appears to improve overall survival and, intriguingly, there was a favorable safety profile compared with docetaxel alone. VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY 7 RIU0313_02-13.qxd 2/14/07 6:06 PM Page 8 Intermittent DN-101 in Advanced Prostate Cancer continued DN-101 in combination with docetaxel. If they confirm the observations of the ASCENT phase II investigation, then it is likely this treatment will become a mainstay in our armamentarium for advanced prostatic carcinoma. References 1. 2. 3. 4. 5. 6. 8 8. 9. 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;351:15131520. 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;351:1502-1512. Figg WE, Arlen P, Gulley J, et al. A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clin Cancer Res. 2001;7:18881893. Retter AS, Ando Y, Price DK, et al. 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