**7. Summary**

There has been a significant increase in the number of treatment options available to men with CRPC. These advancements have included therapies with new taxane derivatives, drugs targeting the androgen axis, immunotherapy and bone targeting agents. Cabazitaxel, abiraterone and sipuleucel-T all show survival benefits, while Denosumab appears to reduce the risk of new bone metastases and skeletal related events in CRPC patient with bone metastases. But, with these new options comes new questions, such as, what is the optimal sequencing of these agents. As sequencing strategies become increasingly common, comparison of survival against historic data in addition to comparison of outcomes between newer agents and their associated trials will become increasing difficult to analyze. Whether results in the post docetaxel setting will be replicated in the chemonaive prostate cancer population awaits further definition. Also it is unclear if any of these agents will work better in combination with each other or with other molecular targeted therapies, although to date the latter have been disappointing in prostate cancer. What is very exciting however, is the fact that through drug development new information has become available enhancing our understanding of tumor progression in prostate cancer. Future areas of exploration include the use of newer agents in the prechemotherapy and neoadjuvant setting, using objective biologic endpoints such as pathologic response and radiographic response over short treatment intervals. Defining new endpoints may assist in circumventing the eventual difficulty in proceeding with large trials of heterogeneous patients in whom a placebo controlled trial design may not be feasible. Lastly, as the understanding of the molecular drivers of disease progression become increasingly understood, molecular markers that may serve as surrogate clinical trial endpoints may emerge, further enhancing a flourishing field.

Current Options and Future Directions in Castrate Resistant Prostate (CRPC) 269

Niraula, S., and Tannock, I.F. (2011) Broadening horizons in medical management of

Petrylak, D.P., Tangen, C.M., Hussain, M.H., Lara, P.N., Jr., Jones, J.A., Taplin, M.E., Burch,

Ryan, C.J., Smith, M.R., Fong, L., Rosenberg, J.E., Kantoff, P., Raynaud, F., Martins, V., Lee,

Saad, F., Gleason, D.M., Murray, R., Tchekmedyian, S., Venner, P., Lacombe, L., Chin, J.L.,

Saad, F., and Hotte, S.J. (2010) Guidelines for the management of castrate-resistant prostate

Seruga, B., Ocana, A., and Tannock, I.F. (2010) Drug resistance in metastatic castration-

Sharifi, N., Gulley, J.L., and Dahut, W.L. (2005) Androgen deprivation therapy for prostate

Small, E.J., Halabi, S., Dawson, N.A., Stadler, W.M., Rini, B.I., Picus, J., Gable, P., Torti, F.M.,

Small, E.J., Schellhammer, P.F., Higano, C.S., Redfern, C.H., Nemunaitis, J.J., Valone, F.H.,

Smith, M.R., Egerdie, B., Hernandez Toriz, N., Feldman, R., Tammela, T.L., Saad, F.,

Storlie, J.A., Buckner, J.C., Wiseman, G.A., Burch, P.A., Hartmann, L.C., and Richardson,

Tannock, I.F., de Wit, R., Berry, W.R., Horti, J., Pluzanska, A., Chi, K.N., Oudard, S.,

Kaplan, E., and Vogelzang, N.J. (2004) Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients:

Verjee, S.S., Jones, L.A., and Hershberg, R.M. (2006) Placebo-controlled phase iii trial of immunologic therapy with sipuleucel-t (apc8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. *J Clin Oncol*, 24,

Heracek, J., Szwedowski, M., Ke, C., Kupic, A., Leder, B.Z., and Goessl, C. (2009) Denosumab in men receiving androgen-deprivation therapy for prostate cancer. *N* 

R.L. (1995) Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma. *Cancer*, 76,

Theodore, C., James, N.D., Turesson, I., Rosenthal, M.A., and Eisenberger, M.A. (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced

P.A., Berry, D., Moinpour, C., Kohli, M., Benson, M.C., Small, E.J., Raghavan, D., and Crawford, E.D. (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. *N Engl J* 

G., Kheoh, T., Kim, J., Molina, A., and Small, E.J. (2010) Phase i clinical trial of the cyp17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. *J Clin* 

Vinholes, J.J., Goas, J.A., and Chen, B. (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate

prostate cancer. *Acta Oncol*, 50 Suppl 1, 141-7.

carcinoma. *J Natl Cancer Inst*, 94, 1458-68.

resistant prostate cancer. *Nat Rev Clin Oncol*, 8, 12-23.

A phase iii trial (calgb 9583). *J Clin Oncol*, 22, 1025-33.

cancer. *Can Urol Assoc J*, 4, 380-4.

cancer. *Jama*, 294, 238-44.

*Engl J Med*, 361, 745-55.

prostate cancer. *N Engl J Med*, 351, 1502-12.

3089-94.

96-100.

*Med*, 351, 1513-20.

*Oncol*, 28, 1481-8.

#### **8. References**


Chin, S.N., Wang, L., Moore, M., and Sridhar, S.S. (2010) A review of the patterns of

de Bono, J.S., Logothetis, C.J., Molina, A., Fizazi, K., North, S., Chu, L., Chi, K.N., Jones, R.J.,

de Bono, J.S., Oudard, S., Ozguroglu, M., Hansen, S., Machiels, J.P., Kocak, I., Gravis, G.,

Fizazi, K., Carducci, M., Smith, M., Damiao, R., Brown, J., Karsh, L., Milecki, P., Shore, N.,

Gan, P.P., and Kavallaris, M. (2008) Tubulin-targeted drug action: Functional significance

Heng, D.Y., and Chi, K.N. (2006) Prednisone monotherapy in asymptomatic hormone

Higano, C.S., Schellhammer, P.F., Small, E.J., Burch, P.A., Nemunaitis, J., Yuh, L., Provost,

Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., and Forman, D. (2010) Global cancer

Jordan, M.A., Toso, R.J., Thrower, D., and Wilson, L. (1993) Mechanism of mitotic block and

Kantoff, P.W., Higano, C.S., Shore, N.D., Berger, E.R., Small, E.J., Penson, D.F., Redfern,

Mita, A.C., Denis, L.J., Rowinsky, E.K., Debono, J.S., Goetz, A.D., Ochoa, L., Forouzesh, B.,

docetaxel use for hormone-resistant prostate cancer at the princess margaret

Goodman, O.B., Jr., Saad, F., Staffurth, J.N., Mainwaring, P., Harland, S., Flaig, T.W., Hutson, T.E., Cheng, T., Patterson, H., Hainsworth, J.D., Ryan, C.J., Sternberg, C.N., Ellard, S.L., Flechon, A., Saleh, M., Scholz, M., Efstathiou, E., Zivi, A., Bianchini, D., Loriot, Y., Chieffo, N., Kheoh, T., Haqq, C.M., and Scher, H.I. (2011) Abiraterone and increased survival in metastatic prostate cancer. *N Engl J Med*, 364,

Bodrogi, I., Mackenzie, M.J., Shen, L., Roessner, M., Gupta, S., and Sartor, A.O. (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castrationresistant prostate cancer progressing after docetaxel treatment: A randomised

Rader, M., Wang, H., Jiang, Q., Tadros, S., Dansey, R., and Goessl, C. (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study. *Lancet*, 377,

of class ii and class ivb beta-tubulin in vinca alkaloid sensitivity. *Cancer Res*, 68,

N., and Frohlich, M.W. (2009) Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-

inhibition of cell proliferation by taxol at low concentrations. *Proc Natl Acad Sci U S* 

C.H., Ferrari, A.C., Dreicer, R., Sims, R.B., Xu, Y., Frohlich, M.W., and Schellhammer, P.F. (2010) Sipuleucel-t immunotherapy for castration-resistant

Beeram, M., Patnaik, A., Molpus, K., Semiond, D., Besenval, M., and Tolcher, A.W. (2009) Phase i and pharmacokinetic study of xrp6258 (rpr 116258a), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid

**8. References** 

1995-2005.

813-22.

9817-24.

*A*, 90, 9552-6.

hospital. *Curr Oncol*, 17, 24-9.

open-label trial. *Lancet*, 376, 1147-54.

refractory prostate cancer. *Can J Urol*, 13, 3335-9.

t in advanced prostate cancer. *Cancer*, 115, 3670-9.

statistics. *CA Cancer J Clin*, 61, 69-90.

prostate cancer. *N Engl J Med*, 363, 411-22.

tumors. *Clin Cancer Res*, 15, 723-30.


**13** 

*USA*

**The Role of PDE-5 Inhibitors in Prostate Cancer** 

Prostate cancer currently stands as the most frequently diagnosed solid tumor in men, and remains one of the leading causes of cancer mortality in men in the Western world, accounting for an estimated 32,050 deaths in the United States in 2010 (Jemal *et al.*, 2010). With the wellknown use of serum prostate-specific antigen (PSA) as a screening tool, men are being diagnosed with earlier stage disease at younger ages. However, a significant number of men continue to be diagnosed with high-risk localized prostate cancer. Radical prostatectomy, radiotherapy, cryotherapy, high-intensity focused ultrasound, radiation therapy, and androgen deprivation as well as androgen receptor blockade have been the mainstays of

As prostate cancer cell growth is androgen dependent, its deprivation is an important therapeutic strategy. However, long-term androgen-ablation results in androgenindependent cancer cell growth in metastatic patients, leading to hormone refractory prostate cancer (HRPC) (Sonpavde *et al.*, 2006). Prostate cancer tends to invade the pelvic lymph nodes and spread to distant organs, mainly via the blood stream, showing a strong predilection for bones (Koutsilieris, 1993;Sourla *et al.*, 1996). This disease frequently metastasizes to bone and almost invariably progresses from an androgen-sensitive to an androgen-independent status, greatly limiting therapeutic options and significantly reducing life expectancy in patients. Skeletal metastases occur in more than 80% of cases of advanced-stage prostate cancer and they confer a high level of morbidity. Metastasis of prostate cancer, like that of other solid tumors, involves multiple steps, including angiogenesis, local migration, invasion, intravasation, circulation and extravasation of tumor cells and then angiogenesis and colonization in the new site. Treatment-naive metastatic prostate cancer is largely sensitive to androgen-deprivation therapy (ADT), but the effectiveness of ADT is temporary, and tumors in the majority of patients eventually relapse and evolve into castration-resistant prostate cancer (CRPC), from which most patients die (Eisenberger and Walsh, 1999). These tumors eventually become incurable or resistant to antihormonal therapy. Indeed, there is an association between ADT and high risk of cardiovascular disease and mortality, and men with a history of recent or active cardiac disease are particularly at risk (Saigal *et al.*, 2007). In men with a history of coronary artery disease, chronic heart failure, or myocardial infarction, ADT was associated with an increased risk of mortality (Nguyen *et al.*, 2011). Continuous ADT use for at least 6 months in older men is also associated with an increased risk of diabetes and fragility fracture (Alibhai *et al.*, 2009). For this reason, new agents and therapeutic modalities are needed,

treatmentfor cancer patients with localized and androgen-dependent prostate cancer.

**1. Introduction** 

*Division of Cardiology, Pauley Heart Center, Department of Internal Medicine* 

Anindita Das, Fadi N. Salloum and Rakesh C. Kukreja

*Virginia Commonwealth University, Richmond* 

Tannock, I.F., Osoba, D., Stockler, M.R., Ernst, D.S., Neville, A.J., Moore, M.J., Armitage, G.R., Wilson, J.J., Venner, P.M., Coppin, C.M., and Murphy, K.C. (1996) 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*, 14, 1756-64.
