The Future in Advanced Prostate Cancer: Take Your Partners or Is the Last Dance For Me?

ADVANCES IN PROSTATE CANCER The Future in Advanced Prostate Cancer: Take Your Partners or Is the Last Dance For Me? David I. Quinn, MD, PhD, FRACP Clinical Investigations Support Office, Kenneth J. Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA Recent therapeutic initiatives have improved quality of life and survival for patients with advanced prostate cancer. This review focuses predominantly on prostate cancer that has become refractory to standard androgen ablation treatment. Planned trials will answer further questions on the optimal use and sequencing of currently available hormonal agents, cytotoxic therapies, and radiolabeled nucleotides. Future therapeutic advances are likely to come in 2 areas: targeted therapies and response prediction. Molecular targeted agents will be most useful in combination with each other or with established systemic therapies. The selection of combinations will require the application of paradigms targeting key biochemical pathways and specific microenvironments in prostate cancer. Response prediction for individual patients may be assisted by either pretreatment or sequential molecular profiling, or sequential imaging, or biochemical studies that predicate outcome prior to or soon after treatment has been initiated. To bring these advances to the metastatic prostate cancer patient, a series of well-designed clinical trials is needed that integrates the lessons learned through laboratory, translational, and clinical studies in recent years. [Rev Urol. 2004;6(suppl 10):S29–S44] ©2004 MedReviews, LLC Key words: Targeted therapy • Response prediction • Hormonal agents • Cytotoxic therapy • Radiolabeled nucleotides denocarcinoma of the prostate is a major health issue for patients, physicians, and healthcare providers. Prostate cancer (PCa) is the most common malignancy among men in developed countries and the second most common cause of cancer death.1 In the United States there will be an estimated 230,000 cases of and 30,000 deaths from carcinoma of the prostate in 2004.2 The lifetime A VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S29 The Future in Advanced Prostate Cancer continued risk of developing PCa has risen to 1 in 5.3,4 The natural clinical history of PCa is long, with projected transition from the first malignant cell in the prostate to distant metastatic disease taking more than 15 years in some patients, and not occurring within the lifespan of a proportion of men.5 In a population with increased longevity, it is likely that PCa will become more clinically prevalent in the future. The vast majority of deaths from PCa occur as a consequence of progressive metastatic hormone-refractory prostate cancer (HRPC). Current Therapy Hormone therapy is the cornerstone of first-line therapy for advanced disease. However, the effect of androgen • Surviving cells undergo a variable quiescent or remission phase. • Cell-cycle induction and increased proliferation occur at the onset of hormone independence in a subset of cells that correlates with biochemical and clinical progression. A small number of patients survive more than 10 years following castration for advanced PCa.15 However, the vast majority of patients go on to develop HRPC characterized by worsening clinical symptoms, including bone pain, coupled with rising serum PSA value. An increase in serum PSA levels subsequent to a hormone-induced nadir may precede clinical recurrence by several months.16 Unfortunately, progress in Hormone therapy is the cornerstone of first-line therapy for advanced disease. However, the effect of androgen ablative therapy is transient, with a duration of response of 12 to 36 months in most cases. ablative therapy is transient, with a duration of response of 12 to 36 months in most cases. In advanced or metastatic PCa, tumor response (measured by a variety of criteria) is reported in 80% to 100% of cases with bilateral orchiectomy, exogenous estrogen therapy, or hormone therapy directed at the hypothalamic–pituitary–gonadal axis and/or intracellular androgen receptor pathway.6–10 This response is characterized by improvement in clinical symptoms (usually bone pain) and a fall in serum prostate-specific antigen (PSA) level.11 The biological correlate of this transient response to hormonal manipulation is triphasic12,13: • Initial androgen withdrawal results in a variable proportion of PCa cells undergoing apoptosis.14 The remaining cells enter an androgen ablation–induced cell-cycle arrest rather than undergoing apoptosis. improving the survival of patients with HRPC has been slow, and the interval between development of HRPC and death is usually between 6 and 18 months. External beam radiation therapy is useful for the palliation of local bone pain but does not improve survival time. Attempts at using hormonal agents that act on nonandrogen steroid hormonal pathways, such as estrogen or progesterone, have met with little success and, at times, significant toxicity.17–20 Prior estimates of median survival for patients with HRPC have been approximately 8 to 12 months; however, recent prospective trials in this patient population reported median survival times of 16 to 18 months.21–23 This apparent change in the median survival time in large part reflects stage migration resulting from inclusion of patients with a rising PSA in the absence of measurable disease in more modern HRPC trials.24 Recent ad- S30 VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY vances in supportive and chemotherapeutic therapy of these patients have improved quality of life and may have a positive impact on survival, but more efficacious and durable therapies are required. Presently, 3 chemotherapeutic agents have been approved for the treatment of androgen-independent PCa: mitoxantrone, docetaxel (one of the taxanes), and estramustine. Mitoxantrone Many different cytotoxic agents have been used in HRPC in an attempt to palliate symptoms and improve survival.25 Although no therapy demonstrated increased survival until very recently, physicians using chemotherapy in patients with HRPC believed that significant improvement in symptoms occurred in many of these patients.26–28 During the 1990s, mitoxantrone-based chemotherapeutic regimens definitively demonstrated symptomatic and health-related quality-of-life improvement in patients with HRPC in 2 phase III trials.23,28–30 Mitoxantronebased regimens became the first-line standard of care for patients with symptomatic progressive HRPC, although time to symptomatic progression is about 6 months. Taxanes The taxanes (paclitaxel, docetaxel) have activity in HRPC when used alone or in combination with other cytotoxic agents.31–33 Taxanes have been combined with estramustine with possible synergistic effect but at the cost of significant procoagulantderived side effects. Another important issue in taxane-based therapy for PCa is dose scheduling, with differential side effects between dosing every 3 weeks and dosing at shorter intervals such as every week or 2 out of every 3 weeks. The best schedule for disease response has not been defini- The Future in Advanced Prostate Cancer tively determined. Efforts at improving front-line therapy are important, and several multicenter trials are currently accruing patients to determine what approach should be first-line standard care. Concurrently, new approaches improve the response to firstline therapy with increased efficacy, diminished toxicity, and better selection of patients for individual therapy. Regardless of the first-line approach used in HRPC, eventually all patients relapse.25,34,35 Recent data suggest that patients failing to respond to either taxane- or mitoxantrone-based therapy may respond when switched to the other agent. Docetaxel Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Bcell lymphoma-2 (Bcl-2) function is implicated in the maintenance of microtubule integrity,36 and taxane action on the microtubule may be dependent on the phosphorylation of Bcl-2 or Bcl-xL.31,37,38 Recent work suggests that variation in -tubulin expression may predict response to docetaxel, with higher levels of expression of class IIb -tubulin correlating with decreased response to therapy.39,40 An understanding of the molecular action of docetaxel in cancer cells is important when trying to select drugs that may potentiate its effect either by acting synergistically on microtubules or by modulating other cellular pathways not affected by taxanes. Estramustine Estramustine is constituted by the carbamate linkage of estradiol and nornitrogen mustard molecules and is therefore best considered a combination hormonal-cytotoxic therapy. However, the mechanism by which estramustine exerts its antineoplastic effect is unclear. Following oral ingestion estramustine is preferentially taken up by and retained in prostate tissue and PCa cells. As a single agent estramustine has not demonstrated benefit over continued or alternate hormonal therapy in HRPC.17 However, in preclinical experiments in combination with cytotoxic agents, estramustine appeared to contribute to cytotoxic effect. Although the mechanism for this is unclear, the effect of estramustine may occur through a phase activation of PCa cells so that they are more sensitive to subsequent or concurrent cytotoxic effect. Estramustine alters cellular microtubular configuration and may have synergy with other drugs that act on microtubules, such as taxanes (paclitaxel, docetaxel) and vinca alkaloids (vincristine, vinblastine).37,41–46 Early studies and comparison of phase II cohorts with a variety of regimens incorporating estramustine suggest potential increased efficacy with its addition to microtubule modulators such as vinca alkaloids and taxanes,41,43,45,46 although results of published studies have been inconclusive. In a randomized study of 201 patients with HRPC comparing vinblastine and estramustine with vinblastine, time to progression and PSA response favored the combination, but this did not translate into a survival benefit.43 Similarly, a US oncology group study showed a nonsignificant trend toward improved time to progression and survival with combination therapy when paclitaxel was compared with paclitaxel combined with estramustine in an underpowered study. In addition to a range of estrogenic-related side effects such as painful gynecomastia and fluid retention, estramustine carries with it the potentially serious side effect of venous or arterial thrombosis in as many as 50% of patients.47,48 This mitigates anticoagulation with warfarin and aspirin for patients receiving therapy and excludes many patients who are in an age and disease group where they are more likely to have had a past thrombotic event such as venous thrombosis or coronary artery insufficiency. Estramustine and Docetaxel in Combination In HRPC, single-agent docetaxel given at 3-week intervals was reported to produce a PSA response in 46% and measurable soft tissue disease response in 28% of patients.49 Beer and colleagues50 reported a PSA response rate of 48% and measurable response of 20% in HRPC patients treated with a weekly schedule of docetaxel. Weekly and every third week docetaxel regimens have different toxicity profiles, and many community oncologists preferred weekly regimens in patients with PCa. The combination of estramustine and docetaxel produced a higher PSA response of 69%, measurable response in 23% of patients, and time to progression of 11 months in a Cancer and Leukemia Group B (CALGB) phase II study.51 These responses and outcome figures for the combination were consistent with other early-phase trials conducted in HRPC patients at a variety of centers.47,52–58 Longer follow-up on at least one study suggested that the combination improved survival, at least compared to historical controls.59 Even so, many community oncologists did not include estramustine in taxanecontaining regimens because of potential side effects and logistic difficulties with dosing estramustine to overlap with the taxane dose. On the basis of these data, several questions were identified and remained to be addressed: VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S31 The Future in Advanced Prostate Cancer continued • Did docetaxel-based regimens provide an advantage, preferably a survival advantage, over mitoxantrone? • Did estramustine add to the potential effect of docetaxel on palliation or survival? • Did weekly and third weekly docetaxel produce equivalent outcomes? H3SWOG Intergroup 9916 and TAX327: Advantage docetaxel sans estramustine. The Southwest Oncology Group (SWOG)60 began planning a definitive comparison of mitoxantrone plus prednisone with estramustine plus third weekly docetaxel based on encouraging phase I data from Columbia University. The result was SWOG 9916, by far the largest phase III trial in HRPC yet planned, a trial that from its inception to its publication realigned the way trials are conducted for this disease and stage. Subsequently, Aventis Pharmaceuticals, the manufacturer of docetaxel, sponsored the TAX327 trial61, a 3arm trial of 75 mg docetaxel every 3 weeks, 30 mg weekly docetaxel, and a control arm of 12 mg mitoxantrone plus prednisone every 3 weeks. The entry criteria for the 2 trials were similar by design. The combination of estramustine and docetaxel compared with mitoxantrone plus prednisone in SWOG 9916 demonstrated a statistically superior median survival of 17.5 months versus 15.6 months (log rank P  .02). A similar result was seen in the TAX327 trial, where third weekly docetaxel and twice daily oral prednisone produced better median survival than mitoxantrone and prednisone (18.9 vs 16.5 months, log rank P  .009). Weekly docetaxel was not statistically better than mitoxantrone (P  .36). In SWOG 9916, toxicity was less in the mitoxantrone arm, but there was no net difference in severe toxicity or in treatment-attributed mortality between the 2 arms, with a similar finding in TAX327. The docetaxel arm (75 mg every 3 weeks) produced improved quality of life over mitoxantrone in both studies, predicated on a higher response rate and longer duration of effect on clinical symptoms. Summary verdict. Docetaxel in thrombotic event. Given this construct alone, even though estramustine may have a role in increasing response rate or time to progression in HRPC in a hypothetical phase III comparison, Docetaxel in combination with estramustine or prednisone confers a modest survival advantage and significant palliative benefit in a larger proportion of patients compared with mitoxantrone plus prednisone. combination with estramustine or prednisone confers a modest survival advantage and significant palliative benefit in a larger proportion of patients compared with mitoxantrone plus prednisone.60,61 The first trials demonstrating a survival advantage in HRPC are encouraging but leave room for improvement. Particularly sobering is the fact that for more than 80% of patients in both trials, disease had progressed by 12 months after entry. What role do estramustine, mitoxantrone, and weekly taxane schedules now play in therapy for HRPC? A remaining issue was the role of concurrent estramustine/docetaxel administration. Based on several smaller ongoing trials, data on file from Aventis Pharmaceuticals62 suggest that outcomes in terms of survival from first treatment with docetaxel are virtually the same regardless of whether estramustine was coadministered. In SWOG 9916, prophylactic anticoagulation with low-dose warfarin and aspirin was introduced to ameliorate the thromboembolic risk in the estramustine arm. Analysis of clinical clotting events before and after the introduction of prophylaxis failed to demonstrate a reduction in these events with warfarin and aspirin. Given the striking similarity of the results of the 2 studies in terms of overall survival, it seems that the addition of estramustine to docetaxel is unlikely to produce a survival advantage, particularly in light of the potential for a major S32 VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY there is probably very little value in adding it to taxane treatment in the first-line setting. Evaluation in patients with disease that has progressed on first- and possibly second-line therapies may be worthwhile, provided the patient is educated about the relative risks of estramustine. However, given community oncologists’ antipathy to the drug before the most recent trial data became available, one suspects estramustine is not a viable PCa drug outside the research setting. Mitoxantrone has significant clinical activity in HRPC. The SWOG investigators evaluated a decrease in PSA levels as a predictor of survival and found that a 50% fall from baseline predicted improved survival (P  .0001). This effect was independent of treatment arm, and patients with such a PSA response had a median survival of 21 months in both docetaxel and mitoxantrone arms. Prostate-specific antigen response occurred in 50% of patients given docetaxel and 27% of patients receiving mitoxantrone, suggesting that the difference in outcome was based on number of patients responding rather than on a differential effect on response duration for either agent. Hence, mitoxantrone may have a role in second-line therapy for patients failing to respond to taxanes and may be used as first-line therapy in patients who may not tolerate taxanes because of premorbid conditions such as neuropathy. Similar statements can be made about the potential role for The Future in Advanced Prostate Cancer weekly docetaxel as a regimen of utility after first- and second-line therapy failure in HRPC. Whether these therapies are better than newer chemotherapeutic options for second-line and subsequent therapies is currently being tested. An example of this is the trial comparing mitoxantrone and epothilone B for patients unresponsive to taxanes now being undertaken between the Dana Farber and Memorial Sloan-Kettering Cancer Centers. New Therapeutic Approaches Cancer cells exhibit profound genetic sis, androgen receptor signaling, signal transduction, cell-cycle regulation, cell adhesion and cohesion, and angiogenesis (Table 1). Variations at the DNA, RNA, and/or protein levels of molecules involved in these pathways are all potential candidate markers of prognosis and therapeutic response. Detailed cohort studies have been recently reviewed that delineate the clinical and pathologic factors that predict outcome for men diagnosed with PCa on biopsy and after a variety of treatments for clinical PCa.65 The molecular biology of prostate cancer and its progression is characterized by aberrant activity of several regulatory pathways both within the prostate cells and in the surrounding milieu. instability and over a period of time accumulate genetic mutations that enhance their metastatic potential and render them resistant to chemotherapeutic agents.63 One strategy for developing therapies is to identify and inhibit host-mediated functions that are necessary for tumor growth and spread.64 The molecular biology of prostate cancer and its progression is characterized by aberrant activity of several regulatory pathways both within the prostate cells and in the surrounding milieu. These pathways can be broadly grouped into apopto- There are 3 possible approaches to targeting these pathways: 1. Annie, Get Your Gun! A single shot will work if it hits the right target, assuming you can see the target. This is likely to be the case only in cancers that have a single gene mutation or translocation at their genesis, such as for imatinib in gastrointestinal stromal cell tumor (GIST, C-kit mutation, CD117, imatinib), chronic myeloid leukemia (Philadelphia chromosome translocation 8:22, Bcr-Abl, imatinib), and der- matofibroma protuberans.66 Other tumor types may have a common gene anomaly that is important in disease progression in selected patients, such as in breast cancer (Her2/neu amplification, trastuzumab). The first scenario seems unlikely in PCa, where a sequence of genetic anomalies occur but no single gene effect is dominant in pathogenesis or progression. The second scenario has potential in PCa but will require better delineation of the targets, perhaps through a selective genomic/proteomic approach. 2. Take Your Partners Please. This assumes that the combinations will be exponentially beneficial and might be selected to target the same pathway, parallel pathways, or disparate pathways, with potential for additive or synergistic effect. This assumption is supported by results in colorectal cancer with targeted therapy and cytotoxic agents in combination. It is driven in part in PCa by a desire to replace estramustine with an efficacious and tolerable partner for cytotoxic agents. This combination approach has considerable potential therapeutic profit and is likely to be a major focus of trial efforts in the coming few years (see below, and Table 2). 3. Is Only the Last Dance for Me? This assumes that targeted thera- Table 1 Summary of Molecular Aberrations in Prostate Cancer Process Apoptosis Androgen receptor signaling Signal transduction Cell-cycle regulation Cell adhesion and cohesion Angiogenesis Key Molecules/Markers Selected References p53, Bcl-2 AR, possible alternative signal transduction pathways Epidermal growth factor receptor family C-myc, p16INK4A, p27Kip1, pRb, apoptotic index, Ki67 E-cadherin, -catenin, metalloproteinases, chondroitin sulfate, endothelin pathway VEGF, VEGF receptors, nitric oxide 106, 107, 152–156 157–164 165, 166 167–172 173–184 88–91, 93 Bcl-2, b-cell lymphoma-2; AR, androgen receptor; VEGF, vascular endothelial growth factor. VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S33 The Future in Advanced Prostate Cancer continued pies might only be used at the end of life once other therapies have failed, as demonstrated with gefitinib in non–small cell lung cancer, where there is no benefit to first-line combination with chemotherapy but later single-agent treatment improves quality of life. This theory has been questioned by the improvement in survival with the combination of bevacizumab or cetuximab with cytotoxic therapy in colon cancer. However, the value of stabilizing or maintenance therapy should not be dismissed in advanced PCa, where we are able to elicit a greater than 80% response with primary androgen ablation and a 50% response with first-line chemotherapy for hormone-refractory disease. Trials in the maintenance setting certainly seem warranted with agents that have clinical effects that are cytostatic rather than cytotoxic in most cases (angiogenesis inhibitors) or do not require cell proliferation to be active, have differentiating effects on cancer cells, and/or are antiproliferative (such as bortezomib, calcitriol, metalloproteinase inhibitors, or epidermal growth factor inhibitors). Given priorities in research agendae, it appears likely that these studies will only be undertaken once evaluation of targeted agents in combination with cytotoxic agents are underway. Targeting Chemokines, Angiogenesis, and Adhesion in the Bone Microenvironment Bone metastases are almost universal in fatal prostate cancer. On this basis, therapeutic targeting of the bone milieu may bring considerable profit. Prior to the advent of chemotherapy for HRPC, radionuclides directed at the diphosphate incorporation into osteoblastic metastases with agents such as strontium-89 and samarium-153 were an important part of therapy. With the better delineation of chemotherapy as a treatment for HRPC, the issue of whether early use of bone targeted radionuclides in combination with or in tandem with chemotherapy may improve outcome has become important. A recent study evaluated the addition of strontium-89 to chemotherapy in 72 HRPC patients without prior exposure to chemotherapy and found a remarkable improvement in median survival for those given additive strontium-89 versus those given chemotherapy alone (27.7 vs 16.8 months).67 The concept has now been expanded in an MD Anderson/ Southwest Oncology Group-supported trial of chemotherapy “induction” followed by strontium-89 therapy. Despite good outcomes for those patients placed on the trial thus far it has accrued slowly, primarily due to concern over protracted myelosuppression from strontium-89. Discussion is underway regarding the use of samarium-153 in this setting, with an expectation of less profound and briefer bone marrow toxicity compared to strontium-89.68 Further trials of targeted radiation delivery coupled with cytotoxic drugs and perhaps other agents with activity in prostate cancer are planned. The endothelin (ET) pathway is particularly important in several phases of PCa development and progression but appears to be especially important in the progression of bone metastases.69,70 In the normal prostate gland, ET-1 is produced by epithelial cells. The highest concentrations of ET-1 in the body are found in seminal fluid.71 In PCa, key components of ET-1 clearance, ET-B receptor binding,72 and neutral endopeptidase (NEP) activity are diminished,73 resulting in an increase in local ET-1 concentrations. Neutral endopeptidase is a metalloendopeptidase that is responsible for the metabolism of several bioactive pep- S34 VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY tides, including endothelins.73 Increased ET-A receptor expression is also seen with advancing tumor stage and grade in both primary and metastatic prostate cancer.69,70,71 By contrast, ET-B tends not to be expressed, probably due to gene silencing through methylation of the promoter.67,74,75 Hence, the ET axis is hyperactive in PCa, and the pathway has an important and perhaps essential role in the progression of bone metastases from PCa.76,77 Atrasentan inhibits prostate cancer cell–related paracrine mitogenic stimulation of cocultured osteoblasts, mediated in part through the insulin growth factor pathway and thought to be important in the initiation of bone metastases.78,79 Atrasentan also inhibits the cascading selfstimulatory autocrine effects of ET 1 during the metastatic process seen in model systems.78 Atrasentan (ABT-627) is an orally bioavailable inhibitor of the ET-A receptor.80 In phase I trials, assessment doses of up to 95 mg per day were tolerated without development of dose-limiting toxicity. However, adverse effects due to the vasodilatory effect of the drugs were evident and included rhinitis, headache, and peripheral edema.81 An initial randomized phase II study in patients with HRPC comparing atrasentan at doses of 2.5 mg and 10 mg daily versus placebo suggested an improvement in time to progression (6 months) with the drug over placebo (4 months).82 This did not reach statistical significance when evaluated on an intent-totreat basis, but was statistically different in favor of the drug therapy when only evaluable patients were considered. In a companion study directed at markers of bone remodeling, bone alkaline phosphatase was suppressed by the administration of atrasentan (P  .0001).83 N-telopeptides, C-telopeptides, and deoxypyridinoline elevations from baseline were lower in patients receiv- The Future in Advanced Prostate Cancer ing 10 mg atrasentan compared with placebo. Subsequently, a more extensive randomized phase III study was undertaken of 10 mg atrasentan daily versus placebo in 809 patients. There was a nonsignificant trend to longer time to progression (TTP) in the group given atrasentan versus placebo (hazard ratio, 0.89; P  .16). However, there was a significant delay in PSA progression in patients given atrasentan (hazard ratio, 0.83; P  .05), delay in time to any progression in patients deemed evaluable (hazard ratio, 0.80; P  .01), and delay in time to any progression in patients with only bone metastases at study entry (hazard ratio, 0.72; P  .002). Also, statistically significant slower rises in serum alkaline phosphatase and serum PSA concentra- months in the placebo group. Interestingly, among patients with bone metastases there was a trend toward a survival advantage, with a median survival of 22.5 months in patients given atrasentan and 20 months in those observed. Based on this, accrual to any subsequent trial might have an inclusion criterion of demonstrated bone metastases, effectively excluding about 10% of a screened cohort of patients with HRPC. There is good preclinical evidence for the additive effect of atrasentan and taxanes.84–86 Study results suggest that atrasentan has biological activity in prostate cancer, particularly in bone metastases, where the bulk of disease burden is cloistered in the majority of patients. Data from a phase I trial of combination atrasentan and docetax- Studies suggest that atrasentan has biological activity in prostate cancer, particularly in bone metastases, where the bulk of disease burden is cloistered in the majority of patients. tions were seen in patients given the drug. Very importantly, however, atrasentan improved quality-of-life measurements assessed by Functional Assessment of Cancer Therapy– Prostate (FACT-P) score (P  .05), particularly in patients with bone metastases (P  .008). A recent metaanalysis of the 2 randomized trials of atrasentan in prostate cancer demonstrates a statistically significant progression-free survival benefit in favor of atrasentan over placebo on an intent-to-treat basis (P  .014). Despite the fact that these trials were not designed with survival as an endpoint, combined data from the phase II (M96-594) and phase III (M00-211) studies of atrasentan in HRPC patients demonstrated a nonsignificant trend to improved survival in the treated group over the placebo group; overall survival was 20.0 to 20.3 months in the atrasentan-treated patients and 18.9 el in HRPC patients provided evidence that biologically active doses of atrasentan can be delivered safely concurrent with usual doses of cytotoxic agents, most particularly taxanes.87 These data suggest that atrasentan has biological activity in metastatic PCa, especially in the more than 90% of patients with bone involvement. Further assessment in combination with known active agents with good response rates in soft tissue disease would be of interest to determine whether effects are likely to be additive. Docetaxel has reported soft tissue partial response rates of 20% to 28%, compared with 10% for mitoxantrone and vinca alkaloid– containing regimens.23,43,53 In SWOG 9916 the docetaxel arm produced an objective response in 17% of patients compared with 10% in the mitoxantrone arm. On this basis, docetaxel and atrasentan may act additively in the bone microenvironment whereas docetaxel produces a response in soft tissue disease (predominantly lymph nodes) that is superior to other cytotoxic treatments. The Southwest Oncology Group has proposed a 2005 study to examine the effect of atrasentan or placebo with docetaxel, integrating translational evaluation of serum markers of bone metabolism. Targeting Vasculature Microenvironment by Specific Inhibition of VEGF Isoform A: Bevacizumab Neoangiogenesis is essential for the growth and metastatic propagation of cancer. Increased microvessel formation is a feature of many cancers, including PCa, where quantification of microvessel density correlates with disease stage and outcome.88–94 Aberrant blood vessel formation is associated with anomalies in pathways involved in apoptosis, androgen receptor signaling, signal transduction, cytokine function, and cellular adhesion.95–100 Blood vessel formation is regulated by molecules involved in adhesion as well as by VEGF, nitric oxide, and cyclooxygenases. Vascular endothelial growth factor (VEGF) is crucial for the development of tumor masses exceeding a diameter of 3 to 5 mm.101 Therapeutic efforts at modulating or inhibiting this essential process are ongoing in many tumor types, most notably colorectal cancer and renal cancer, where encouraging results have recently been reported.102–105 Preclinical data with PCa cell lines demonstrate that VEGF is a potentially important factor in stimulating cell proliferation and that VEGF expression is most likely induced by autocrine and paracrine mechanisms, including cytokine-like tumor necrosis factor-.99 The dual role of VEGF in regulating angiogenesis and the net proliferative VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S35 The Future in Advanced Prostate Cancer continued status of the PCa cells may be related to Bcl-2 overexpression in the cell.98 Apoptotic dysregulation is very common in human PCa,106 and Bcl-2 overexpression is present in more than 30% of localized prostate cancers107,108 and increases with development of metastases.109,110 In experimental PCa models, VEGF expression is upregulated in prostate and PCa tissue by androgens, and castration results in an initial fall in VEGF.111–113 In a xenograft model of PCa in nude mice, VEGF monoclonal antibody therapy and paclitaxel resulted in significant inhibition of tumor growth with either agent and suggested at least additive activity for the combination.114 Recent cohort studies in humans suggest that genetic polymorphisms of VEGF, and other potentially angiopoietic genes, correlate with the risk of development of PCa.115,116 VEGF is highly expressed in most prostate cancers.89,94,117 Higher VEGF tissue expression predicted biochemical PSA level relapse following prostatectomy97 and death from PCa in a cohort of patients who underwent observation for clinically localized disease.94 In patients undergoing radical prostatectomy, elevated preoperative serum or urine VEGF levels are predictive of earlier disease progression.118,119 Serum VEGF falls after prostatectomy.120 Patients with advanced PCa have serum VEGF concentrations significantly higher than normal populations.121,122 In the CALGB trial of suramin versus placebo in patients with HRPC, elevated serum VEGF correlated with shorter time to progression in the cohort as a whole.123 Docetaxel has antiangiogenic and cytotoxic synergy with anti-VEGF antibody in a number of systems.124 Anti-VEGF monoclonal antibody therapy has been tested in combination with a variety of cytotoxics including paclitaxel and carboplatin.125 Full doses of the cytotoxic therapy were deliverable with manageable side effects. Bevacizumab and docetaxel have been used in combination in a completed phase II trial of advanced breast cancer, with a partial response rate of 54% as second-line cytotoxic therapy.126 As a single agent in hormone-refractory prostate cancer, bevacizumab produced stable disease at the best response seen in 7 of 14 patients treated and evaluated over a 10week period, with no patients having a PSA response.127 In a CALGB trial that recently closed to accrual, bevacizumab (at a dose of 15 mg/kg every 21 days) was given in concert with estramustine and docetaxel, using the same dosing schedule as for SWOG 9916, in 79 patients with HRPC.128 Patients were treated prophylactically for thrombosis with 2 mg warfarin orally daily. Results are still awaiting full analysis, but the combination regimen produced a PSA response rate (fall to less than 50% of baseline) in 77% of patients and measurable response rate of 44%, with an estimated median time to progression of 10.3 months. Median survival has not been reached but will likely exceed 11 months. The notable toxicities seen were thromboembolic phenomena (2 sponse rate, there is good rationale for proceeding with a trial of bevacizumab and docetaxel in HRPC. This is planned within the confines of the CALGB trial to start in 2005. Targeting the Protein Garbage Disposal System in the Intracellular Microenvironment: Proteasome Inhibition by Bortezomib (PS341) The ubiquitin–proteasome pathway plays an important role in regulating the cell cycle, neoplastic growth, and metastasis.129 The proteasome is a final degradative enzyme complex that has important functions in the catabolic pathway for numerous intracellular regulatory proteins. It achieves this by tagging protein and peptide degradation by adding ubiquitin moieties to the amine residue attached to the amino acid lysine in the molecular structure. PS341 (bortezomib) is a potent, specific, and reversible smallmolecule proteasome inhibitor with postulated anticancer effects through modulation of apoptotic (eg, Bcl-2 downregulation130) and cell-cycle pathways (eg, p27Kip1 and p21Cip1 upregulation129,131,132) as well as NF-B stabilization and inhibition of angio- Despite a negligible single-agent response rate, there is good rationale for proceeding with a trial of bevacizumab and docetaxel in hormone-refractory prostate cancer. deep vein thrombi, 2 nonfatal pulmonary emboli, 1 fatal mesenteric thrombosis), bleeding (2 CNS bleeds, overall 3% grade 3–4 bleeding), and bowel perforation (fatal ruptured sigmoid diverticulum). Grade 3 to 4 febrile neutropenic fever occurred in only 3% of patients. Other grade 3 to 4 toxicities included fatigue (19%), transient hypertension (4%), cardiac arrhythmia (7%), anorexia/nausea (6%), diarrhea (5%), and hyponatremia (5%). This trial was notable for its high response rate. Despite a negligible single-agent re- S36 VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY genesis.133,134 A number of key regulatory proteins are temporarily degraded during the cell cycle by the ubiquitin–proteasome pathway, and the ordered degradation of these proteins is required for the cell to progress through the cell cycle and undergo mitosis. One of the targets of the ubiquitin–proteasome–mediated degradation is the tumor suppressor p53, which acts as a negative regulator of cell growth. This tumor suppressor is required for the transcription of a number of genes involved in cell-cy- The Future in Advanced Prostate Cancer cle control and DNA synthesis and also plays an important role in apoptosis induced by cellular damage, including ionizing radiation.129 Cyclins and the cyclin-dependent kinase inhibitors p21 and p27 are another set of growth regulatory proteins that are regulated by proteasome-dependent proteolysis. Both p21 and p27 can induce cell-cycle arrest by inhibiting the cyclin D-, E-, and A-dependent kinases.135 Cell adhesion molecules (CAMs) such as E-selectin, ICAM-1, and VCAM-1 are regulated by NF-B and are involved in the development of tumor metastasis and angiogenesis in vivo.136 During metastasis, these molecules direct the adhesion and extravasation of tumor cells from the vasculature to distant tissue sites within the body. As such, tumor cell metastasis will also be limited by the downregulation of NF-B–dependent cell adhesion molecule expression. Moreover, NF-B is required in a number of cell types to maintain cell viability as an antiapoptotic controlling factor through the production of either cell survival proteins such as Bcl-2 or growth factors such as interleukin-6 (IL-6).137 Inhibiting NF-B activation by stabilizing the I B protein therefore makes cells more sensitive to environmental stress and cytotoxic agents, ultimately leading to apoptosis. Preclinical data demonstrate synergy between PS341 and a number of chemotherapeutic agents, including gemcitabine and fluoropyrimidines.138,139 Docetaxel, as noted earlier, works through a mechanism of microtubule assembly enhancement that inhibits the depolymerization of tubulin, thereby blocking cells in the M phase of the cell cycle and inhibiting cell division. Hypothetically, this should increase the apoptotic effect of PS341. Further in vitro data demonstrate synergy between PS341 and the taxanes140 as well as the ability of PS341 to reverse taxane resistance.141 In vitro data also suggest that administration of taxanes before PS341 produces more pronounced changes in the level of key molecules, such as p27, and a higher apoptotic index and cell kill than if PS341 is given first.140 These data have resulted in 2 phase I studies directed at evaluating the safety of the combination of docetaxel and PS341 in lung cancer and PCa. In the HRPC trial, dosing was scheduled so that docetaxel was administered on day 1 and 8 with PS341 administered on days 2 and 9 of a 21-day cycle. Some PSA and clinical responses are reported from this phase I trial in heavily pretreated patients, suggesting that the combination is promising. However, since this trial was conceived more has been learned about the pharmacokinetics of PS341, in particular that the drug accumulates in extravascular tissue with repeated dosing, probably due to Response Prediction in Advanced Prostate Cancer Response prediction for any cancer can be undertaken based on clinical, pathologic, tissue marker, serum marker, or imaging features either before systemic therapy is given or early enough in the course of therapy to allow an alteration in treatment that avoids unnecessary toxicity and allows the opportunity to respond to an alternative therapy. In PCa, clinical and pathological features predicting outcome at various stages of the disease have been well defined and will not be addressed here. Tumor Expression of Molecules of Putative Importance in Prostate Cancer Progression and in Response to Therapy Docetaxel targets -tubulin whereas mitoxantrone is a topoisomerase II inhibitor. Across a variety of tumor Response prediction for any cancer can be undertaken based on clinical, pathologic, tissue marker, serum marker, or imaging features either before systemic therapy is given or early enough in the course of therapy to allow an alteration in treatment that avoids unnecessary toxicity and allows the opportunity to respond to an alternative therapy. protein binding. This suggests that whereas the sequence effect of PS341 and docetaxel may be important in cell culture, it may be less so in clinical practice. Recent work from the MD Anderson Cancer Center, which has yet to be fully presented, suggests that PS341 may also be synergistic or additive in effect with mitoxantrone. These results are promising and have led to discussion of a company-sponsored international phase III trial combining bortezomib with cytotoxic therapy. A listing of some novel therapies or therapies with potential for trials in advanced prostate cancer, either as single agents or in combination is presented in Table 2. types there is evidence that tubulin mutations may predict taxane response.40,142,143 A single PCa study suggests that increased topoisomerase II expression predicts lack of PSA response in HRPC patients treated with that drug.144 The expression of -tubulin and topoisomerase I should be more fully explored in prospective trials. A further aspect of tissue-based research is the use of a biopsy soon after the start of treatment to determine the cellular effect of the agent being used. This technique has been used to validate the effect of epothilone on tubulin in tumor cells soon after treatment.145 Many patients are reluctant to undergo further biopsies for research, especially VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S37 The Future in Advanced Prostate Cancer continued Table 2 Listing of Some Novel Therapies or Therapies With Potential for Trials in Advanced Prostate Cancer Either as Single Agents or in Combination Pathway or Therapy Type Apoptosis Androgen receptor pathway Signal transduction Cell cycle Angiogenesis Cell adhesion and/or cohesion Cytotoxic Selected References Target Drug Cyclooxygenase-2 Cyclooxygenase Bcl-2, p53 Unknown PDGF, C-kit EGFr Celecoxib Exisulind Bortezomib Raloxifene Imatinib Erlotinib Gefitinib Calcitriol Celecoxib Thalidomide/Revimid Bevacizumab VEGF Trap Veglin Bortezomib Multiple ABT-627 BMS-247550 Epothilone B Epo309 CT-2103 SB-715992 GTI2040 Capecitabine ST1481 Strontium-89 Samarium SM 153 lexidronam Vitamin D receptor? others Cyclooxygenase-2 Unknown VEGF A VEGF A, C, and D CAMs? integrins Metalloproteinases Endothelin -Tubulin Kinetic spindle protein Ribonucleotide reductase Thymidylate synthetase Topoisomerase I inhibition Osteoblast diphosphates 185 186, 187 188, 189 190 191, 192 185 193 128 194 188, 189 146 82, 195, 196 145, 197 198 199, 200 201 202 67 68 Bcl-2, b-cell lymphoma-2; PDGF, platelet derived growth factor; EGFr, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; CAMs, cell adhesion molecules. when this is not part of malignancy management. However, within the California Cancer Consortium we have been successful in accruing patients into studies with protocols that include patients with tumors that can be biopsied sequentially. Unfortunately, this is not often the case in PCa, where marrow aspirates are usually not often undertaken. Serum Expression of Markers of Outcome at Baseline or with Treatment The best illustration of this is a 50% fall in serum PSA levels as a predictor of survival in SWOG 9916. The most fertile potential areas for exploring new serum markers are in 2 distinct but potentially overlapping microenvironments: the bone and blood vessels. In trials of atrasentan in HRPC there have been characteristic differences between drug and placebo for changes in serum concentrations of total and bone alkaline phosphatase.83 In addition, a recent California Cancer Consortium trial of the metalloproteinase inhibitor BMS-275291 demonstrated the potential prognostic effect of a number of other bone markers, including N-telopeptide, osteocalcin, procollagen I, and procollagen III both at baseline and with therapeutic effect or disease progression.146 Other investigators have examined the role of a variety of vasogenic factors in advanced PCa, including VEGF, IL-6, S38 VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY and IL-8, although no study has been undertaken examining the role of these factors in sequence over the first few weeks of treatment. In ongoing PCa trials of bone-targeted therapies, such as atrasentan, and vascular-targeted treatments, these markers are of potential interest with regard to whether response can be predicted by early changes in response to therapy. In the upcoming evaluation of bevacizumab and docetaxel in the CALGB trial and atrasentan and docetaxel in the SWOG trial, sequential evaluation of these markers may allow better selection of patients for future therapy. A discovery approach to serum markers can be taken using oligonucleotide profiling of tumors with The Future in Advanced Prostate Cancer Table 3 Examples of Early Response Prediction in Current Practice or in Development Modality Target Cancer Therapy Selected References Tissue expression Serum or plasma expression Change in expression Estrogen receptor Serum PSA Serum Her2 CA 125 PSA PSMA PET scanning Breast Prostate Breast Ovarian HRPC Prostate NSCLC Tamoxifen Therapy for localized or locally advanced disease Aromatase inhibitor response better than tamoxifen Platin-based chemotherapy Docetaxel or mitoxantrone-based therapy Hormone therapy Chemotherapy 203 204, 205 206 207, 208 209 210 211, 212 Change in imaging PSA, prostate-specific antigen; CA; cancer antigen; HRPC, hormone-refractory prostate cancer; PSMA, prostate-specific membrane antigen; PET, positron-emission tomography; NSCLC, non–small-cell lung cancer. subsequent molecule selection based on characteristics that increase its chance of being present in circulating blood.147,148 Appropriate assays can then be undertaken in serum or plasma for the molecules of interest with a much better yield than with a shotgun proteomic approach alone. Imaging The utilization of radionuclide imaging in advanced PCa is generally limited to bone scans with ProstaScint® (Cytogen Corporaton, Princeton, NJ) scans reserved for particular clinical scenarios. Attempts at quantification of bone involvement to predict outcome have been undertaken at select specialized institutions.149 However, widespread use of these techniques is limited by technology transfer to the community setting. The utility of fluorodeoxyglucose positron emission tomography (PET) scanning in PCa has not been established, for reasons that are not Main Points • Hormone therapy is the cornerstone of first-line therapy for advanced prostate cancer (PCa). However, the effect of androgen ablative therapy is transient, with a duration of response of 12 to 36 months in most cases. • During the 1990s, mitoxantrone-based chemotherapeutic regimens definitively demonstrated symptomatic and health-related quality-of-life improvement in patients with hormone-refractory prostate cancer (HRPC), and mitoxantrone-based regimens became the first-line standard of care for patients with HRPC, although time to symptomatic progression is about 6 months. • Early studies and comparison of phase II cohorts with a variety of regimens incorporating estramustine suggested potential increased efficacy with its addition to microtubule modulators such as vinca alkaloids and taxanes, although published studies to prove this have been inconclusive prior to the SWOG 9916 and TAX327 trials. • An understanding of the molecular action of docetaxel in cancer cells is important in selecting drugs that may potentiate its effect either by acting synergistically on microtubules or by modulating other cellular pathways not impacted by taxanes. • A variety of agents targeting pathways involved in disparate molecular processes such as angiogenesis, apoptosis, and proteosome function are now available. These agents have potential efficacy in prostate cancer when used in combination with cytotoxic agents. • With the better delineation of chemotherapy as a treatment for HRPC, the issue of whether early use of bone-targeted radionuclides combined with chemotherapy may improve outcome has become important. • Specific targeting of a therapeutic milieu commonly affected by a particular cancer is a new strategy. Data suggest that atrasentan has biological activity in metastatic PCa, especially in the more than 90% of patients with bone involvement. Further assessment in combination with known active agents with good response rates in soft tissue disease would be of interest to determine whether effects are likely to be additive. • Prostate-specific membrane antigen (PSMA) is present on virtually all primary prostate tumors, and its abundance on the cell surface increases as a tumor metastasizes. This makes PSMA an excellent target for antibody therapy, which is being explored in early-phase trials. VOL. 6 SUPPL. 10 2004 REVIEWS IN UROLOGY S39 The Future in Advanced Prostate Cancer continued entirely clear given its widespread use in lung, breast, and colorectal cancer. However, recent work using PET scanning in non–small cell lung cancer demonstrates that an early decline in standardized uptake values within 3 weeks of the start of chemotherapy predicts response and subsequent survival. Prostate-Specific Membrane Antigen Prostate-specific membrane antigen (PSMA) is a protein found on the surface of PCa cells as well as other nonprostate tumor cells. It is present on virtually all primary prostate tumors, and its abundance on the cell surface increases as a tumor metastasizes. This makes PSMA an excellent target for antibody therapy, and this is being explored in early-phase trials. However, of further interest is the use of PSMA as an imaging modality for staging PCa.150,151 In the advanced setting the ability to detect early changes (within 12 weeks of starting therapy) predictive of outcome would be of considerable utility. To this point the concept of quantitative imaging in sequence with therapy has not been explored in HRPC but deserves consideration. Examples of early response prediction in current practice or in development are presented in Table 3. tailoring therapy for the patient may  be close to fruition. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Conclusions We have reached an exciting juncture in the treatment of advanced prostate cancer with a chemotherapeutic agent that improves survival. Efforts to build on this with clinical testing of cytotoxics in combination with new molecular targeted therapies has the potential to produce further substantial gains for our patients. 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