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editorials

n engl j med 363;5 nejm.org july 29, 2010 479

New Therapies for Castration-Resistant Prostate CancerDan L. Longo, M.D.

On April 29, 2010, the Food and Drug Adminis-tration (FDA) approved a new immunotherapy, sipuleucel-T, for the treatment of patients with asymptomatic or minimally symptomatic cas-tration-resistant prostate cancer. Traditionally, immune-based therapies have been categorized according to whether the agent has direct anti-tumor effects (so-called passive immunotherapy) or stimulates a host antitumor response (active immunotherapy) and whether the agent elicits a general increase in immune activation (nonspe-cific) or an immune response based on tumor recognition (specific). Sipuleucel-T is a form of active specific immunotherapy.

The sipuleucel-T intervention involves harvest-ing the patients peripheral-blood mononuclear cells (PBMCs), culturing them with a chimeric protein containing granulocytemacrophage col-ony-stimulating factor (GM-CSF) to activate an-tigen presentation together with prostatic acid phosphatase as a tumor-associated antigen, and then infusing the antigen-pulsed antigen-present-ing cells (APCs) back into the patient. Three in-travenous infusions of antigen-pulsed APCs are given once every 2 weeks; a course of therapy is completed in a month.

In this issue of the Journal, Kantoff et al.1 re-port the results of a clinical trial that helped con-vince the FDA to approve sipuleucel-T for clinical use. Men whose tumors had progressed after combined androgen blockade were randomly as-signed in a 2:1 ratio to receive sipuleucel-T im-mune activation or a placebo composed of autol-ogous PBMCs not cultured with the chimeric protein. Tumor response was assessed on the ba-sis of the level of prostate-specific antigen (PSA), computed tomography, and bone scans. The me-dian survival was 25.8 months in the sipuleucel-T group, as compared with 21.7 months in the pla-cebo group (unadjusted hazard ratio for death in the sipuleucel-T group, 0.77; P = 0.02). Study-group assignment had no significant effect on the time to tumor progression; 1 of 341 patients in the sipuleucel-T group had a partial tumor response, and 3% had a reduction of at least 50% in PSA level on two visits at least 4 weeks apart. Thus, the improvement in survival came without evi-dence of a measurable antitumor effect. Two thirds of patients receiving sipuleucel-T had anti-

body responses to the immunogen, and nearly three fourths had T-cell proliferative responses. Survival was improved for patients who had an antibody response but not for those with a T-cell response. Nearly identical results emerged from a previous smaller study with the same agent.2

Patients with metastatic cancer have myriad tumor-induced immune defects,3 including abun-dant regulatory T cells that suppress cytotoxic T-cell responses, myeloid suppressor cells, immu-nosuppressive cytokines, defective antigen pre-sentation, and T cells bearing signaling defects. Any immune therapy in a tumor-bearing host has an uphill battle that probably involves barriers that have not yet been defined. The adjuvant set-ting may provide a larger window of opportu-nity for immune-activating therapies. Thus, a 23% reduction in the risk of death in patients with metastatic disease is an important step.

The findings in this study raise a few ques-tions. First, a better control group would have in-cluded patients receiving PBMCs incubated with GM-CSF alone so that the main variable between the two study groups would be the tumor anti-gen. The current design does not allow one to conclude that the tumor antigen is a key compo-nent of the therapy. Second, the prolongation of survival without a measurable antitumor effect is surprising. It is hard to understand how the nat-ural history of a cancer can be affected without some apparent measurable change in the tumor, either evidence of tumor shrinkage or at least dis-ease stabilization reflected in a delay in tumor progression. This lack of tumor effect raises con-cern that the results could have been influenced by an unmeasured prognostic variable that was accidentally imbalanced in study-group assign-ments. As the authors point out, differences in subsequent treatments (e.g., docetaxel) do not appear to account for the survival differences, but methods for assessing such effects are imperfect. New prognostic variables such as statin use,4 the duration of the first off-treatment interval,5 circulating tumor cells (as assessed as EpCAM+ CK+CD45 objects),6 and new prognostic algo-rithms may need to be accounted for in assess-ing therapeutic effects.

Other immunization strategies are being test-ed in patients with prostate cancer. A vaccine

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Copyright 2010 Massachusetts Medical Society. All rights reserved.

Th e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 363;5 nejm.org july 29, 2010480

called GVAX that is composed of two allogeneic prostate-cancer cell lines infected with adeno-viruses that allow the cells to secrete GM-CSF was unsuccessful in phase 3 testing.7 However, another product, called PROSTVAC-VF, composed of two recombinant vaccinia-based viral vectors containing PSA and three immune costimulatory molecules, prolonged median survival by 8.5 months in a randomized phase 2 study.8 Like sipuleucel-T, PROSTVAC-VF improved survival

without improving progression-free survival. It is now being tested in phase 3 studies.

Other prospects for vaccine development in-clude peptide vaccines, DNA-based vaccines, and novel strategies such as targeting antigens to ma-jor histocompatibility complex class I pathways with chemokineantigen chimeric molecules.9

Another concern with sipuleucel-T treatment is the cost. The current cost of care for men with prostate cancer has been estimated to be about

Adrenal glandAdipose tissue Bone

Endothelin-1

Cytosol

Nucleus

Lipid membrane

Zibotentan

Abiraterone

Sipuleucel-T

Trastuzumab

Cetuximab

Denosumab

Osteoblastic stromal cell

Prostate- cancer cell

PAP peptide bound to MHC1 on

prostate-cancer cell

Osteoclast precursor

Androgen receptor

Androgenic steroids

RANKL

RANK

EGF

Heregulin

APC

T cell T cell

Gene transcription

EGFR

Src

Geldanamycin

Cell death

MDV3100

Dasatinib

Ack1

HER2

GM-CSF PAP

PAPpeptide

PAP peptide

CoACT

T

T

T

T T

T

T

T

T T

HSP90

HSP90

APC

Adrenal glandAdrenal gland

T cellT cell

GM-CSFGM-CSFGM-CSF PAP

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Prostate Cancer

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Figure 1. Promising Targets in Castration-Resistant Prostate Cancer.

Sipuleucel-T and other vaccine approaches are aimed at inducing the immune system to recognize and kill prostate-cancer cells. Castration-resistant prostate cancer retains dependence on the androgen receptor. Abiraterone inhibits the 17-hydroxy lase and C17,20-lyase activity of cytochrome P-450 CYP17A1, which blocks androgen synthesis. Experimental drug MDV3100 blocks androgen binding, nuclear transloca-tion of the receptor, and coactivator recruitment to the DNA-binding complex. Heat-shock protein 90 (HSP90) is a chaperone that assists in nuclear transport of the receptor. It can be blocked by geldanamycin and its congeners. Tumor-produced endothelin is in-volved in bone metastasis, which may be blocked by endothelin receptor antagonists (zibotentan and atrasentan). RANK ligand (RANKL) increases osteoclast activity that may be blocked by RANK ligand inhibitor denosumab. Heregulin and epidermal growth factor (EGF) activate tyrosine kinases that phosphorylate the androgen receptor, and their activity is inhibited by dasatinib. Antiangiogenic agents (suni-tinib and bevacizumab) are being evaluated, and several classes of chemotherapeutic agents hold promise, including newer taxanes (cabazitaxel), newer platinum compounds (satra platin and picoplatin), and epothilones (ixabepilone) (not shown). Trastuzumab can block HER2 signaling, and cetuximab can block EGF receptor (EGFR) signaling. Ack1 denotes activated CDC-42associated kinase, APC antigen-presenting cell, CoACT androgen receptor coactivator, GM-CSF granulocytemacrophage colony-stimulating factor HER2 human epidermal growth factor receptor 2, MHC1 major histocompatibility complex class I, PAP prostatic acid phosphatase, Src sarcoma-related tyrosine kinase, and T androgenic steroid hormone.



editorials

n engl j med 363;5 nejm.org july 29, 2010 481

$1,800 per month.10 The manufacturer has set the cost of a 1-month course of sipuleucel-T at $93,000, or $23,000 per month of survival ad-vantage. The high cost may affect use. It is also uncertain what role sipuleucel-T will ultimately play in the treatment of prostate cancer, given the other promising treatments in development.

Castration-resistant prostate cancer was for-merly known as hormone-refractory prostate can-cer. However, even after tumors progress through combined androgen blockade, they retain depen-dence on the androgen receptor.11 Many novel agents are in development, some of which have shown dramatic antitumor effects in the earliest phases of clinical testing12 (Fig. 1). Abiraterone blocks the synthesis of androgens; 51% of men who were treated with 1 g of the drug per day had a reduction in PSA levels of at least 50%, and 27% of patients had a partial tumor re-sponse.13 Experimental drug MDV3100 blocks nuclear translocation of the androgen receptor. In a phase 1 and 2 study, antitumor effects were noted at every dose of the agent, including a re-duction in PSA levels of at least 50% in 56% of patients, responses in soft-tissue lesions in 22% and in stabilized bone lesions in 56%, and a re-duction in circulating tumor-cell counts in 49%.14

The prospects for improved therapy for pros-tate cancer have never been so encouraging. The poor prognosis for men with prostate cancer will probably be substantially improved by the findings that emerge from ongoing clinical re-search.

Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immu-1. notherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411-22.

Small EJ, Schellhammer PF, Higano CS, et al. Placebo-con-2. trolled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006;24:3089-94.

de Souza AP, Bonorino C. Tumor immunosuppressive envi-3. ronment: effects on tumor-specific and nontumor antigen im-mune responses. Expert Rev Anticancer Ther 2009;9:1317-32.

Gutt R, Tonlaar N, Kunnavakkam R, et al. Statin use and risk 4. of prostate cancer recurrence in men treated with radiation therapy. J Clin Oncol 2010;28:2653-9.

Yu EY, Gulati R, Telesca D, et al. Duration of first off-treat-5. ment interval is prognostic for time to castration resistance and death in men with biochemical relapse of prostate cancer treat-ed on a prospective trial of intermittent androgen deprivation. J Clin Oncol 2010;28:2668-73.

Coumans FA, Doggen CJ, Attard G, de Bono JS, Terstappen 6. LW. All circulating EpCAM+CK+CD45- objects predict overall survival in castration-resistant prostate cancer. Ann Oncol 2010 February 10 (Epub ahead of print).

Antonarakis ES, Drake CG. Current status of immunological 7. therapies for prostate cancer. Curr Opin Urol 2010;20:241-6.

Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall sur-8. vival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic cas-tration-resistant prostate cancer. J Clin Oncol 2010;28:1099-105.

Schiavo R, Baatar D, Olkhanud P, et al. Chemokine receptor 9. targeting efficiently directs antigens to MHC class I pathways and elicits antigen-specific CD8+ T-cell responses. Blood 2006; 107:4597-605.

Alemayehu B, Buysman E, Parry D, et al. Economic burden 10. and healthcare utilization associated with castration-resistant prostate cancer in a commercial and Medicare Advantage US patient population. J Med Econ 2010;13:351-61.

Knudsen KE, Penning TM. Partners in crime: deregulation 11. of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab 2010;21:315-24.

Di Lorenzo G, Buonerba C, Autorino R, et al. Castration-12. resistant prostate cancer: current and emerging treatment strat-egies. Drugs 2010;70:983-1000.

Reid AH, Attard G, Danila DC, et al. Significant and sus-13. tained antitumor activity in post-docetaxel, castration-resistant prostate cancer with CYP17 inhibitor abiraterone acetate. J Clin Oncol 2010;28:1489-95.

Scher HI, Beer TM, Higano CS, et al. Antitumour activity of 14. MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010;375:1437-46.Copyright 2010 Massachusetts Medical Society.

In CPR, Less May Be BetterMyron L. Weisfeldt, M.D.

Fifty years have passed since Kouwenhoven, Jude, and Knickerbocker1 proposed external chest com-pression to provide circulation of blood to the brain and heart after cardiac arrest. Shortly thereafter, mouth-to-mouth rescue breathing was adopted as an essential addition to this lifesaving procedure. Since that time, there has been very little fundamental change in the method or manner of cardiopulmonary resuscitation (CPR). Decades of observational studies have shown that survival is improved if CPR is performed by

bystanders rather than being provided only when emergency medical services (EMS) staff arrives. The use of automated external defibrillators by bystanders and the use of in-hospital hypother mia in comatose patients have also been found to im-prove outcomes in patients with cardiac arrest.

Only relatively recently, however, have the fun-damentals of the initial resuscitation been inves-tigated. Focused, impressive laboratory research has resulted in a surge of interest in these fun-damentals. Most of the studies have involved pigs



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