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PROSTATE CANCER: THERAPIES AND BONE DISEASE
Audio-Digest Urology
Volume 36, Issue 05
March 7, 2013

Vaccine Therapy and Immunotherapy – Neal Shore, MD
Treatment of Castration-Resistant Disease – Daniel Petrylak, MD
Targeted Therapy for Bone Disease – Matthew R. Smith, MD, PhD

  
From International Prostate Cancer Update, Sponsored By Medical Education Resources, Inc., Grand Rounds In Urology, And Cjp Medical Communications
Digital Media $24.99
Audio CD $27.99
 


The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

Urology Program Info  Accreditation InfoCultural & Linguistic Competency Resources

Educational Objectives

The goal of this program is to improve diagnosis and management of prostate cancer. After hearing and assimilating this program, the clinician will be better able to:

1. Describe the advantages of immunotherapy over other treatments for advanced prostate cancer (PC).

2. Summarize approved treatments and therapies currently in development for treatment of advanced PC.

3. Design a treatment plan for a patient with castration-resistant PC.

4. Manage side effects in a patient undergoing immune-, chemo-, or radiotherapy for advanced PC.

5. Recommend therapy for a patient with PC at risk for bone metastases.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Petrylak is on the advisory board for Bellicum Pharmaceuticals and Egenix; a consultant for Amgen, Bayer AG, Dendreon Corporation, Ferring Pharmaceuticals, GlaxoSmithKline, Johnson & Johnson, Millennium Pharmaceuticals (subsidiary of Takeda Pharmaceuticals), Novartis AG, and Pfizer; and receives grant support from AstraZeneca, Boehringer Ingelheim GmbH, Celgene, Dendreon Corporation, GlaxoSmithKline, Pfizer, and sanofi-aventis US. Drs. Shore and Smith and the planning committee reported nothing to disclose. In his lecture, Dr. Smith presents information related to the off-label or investigational use of a therapy, product, or device.

Prostate Cancer: Therapies and Bone Disease

From International Prostate Cancer Update, sponsored by Medical Education Resources, Inc., Grand Rounds in Urology, and CJP Medical Communications

Vaccine Therapy and Immunotherapy

Neal Shore, MD, Medical Director, Carolina Urologic Research Center, Myrtle Beach, SC

Rationale: immunotherapy theoretically offers more tolerable therapy than cytotoxics, with long-term memory and ability to target and enter multiple tissues through reticuloendothelial system; malignancies associated with development of tolerance to foreign antigens

Allogeneic therapies: include gene-transduced tumor vaccine (GVAX); vector-based therapies (eg, PROSTVAC) in phase III development; sipuleucel-T approved in 2010; antibody blockade therapy (ipilimumab); antibody-drug conjugates

Immune response: antigen-presenting cell (APC) stimulates T cells that attack foreign antigens; major histocompatibility complex class I most important; class II also involved; key cells include CD8+ (natural killer cells or cytotoxic T lymphocytes) and CD4+ (helper cells)

Immunotherapy: involves recognizing antigen and promoting response to activate T cells and ultimately B cells; some immunotherapies upregulate IgG and IgM; rise in IgG correlates with memory; immunotherapy offers many targets and ability to treat patients resistant to chemotherapy

Challenges: circulating cytokines such as interleukin (IL)-6 and transforming growth factor (TGF)-β may impede antigen presentation to dendritic cells; ultimate goal of immunotherapy to break tolerance to tumor antigens, overcoming immunosuppressive regulatory T cells; requirements for immunotherapies include ability to scale for production, accessible mode of administration, safety, and efficacy

Allogeneic vaccine (GVAX): uses irradiated LNCaP and PC-3 tumor antigens and granulocyte-macrophage colony-stimulating factor (GM-CSF) (immunomodulator); promising early trials using subcutaneous (SQ) administration showed upregulation of dendritic cells and improved T cell activation; GM-CSF facilitates antigen presentation; Vaccine Immunotherapy with Allogeneic Prostate Cancer Cell Lines (VITAL-1) trial conducted in asymptomatic patients not previously treated with chemotherapy; VITAL-2 included symptomatic patients; data and safety monitoring committee stopped VITAL-1 due to futility; subgroup analyses showed trend toward improved survival; unclear whether further development of GVAX expected

Vector-based vaccine (ProstVac): given SQ; combines 3 costimulatory molecules and tumor-associated antigen with DNA plasmid; attenuated viral vaccine uses priming with vaccinia followed by boost with fowlpox; causes APCs to upregulate T cells which attack tumor antigen; phase II study using empty vector as placebo showed no difference in progression-free survival (PFS); vaccine had little effect on prostate-specific antigen (PSA), since mechanism of action involves T-cell activation rather than cytotoxicity; however, vaccine demonstrated >8 mo survival benefit; possible baseline imbalance between arms based on Halabi nomogram; ongoing phase III 3-arm trial compares GM-CSF plus ProstVac, GM-CSF plus placebo, and placebo

Antibody blockade therapy (ipilimumab): cytotoxic T-lymphocyte antigen 4 (CTLA-4) downregulates T cells; administration of antibodies to CTLA-4 causes rejection of tumors in preclinical model; ipilimumab blocks engagement of APC by CTLA-4 receptor, allowing activation of T cells; autoimmune side effects include skin reactions, colitis, diarrhea, and hypothalamic-adrenocortical endocrinopathy; vaccine approved for treatment of advanced melanoma; phase III trials ongoing in prostate cancer (PC) comparing radiotherapy (RT) plus placebo vs RT plus ipilimumab

Antibody-drug conjugates: humanized antibody to prostate-specific membrane antigen (PSMA) conjugated with antitubulin agent monomethyl auristatin E (MMAE); conjugate internalized into cells of prostate; in phase I trials

Sipuleucel-T (Provenge): prostatic acid phosphatase linked to GM-CSF, exposed to APC, and taken up as epitope on its surface; reinfused cells potentiate CD8+ and CD4+ cells, halting progression of cancer; may slow progression of disease without radiographic regression or change in PSA; mode of administration — patients undergo 3-hr leukapheresis to remove peripheral mononuclear cells; cells cultured with fusion protein over 2 to 3 days, then reinfused over 1 hr after premedication with acetaminophen (FeverAll, Tylenol) and diphenhydramine (Benadryl, Simply Sleep); treatment administered for 3 cycles, 3 wk apart; 4.1-mo survival benefit demonstrated in phase III trial; fever, headache, and myalgia observed

Challenges: no good biomarker for efficacy of immunotherapies, since progression of disease and PSA not altered; Response Evaluation Criteria in Solid Tumors (RECIST) inadequate for evaluating partial response, even for chemotherapeutic agents; flare phenomenon observed with abiraterone (Zytiga) can cause transient increase in size of lesion or level of PSA; proposed mechanisms of immunotherapies include altering phenotype of tumor cell, activating T cell response, decreasing T regulatory cells and immunosuppression, or combination of all mechanisms

Treatment with sipuleucel-T: per National Comprehensive Cancer Network guidelines, discuss sipuleucel-T with all patients with asymptomatic metastatic castration-resistant prostate cancer (MCRPC); important to treat early while immune system still robust, before patient develops diminished performance status and myelosuppression; use of corticosteroids and other immunosuppressants before and after therapy with sipuleucel-T controversial; unclear how to combine or use sequentially with other second-line hormonal manipulations

Treatment of Castration-Resistant Disease

Daniel Petrylak, MD, Leader, Prostate Medical Oncology at the Yale Cancer Center, New Haven, CT

History: 10 yr ago, no drug improved survival, and mitoxantrone (MXT) had demonstrated only palliative benefit; several drugs now approved, but many patients progress in 18 to 24 mo, raising question of how to sequence new agents

Definition: patients with castration-resistant prostate cancer (CRPC) have testosterone levels <50 ng/dL; some use <25 ng/dL as cutoff; criteria from Prostate Cancer Working Group include 3 consecutive PSA increases 1 wk apart, or 2 levels above nadir and 2 ng/mL above baseline; CRPC more difficult to define now that agents such as MDV3100 and abiraterone can cause tumor regression; no molecular marker available to indicate need to proceed to cytotoxic therapy; to diagnose, perform antiandrogen withdrawal; withdrawal syndrome possibly due to chaperoning of androgen receptor across nuclear membrane; changes on computed tomography or bone scan may aid detection of CRPC

Tubulin inhibitors: include drugs that stabilize or destabilize tubulin; docetaxel prevents tubulin from polymerizing, arresting cell division; androgen receptor does not translocate to nucleus with exposure to docetaxel, but translocation observed in patients resistant to docetaxel

Docetaxel: in study comparing docetaxel plus prednisone weekly, docetaxel plus prednisone every 3 wk, and MXT plus prednisone, superior survival observed with docetaxel every 3 wk, with median survival 19 mo and 17% of patients surviving 3 yr; 32% of patients developed grade 3 or 4 neutropenia, and 26% had serious adverse events (SAEs); rate of SAEs higher in docetaxel arm than MXT arm; in another study, survival similar in patients treated with combined docetaxel plus estramustine and those treated with MXT plus prednisone; significant crossover in both trials; deep venous thromboses (DVT) associated with estramustine in second trial; newer studies use combinations of docetaxel with hormonal agents such as TAK-700 and abiraterone

Cabazitaxel: mechanism — novel synthetic taxane; docetaxel induces p-glycoprotein or multidrug resistance; cabazitaxel works by different mechanism and therefore effective against docetaxel-resistant cell lines; drug given every 3 wk; approval study — comparing cabazitaxel with MXT in patients on prednisone who had previously received chemotherapy found 3-mo survival benefit and superior progression-free survival (PFS) in cabazitaxel arm; toxicity — febrile neutropenia and diarrhea manageable; begin prophylactic growth factors with first dose; in patients heavily pretreated with chemotherapy or radiation therapy, begin cabazitaxel at three-fourths usual dose, increasing to full dose if tolerated; prescribe loperamide for diarrhea; toxic deaths in study seen in patients with febrile neutropenia not treated with growth factors during first cycle

Combination trials: combinations of docetaxel with other agents disappointing, including GVAX, vitamin D analogue, and bevacizumab

Lenalidomide: PSA responses documented in phase I studies in patients previously treated with docetaxel, but DVT and neutropenia observed; later trial stopped due to futility, and full dosage precluded in some patients due to neutropenia; drug works by antiangiogenesis mechanism different from that of bevacizumab or vascular endothelial growth factor receptor trap proteins

Dasatinib: Schmidt-Ruppin A2 (Src) oncogene regulates activation of osteoclasts, leading to osteolysis; dasatinib approved for chronic myeloid leukemia; drug upregulates Src, inhibiting osteoclastic activity; single-agent activity with or without bisphosphonates demonstrated in CRPC, based on declines in PSA, objective soft tissue responses, and declines in urinary N-terminal telopeptide (NTX) and alkaline phosphatase (ALP); phase III trial of dasatinib in combination with docetaxel and prednisone ongoing

Clusterin: protein increases after androgen ablation in tumor cells in patients with CRPC; expression correlated with higher Gleason score and resistance to castration, chemotherapy, and radiation therapy; antisense compounds bind to RNA and prevent gene expression; in randomized phase II study, combination of docetaxel and OXG-011 (Custirsen; antisense to clusterin) showed improvement in OS but not PFS

Radiopharmaceuticals: strontium and samarium approved but underused due to incorrect impression that combining these with other treatments inadvisable; future combinations with abiraterone and MDV3100 likely; strontium-89 and samarium — strontium improves time to pain progression and time to new RT; as β–emitters, both strontium and samarium irradiate broader area; both drugs approved based on relief of pain and trend toward improved OS; pain control in skeletal metastases improved with samarium compared with placebo; radium-223 (Alpharadin)α-emitter that delivers higher level of energy to smaller area; shelf life of compound 28 days, longer than that of strontium and samarium; half-life 11 days; delivers local radiation to skeletal target, but smaller area of penetration spares marrow; high retention of daughter isotopes in bone matrix; causes cell death regardless of phase of cell cycle, and theoretically may kill stem cells at higher rate than cycling cells; radium-223 given intravenously for 4 consecutive weeks of 6-wk cycle; study — comparing radium-223 plus standard of care with standard of care alone; stratified patients with CRPC based on previous treatment with docetaxel and bisphosphonate and on level of ALP; primary end point OS; secondary end points time to first skeletal-related event (SRE), time to progression, and time to ALP progression; study stopped early due to efficacy; 31% reduction in risk for death; hematologic toxicities similar in both study arms; bone-targeting agents may improve survival, palliate patients with skeletal metastases, and prolong median time to first SRE, without myelotoxicity observed with other agents

Targeted Therapy for Bone Disease

Matthew R. Smith, MD, PhD, Director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center, Boston, MA

Therapeutic goals: include treatment of disease-related complications in men with CRPC (50,000 men in United States), treatment of therapy-related fractures due to androgen deprivation therapy (ADT) and aging (800,000 men on ADT, most without detectable bone metastases), and prevention of metastases

Osteoblastic metastases: produce pain, fractures, spinal cord compression, and myelophthisis or ineffective hematopoiesis; bone metastases responsible for most morbidity in advanced PC; in vicious cycle of osteoblastic metastases, growth factors in bone support growth of PC cells in bone, and tumor cells secrete factors affecting bone microenvironment; osteoblast activity as measured by bone ALP (BAP) and osteoclastic activity as measured by NTX both markedly elevated in men with MCRPC; men with high NTX at greater risk for SRE and all-cause mortality, suggesting osteoclast-targeted therapy reasonable although PC osteoblastic disease

Zoledronic acid: (Reclast, Zometa) approved for prevention of SRE in men with CRPC and bone metastases; inhibits osteoclasts and decreases urinary NTX; SRE includes events affecting quality of life such as radiation to bone, pathologic fractures, spinal cord compression, bone surgery, and change in antineoplastic therapy to treat bone pain; 20% of men have elevated NTX levels despite treatment

Denosumab: receptor activator of nuclear factor κ-B ligand (RANKL) mediates crosstalk between osteoblasts and osteoclasts; denosumab (IgG2 human monoclonal antibody) binds and inactivates RANKL and has long half-life; approved to prevent fractures and bone loss during ADT and SRE in men with CRPC and bone metastases; significantly reduces incidences of first SRE and of cumulative SRE, compared with zoledronic acid; role of bone-targeted therapy in castration-sensitive disease unknown

Preventing bone metastases: zoledronic acid, atrasentan, and zibotentan do not prevent metastases in men with CRPC; in men with CRPC, higher baseline PSA and shorter PSA doubling time associated with bone metastases and death; study — compared with placebo, denosumab significantly increased bone metastasis-free survival, time to first bone metastasis, and time to first symptomatic bone metastasis in high-risk CRPC

Treatment-related fractures: morbidities in older men include pain, kyphoscoliosis, loss of height, and respiratory problems; age-related increase in fracture rates occurs later in men than women; main causes of fractures in men alcohol abuse, long-term glucocorticoid therapy, and hypogonadism; gonadotropin-releasing hormone agonists now most common cause of severe hypogonadism in men in United States; every 3 to 5 yr of ADT approximately doubles risk for fracture; other mechanisms contributing to increased risk for fracture during ADT include muscle loss and frailty, which increase risk for falls, especially in oldest patients

Prevention: during ADT, pamidronate, zoledronic acid, and weekly oral alendronate significantly increase bone mineral density (BMD), but rates of fracture not studied; denosumab now approved to prevent fractures during ADT based on large trial conducted in men at high risk for fracture because of age or T score <-1; denosumab significantly increased BMD and reduced new vertebral fractures at 1, 2, and 3 yr

Acknowledgements

Drs. Shore, Petrylak, and Smith spoke at the 22nd Annual Prostate Cancer Update, sponsored by Medical Education Resources, Inc., Grand Rounds in Urology, CJP Medical Communications, and Carden Jennings Publishing Company, Inc., held January 25-28, 2012, in Vail, CO. Information about the International Prostate Cancer Update can be found by going to urology.grandroundseducation.com and clicking on IPCU Meetings, or by visiting our website, audio-digest.org, and clicking the “upcoming meetings” tab at the bottom of the page. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this issue.

Suggested Reading

Araujo JC et al: Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study. Cancer. 2012;118(1):63-71; Brown JE et al: Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst. 2005;97(1):59-69; Bruland ØS et al: High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res. 2006;12(20 Pt 2):6250s-6257s; de Bono JS et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-54; Fizazi K et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813-22; Galsky MD and Vogelzang NJ: Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol. 2010;21(11):2135-44; Kantoff PW et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-22; Kantoff PW et al: Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28(7):1099-105; Mittan D et al: Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab. 2002;87(8):3656-61; Parker CC et al: A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (ra 223) in patients with bone metastases and castration-resistant prostate cancer. Eur Urol. 2013;63(2):189-97; Petrylak DP et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513-20; Sheikh NA et al: Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer Immunol Immunother. 2013;62(1):137-47; Smith MR et al: Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23(13):2918-25; Smith MR et al: Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379(9810):39-46; Smith MR et al: Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745-55; Tannock IF et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996;14(6):1756-64.


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