Castration Resistant, Taxane Naïve Metastatic Prostate Cancer: Current Clinical Approaches and Future Directions

Castration Resistant, Taxane Naïve Metastatic Prostate Cancer: Current Clinical Approaches and Future Directions Gretchen A. Gignac, Michael J. Morris*,† and Maha Hussain‡ From the Genitourinary Oncology Service, Department of Medicine, and Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center (GAG, MJM) and Department of Medicine, Joan and Sanford E. Weill College of Medicine of Cornell University (GAG, MJM), New York, New York, and Departments of Medicine and Urology, University of Michigan Comprehensive Cancer Center (MH), Ann Arbor, Michigan

Purpose: With the wide use of prostate specific antigen to detect response and disease progression resistance to androgen deprivation is being detected at an increasingly earlier stage. We focused on the current management and novel investigational strategies for the chemonaïve patient population with castration resistant metastatic disease. Materials and Methods: We reviewed standard and investigational hormonal, chemotherapeutic, biological and immune based strategies for patients with castration resistant metastatic prostate cancer who have not yet received taxane based chemotherapy. Results: Our understanding of the natural history of this group of patients is evolving. A variety of standard and experimental treatment options are available for this group of patients. Manipulating the androgen receptor signaling axis, targeting antiapoptotic pathways, using antiangiogenic strategies, harnessing the immune system and optimizing docetaxel based regimens and novel cytotoxic agents are under investigation. Conclusions: Multiple agents currently under development offer a promise of palliation and prolongation of survival above and beyond that of docetaxel. In the absence of guidance from randomized trials with regard to chemotherapy timing, and considering the modest effects of docetaxel on survival, decisions regarding choice of therapy (standard chemotherapy or experimental therapies) must be based on careful consideration of the functional status of each individual, presence of symptoms, comorbidities and overall therapeutic objectives. Key Words: prostate; prostatic neoplasms; drug therapy; immunotherapy; receptors, androgen

and their treating physicians, specifically with regard to the timing of systemic therapy. This dilemma is based on the desire to maintain quality of life while minimizing cancer related morbidity. In addition, it is clear that, while docetaxel is effective, this efficacy is modest and better therapies are definitely needed. We addressed the spectrum of therapeutic options that are available for asymptomatic, docetaxel naive patients with metastatic castration resistant prostate cancer. The options include standard second line hormones, standard docetaxel, investigational therapy alone and investigational therapy with docetaxel.

istorically patients with prostate cancer with metastatic disease that progressed through androgen deprivation had no available therapy that could prolong survival. Such patients were faced with the prospect of progressive bone pain, neurological compromise and diminished quality of life before dying of disease. The outlook for these patients improved when 2 large, randomized, prospective trials, TAX327 and Southwest Oncology Group 99-16, involving more than 1,700 patients, compared docetaxel based therapy with mitoxantrone and prednisone, and demonstrated a 20% to 25% improvement in overall survival in favor of the taxane containing arms as well as improved pain control and quality of life.1,2 The use of PSA has resulted in a significant stage migration even in the setting of castration resistant metastatic disease, such that a significant proportion of these men are asymptomatic despite a PSA increase or objective progression on imaging (see figure). Coupled with the availability of effective chemotherapy this poses a dilemma for patients

H

RISK ASSESSMENT AND THERAPEUTIC DECISION MAKING Although metastatic castration resistant prostate cancer is the terminal stage of disease for virtually all patients, the natural history is variable among patients. Thus, clinical trial design and clinical decision making for an individual must consider individual risks. Two models specifically address the risk of dying in the general castrate metastatic patient population, including 1 by the group at Memorial Sloan-Kettering Cancer Center and 1 by Cancer and Leukemia Group B.3,4 However, neither of them distinguish between patients who have not yet received docetaxel based chemotherapy and those who are refractory to it, and the 2 nomograms are based on patients with significantly ad-

Supported by National Institutes of Health Grants 5-T32CA09207 and 5K23CA102544. * Correspondence: Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 444, New York, New York 10021 (telephone: 646-422-4469; FAX: 212-9880701; e-mail: [email protected]). † Financial interest and/or other relationship with Sanofi Aventis, Cytogen and Agensys. ‡ Financial interest and/or other relationship with Merck.

0022-5347/07/1783-0030/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION

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Vol. 178, S30-S35, September 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.04.033

CASTRATION RESISTANT TAXANE NAÏVE PROSTATE CANCER Death from Other Causes

Clinical Metastases: Noncastrate

Clinically Localized Disease

Clinical Metastases: Castrate Taxane Naive

Rising PSA

Rising PSA: Castrate

Clinical Metastases: Castrate Taxane Refractory

Death as a Result of Disease

Clinical states model of prostate cancer progression. Circled indicates castration resistant, taxane naïve metastatic clinical state, which has unique clinical needs relative to taxane refractory population. Adapted from Scher HI and Heller G: Clinical states in prostate cancer: toward a dynamic model of disease progression. Urology 2000; 55: 323. Reprinted with permission from Urology.

vanced disease, which may not describe all patients in this clinical state. With a variable natural history and lack of guidance based on clinical trials with regard to the optimal timing of chemotherapy most clinicians would believe that a patient with rapidly progressive or symptomatic disease warrants treatment that has a likelihood of more rapid action and in this regard taxane based therapy would be implemented. Indeed, TAX-327 demonstrated that symptoms can be effectively palliated using docetaxel and such effects may independently predict survival.1,5 However, to our knowledge it is not known whether patients who are asymptomatic or who have lesser burdens of disease benefit similarly or more. Such patients represent a unique treatment opportunity because their clinical situation does not necessarily demand immediate application of chemotherapy. Such patients and their physicians might elect to explore investigational biological strategies or standard second line hormonal therapy. STANDARD APPROACHES Patients treated with an antiandrogen as part of initial hormone therapy would benefit from antiandrogen withdrawal at PSA progression, which can lead to a decrease in PSA in approximately 20%.6 Second line hormone therapy has been widely used for several decades. This approach is attractive because of the easy administration and the low side effect profile. A common theme among all is suppression or blockade of adrenal androgens, including agents such as antiandrogens (bicalutamide, flutamide and nilutamide), steroids (prednisone and dexamethasone) and ketoconazole. To date no prospective, randomized studies have proved an overall survival advantage to these approaches. However, 20% to 60% of patients demonstrate significant PSA decreases of 50% or more and the drugs are not necessarily cross-resistant, allowing sequential use.7–11

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AR, over expressed AR or nonligand dependent activation.12 The biology underlying these pathways is beyond the scope of this review but it has been well summarized.13,14 Clinicians who have induced PSA decreases using the antiandrogens discussed or after antiandrogen withdrawal have capitalized on the functionality of the AR axis in this clinical state. As summarized, more effective strategies to target the AR axis represent an area of intense investigational activity (Appendix 1). Ligand inhibition. Abiraterone acetate (Cougar Biotechnology, Los Angeles, California) is a specific inhibitor of the 17␣-hydroxylase/c17-20-lyase enzyme complex responsible for adrenal androgen production. It is a more specific inhibitor of androgen synthesis than ketoconazole, may have fewer adverse effects and may not require steroid hormone supplementation. This oral, once daily drug has undergone phase I single and repetitive dose testing. In 4 of 6 castrate men a single dose of 500 mg was able to suppress testosterone to target levels. It appeared that the drug effectiveness may lie in its use to maximally suppress testosterone in men on gonadotropin-releasing hormone agonists and phase II studies are now opening at several centers.15 Targeting AR production and stability. Another method of manipulating AR is not through the ligand, but through AR synthesis and stability. Hsp90 is responsible for maintaining active conformation of steroid receptors such as AR and estrogen receptor. Other client proteins include HER-2/ neu, Raf protein kinase, cyclin D1, Akt, c-Met and epidermal growth factor receptor.16 –18 The ansamycin antibiotics, such as 17-AAG (17-N-allylamino-17-demethoxygeldanamycin) (Kosan Biosciences, Hayward, California), inhibit Hsp90. Preclinical data demonstrated that 17-AAG degrades Hsp90 client proteins such as AR and phase I studies have been performed in which doses up to 157 mg/m2 were shown to be tolerable and achieve serum concentrations in excess of those that suppressed AR in animal models.16,19 Phase I studies using the ansamycins are approaching completion alone and in combination with taxane chemotherapy. Inhibiting AR expression at the transcriptional level. Gene transcription, including AR expression, can be regulated by modifying histones, the central core around which chromatin is wrapped. A new class of drugs known as HDAC inhibitors was developed to target a key enzyme in this process.20 In LNCaP prostate cancer cell lines HDAC inhibitors acetylated Hsp90, leading to AR depletion and reduced levels of Her-2, AKT and Raf-1 proteins, blocked androgen induced PSA production, inhibited cell proliferation and induced apoptosis.21 Suberoylanilide hydroxamic acid (Merck, Whitehouse Station, New Jersey) is a small molecule inhibitor of HDAC that has shown activity in prostate cancer cell lines and in in vivo xenograft models of human CWR22 prostate cancer cells.22 It can be given orally and was shown to be safe and well tolerated in doses sufficient to inhibit HDAC activity in phase I trials of patients with refractory solid tumors.23 It is currently being studied in a phase II multicenter trial of patients with advanced prostate cancer.

INVESTIGATIONAL APPROACHES Targeting the AR Axis Even patients with castration resistant disease have a functional AR axis due to increased intratumor ligand, mutated

Targeting Cell Signaling and Growth Dysregulation Progression through nonAR related growth mechanisms, such as dysregulation of growth factor receptor mediated

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CASTRATION RESISTANT TAXANE NAÏVE PROSTATE CANCER

cell signaling, provides abundant opportunities to develop targeted therapies. An example of this is the phosphatidylinositol 3-kinase pathway, which has been implicated in the progression of prostate cancer. It is regulated by the tumor suppressor gene PTEN, which is frequently lost in advanced prostate cancer.24 Ultimately mutations in this pathway promote sustained activity in mammalian target of rapamycin, causing an increase in the transcription and translation of hypoxia inducible genes, and leading to cell growth and proliferation.25 Two rapamycin analogues, everolimus (Novartis International AG, Basel, Switzerland) and temsirolimus (Wyeth, Madison, New Jersey) are currently in phase II testing.

Immune Based Strategies The exploitation of active immunity is an attractive strategy because vaccine therapy has low toxicity and patient appeal, and it may prolong the time to chemotherapy initiation. Sipuleucel-T (Provenge®) is a vaccine composed of autologous dendritic cells primed with prostatic acid phosphatase granulocyte-macrophage colony-stimulating factor fusion protein. In a phase III, randomized, placebo controlled clinical trial of 127 asymptomatic, progressive, metastatic, castration resistant patients with prostate cancer, although the primary end point of time to progression was not met (11.7 and 10.0 weeks for those receiving vaccine and placebo, respectively, p ⫽ 0.052), median survival was 25.9 months for those receiving vaccine vs 22 months for those in the placebo group at 36 months (p ⫽ 0.01).26 This demonstrates a statistically significant overall survival advantage for the treated cohort. However, because the study primary end point of time to progression was not met and the study was not originally powered to detect a survival difference, this finding must be validated in future studies.26 Although this strategy focuses on stimulating specific T-cell sensitization, another approach focuses on releasing inhibitory controls on T-cell activation by manipulating CTLA4. CTLA4 is a negative co-regulator of the T-cell pathway that appears on the surface of T cells after activation.27 It may have a role in abrogating the immune response.28 MDX-010 (Medarex, Princeton, New Jersey) is a human IgG1␬ anti-CTLA4 monoclonal antibody. Clinical development is ongoing for evaluating multiple dose strategies alone and in combination with other modalities, such as chemotherapy and vaccines.

Bone Directed Therapy Delaying the progression of metastatic disease, particularly in bone, may have significant impact on morbidity and mortality. Osteoblasts in metastatic prostate cancer have high levels of ET-1 receptor and signaling through the ET-1 pathway may contribute to increased osteoblastic activity and osseous metastasis progression.29 Atrasentan (Abbott Laboratories, Abbott Park, Illinois) is a selective ET-1 receptor antagonist. Phase II studies suggested that atrasentan could delay biochemical progression relative to placebo (155 to 71 days, p ⫽ 0.021). However, a formal, phase III study in 809 patients used a

controversial composite end point that mandated discontinuation of therapy when patients had new bone scan findings regardless of other clinical outcomes, obfuscating data interpretation.30 Atrasentan is currently being studied in a Southwest Oncology Group phase III, doubleblind, placebo controlled trial comparing docetaxel plus prednisone with and without atrasentan. Another potential target for inhibiting metastatic spread to bone is RANK (receptor activator of nuclear factor-␬B) ligand.31,32 Denosumab (Amgen, Thousand Oaks, California) is a fully human monoclonal antibody of the IgG2 subtype with high affinity for human RANK ligand. It was been shown to decrease bone turnover in postmenopausal women with low bone mineral density in phase II trials and it is now in phase III testing.33

Taxane and Nontaxane Based Chemotherapy Taxane based combination therapy. The current standard of care in the treatment of metastatic castration resistant prostate cancer is docetaxel, which has become the building block of combination therapy with multiple biological agents that are diverse in their mechanism of action. Current median survival benefits with standard docetaxel are modest, increasing survival by only 2 to 3 months, and the duration of effect is a short 6-month period. These limitations drive a search for more durable and efficacious taxane based combinations, as shown in Appendix 2. Select regimens are described.

Combinations with antiangiogenic targets. With the advent of bevacizumab, an antiVEGF humanized monoclonal antibody, inhibiting tumor growth through antiangiogenic approaches has proved to be an effective strategy for other tumor types. In prostate cancer VEGF is found in the metastatic tumors and plasma of patients with metastatic disease, and increased expression may correlate with disease progression.34,35 The combination of bevacizumab, docetaxel and estramustine demonstrated a PSA decrease rate of 65% and an objective response rate of 58%.36 Bevacizumab is currently being evaluated in a multicenter, phase III, randomized, placebo controlled, double-blind clinical trial in combination with docetaxel.

Combinations with vitamin D receptor element targets. Preclinical models demonstrated the antiproliferative activity of calcitriol and its ability to induce apoptosis and decrease angiogenesis and tumor invasion.37–39 A 250 patient, randomized, double-blind, placebo controlled, phase II trial of weekly high dose calcitriol (DN 101, Novacea, South San Francisco, California) plus weekly docetaxel vs docetaxel plus placebo showed no significant difference in the 2 treatment arms in patients achieving the primary end point, that is a PSA response of 50% or more at 6 months. However, median survival was estimated to be 24.5 months for those receiving DN 101 plus docetaxel vs 16.4 months for those treated with docetaxel alone (multivariate HR 0.67, p ⫽ 0.035).40 Currently DN-101 is in randomized, multicenter, phase III testing in combination with docetaxel vs docetaxel plus placebo.

CASTRATION RESISTANT TAXANE NAÏVE PROSTATE CANCER Nontaxane Based Chemotherapy Novel nontaxane based chemotherapeutics may offer a benefit for patients with taxane naïve, progressive, castration resistant prostate cancer. Epothilones are a new class of tubulin polymerizing agents. There are several epothilones undergoing evaluation. Showing promising activity is ixabepilone (Bristol-Myers Squibb, New York, New York) with significant objective responses and PSA decreases in 33% to 48% of patients as a single agent, and 69% in combination with estramustine in phase II clinical testing of chemotherapy naïve patients.41,42 The halichondrin B analogue, E7389 (Eisai Research Institute, Andover, Massachusetts) also targets the microtubule, inhibiting polymerization and leading to decreased tumor proliferation through the blockade of cell cycle progression at G2-M. Phase II studies of this agent are planned.43 Bcl-2 inhibition is third pathway being explored to disrupt microtubule integrity and potentially abrogate docetaxel resistance. One such agent is oblimersen sodium (Genta, Berkeley Heights, New Jersey), which is an antisense oligonucleotide directed to Bcl-2 mRNA. A phase II trial showed a median survival of 19.8 months in 28 taxane naïve, metastatic, castration resistant patients receiving the combination of oblimersen and docetaxel.44 A European Organisation for Research and Treatment of Cancer phase II, randomized trial of docetaxel plus oblimersen vs docetaxel alone has completed accrual.

CONCLUSIONS Patients in the clinical state of chemonaïve, castration resistant, metastatic prostate cancer represent a significant proportion of patients currently seen in the clinic. It remains unclear who should be treated early with docetaxel and who can be treated with deferred strategies taking advantage of noncytotoxic approaches. However, this setting clearly represents a therapy window of opportunity to evaluate novel treatments. Therapeutic decisions must consider patient symptoms and disease burden, and the risk of imminent disease related morbidities. As our knowledge of the biology of this disease is expanding, so is the experimental therapeutic armamentarium that is available for patients with castration resistant, metastatic disease, such that chemotherapy is not the only choice, but rather 1 of many possible choices. Central to defeating prostate cancer is the commitment to continued clinical/translational research in this area and offering all appropriate patients access to clinical trials.

APPENDIX 2 Select Open Clinical Trials of Taxane Combinations With Biological Therapies Therapeutic Strategy

Agent

Differentiation agent Bcl-2 inhibition Epidermal growth factor receptor Selective cyclooxygenase-2 inhibitors Clusterin inhibitor Farnesyltransferase inhibitor Anti-insulin-like growth factor-1 Endothelin-1 receptor inhibitor Mitochondrial oxidation induction HDAC inhibitor Angiogenesis/platelet-derived growth factor/VEGF

DN101 AT-101 Erlotinib Celecoxib OGX-011 SCH 66336 CP-751,871 Atrasentan Imexon 17-AAG, 17-DMAG Valatinib (PTK787) Thalidomide Bevacizumab Dimethylxanthenone acetic acid (AS1404) Sunitinib Imatinib

Abbreviations and Acronyms AR ⫽ androgen receptor CALGB ⫽ Cancer and Leukemia Group B CTLA4 ⫽ cytotoxic T lymphocyte-associated antigen 4 ET-1 ⫽ endothelin 1 HDAC ⫽ histone deacetylase Hsp90 ⫽ heat shock protein 90 PSA ⫽ prostate specific antigen RANK ⫽ receptor activator of nuclear factor-␬B VEGF ⫽ vascular endothelial growth factor REFERENCES 1.

2.

3.

4.

5.

APPENDIX 1 Select Agents Targeting AR Axis Activation Therapeutic Strategy AR antagonists Adrenal steroidogenesis inhibitors Estrogens HDAC Inhibition

Standard Treatment Options Bicalutamide Flutamide Nilutamide Ketoconazole

Investigational Options BMS-641988

6. 7.

Abiraterone

8.

Diethylstilbestrol Ansamycin antibiotics SAHA LBH598

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