Chemotherapy in Patients with Metastatic Prostate Cancer

Review oncology RESEARCH REVEALS...

Chemotherapy in patients with metastatic prostate cancer

D. Schrijvers

Chemotherapy has had a place in the treatment of metastatic castration-resistant prostate cancer since the nineties of the last century. First-line chemotherapy has led to an increase in overall survival from approximately 11 months for prednisone alone to 18.9 months for docetaxel-prednisone. In second-line treatment, cabazitaxel-prednisone improved overall survival from 10.9 months for prednisone alone to 15.1 months. Also, an improvement in quality of life has been obtained with these treatments. However, toxicity is increased and patient selection is of utmost importance. (Belg J Med Oncol 2011;5:229-32)

Introduction derivative of estrogen and nitrogen mustard and is Prostate cancer is a hormonal-sensitive disease and considered to have an alkylating activity. This agent patients with metastatic prostate cancer and symp- is orally and intravenously available and has a re- toms are treated with several hormonal manipula- sponse rate of 14-48% when used as single agent. tions. These consist of bilateral orchidectomy or However, it induces important toxicities such as biochemical castration with luteinising hormone cardiovascular complications and oedema (20%), releasing hormone (LHRH) agonists or antagonists. gynaecomastia (75%), breast tenderness (71%), and On disease progression, a total androgen block decreased libido (100%), nausea (16%), diarrhoea with the addition of an anti-androgen can control (13%), gastrointestinal symptoms (12%), liver func- the disease for some time, but eventually castration- tion disturbances (increased alanine aminotransfer- resistant prostate cancer (CRPC) develops.1 ase) (2-33%) and dyspnoea (12%).2 Chemotherapy has had a place in the treatment of In randomised trials in patients with metastatic metastatic CRPC (mCRPC) since the nineties of the prostate cancer, single agent estramustine resulted previous century. Before that time, prostate cancer in a similar progression-free survival as goserelin was considered to be resistant to conventional che- (hormone-sensitive prostate cancer)3 and mitomycin In advanced prostate cancer, tumours produce motherapy. C (CRPC)4 and was superior compared to diethyl- 1-4 The role of first- and second-line chemotherapy in stilbestrol.5 However, due to the toxicity profile androgen to fuel their own growth. patients with mCRPC will be reviewed. it was not considered to be the first-line standard treatment in patients with hormone-sensitive metastatic prostate cancer. So wouldn’t it be crucial to stop the production of androgens in the tumour? Estramustine in mCRPC Estramustine has been combined with alkylat- Estramustine has been used in the treatment of ing agents, topo-isomerase inhibitors, and spindle mCRPC since the eighties of the last century. It is a poisons in dual or triple combinations. In phase

References: 1. Montgomery RB et al. Maintenance of intra-tumoral androgens in metastatic prostate cancer: mechanism for castration-resistant tumor growth. Cancer Res 2008; 68 (11): p4447-4454. 2. Locke JA et al. Androgen levels Author: D. Schrijvers MD PhD, Department of Medical Oncology, Ziekenhuisnetwerk Antwerpen-Middelheim, Lindendreef 1, 2020 Antwerp, increase by intratumoral de novo steroidogenesis during progression of castration resistant rostate cancer. Cancer Res 2008; 68 (15): p6407-6415. 3. Stanbrough M et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 2006; 6 (5): p2815-2825. 4. Titus MA et al. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res 2005; 11 (13): p4653-4657. Belgium, tel: +32 (0)3 280 40 30, E-mail: [email protected].

©Janssen-Cilag NV/SA – 10 / 2011 – 5807 – vu/er Dr. Erik Present, Antwerpseweg 15-17, 2340 Beerse Antwerpseweg 15-17, Erik Present, ©Janssen-Cilag NV/SA – 10 / 2011 5807 vu/er Dr. Conflict of interest: the author has served on advisory boards of Janssen Pharmaceutical Companies and Sanofi-Aventis and participated in the Abiraterone actate trials. Key words: Castration-resistant prostate cancer, chemotherapy, first-line, second-line, estramustine, mitoxantrone, docetaxel, cabazitaxel.

Janssen-Cilag NV/SA Belgian Journal of Medical Oncology volume 5, issue 6, 2011 229 6

JAN 0360 ADV androgen-01.indd 1 10/10/11 15:57 Review oncology

Table 1. Evolution of treatment outcome of first-line chemotherapeutic treatment in patients with mCRPC. Treatment P MP DE DP DP weekly 3-weekly PSA response (%) 22 27-33 50 48 45 Median OS (Months) +11 +11-16.5 17.5 17.4 18.9 Pain relief (%) 12 22-29 NR 31 35 P: prednisone; M: mitoxantrone; D: docetaxel, E: estramustine; PSA: prostate specific antigen; OS: overall survival; NR: not reported

Table 2. Evolution of treatment outcome of second-line treatment in patients with mCRPC. Treatment P MP AP CP PSA response (%) 10.1 17.8 38 39.2 Median OS (Months) 10.9 12.7 14.8 15.1 Pain relief (%) NR 7.7 NR 9.2 P: prednisone; M: mitoxantrone; A: abiraterone acetate; C: cabazitaxel; PSA: prostate specific antigen; OS: overall survival; NR: not reported

II trials, prostate-specific antigen (PSA) and objec- in terms of survival and QoL compared to the MP tive responses varied between 17-95% and 0-73% combination. The first study compared docetaxel respectively. plus prednisone in a weekly or 3-weekly schedule In a meta-analysis of different randomised phase II to MP. In this study, the median survival increased trials, the addition of estramustine to chemothera- from 16.5 months in the MP arm to 17.8 months in peutic agents such as taxanes, vinblastin and ep- the weekly docetaxel regimen and to 19.2 months othilone resulted in a better overall survival.6 in the 3-weekly docetaxel schedule. There was a However, due to the toxicity and other treatment significant decrease for the hazard ratio (HR) of options, the use of estramustine as first-line treat- death in the 3-weekly schedule compared to MP ment for patients with mCRPC has been limited (HR:0.79, P=0.004).9 Furthermore, there was also within the medical oncology community. an improvement in QoL as defined by a 16-point improvement from baseline in the Functional Assessment of Cancer Therapy-Prostate score for First-line chemotherapy in patients both the weekly and 3-weekly docetaxel schedule with mCRPC compared to MP.10 The first indications that chemotherapy was active The second study compared 3-weekly docetaxel in patients with mCRPC came from the study by plus estramustine to MP. Again, a survival improve- Tannock et al. who compared the combination of ment was observed with an OS of 15.6 months mitoxantrone with prednisone (MP) to prednisone in the MP arm compared to 17.5 months in the alone.7 Although there was no influence on overall docetaxel arm (HR 0.80, p= 0.02).11 survival (OS), there was an improvement in global When both docetaxel-based regimens were com- quality of life (QoL) and pain control leading to pared in terms of toxicity, the docetaxel-estramus- the approval of this combination as the standard tine led to a higher cardiotoxicity.9,11 Based on the first-line treatment in this patient population in the activity and toxicity profile, the 3-weekly docetaxel- nineties. Several other chemotherapeutic agents prednisone combination is considered as standard were tested in phase II studies in first-line treat- first-line treatment in patients with mCRPC. ment but their activity has not been evaluated in randomised trials.8 In the last decennium, 2 randomised trials showed Second-line chemotherapy in mCRPC that docetaxel-based chemotherapy was superior Since many patients are progressing during or after

Belgian Journal of Medical Oncology volume 5, issue 6, 2011 230 Key messages for clinical practice

1. Docetaxel-prednisone is the standard first-line treatment in patients with metastatic castration-resistant prostate cancer.

2. Cabazitaxel-prednisone is the standard second-line chemotherapy in patients with metastatic castration-resistant prostate cancer.

3. Patient selection for a chemotherapeutic treatment is of utmost importance to avoid chemotherapy-related morbidity and toxicity.

first-line chemotherapy and still have a good gen- Future developments of chemotherapy eral condition, there is need for second-line chemo- in mCRPC therapy in mCRPC. Most patients treated with first- The combination of chemotherapy with different line docetaxel-based chemotherapy and a response new treatments such as vaccines, targeted agents will stop after 9-10 cycles or earlier if toxicity oc- and immunostimulants in the treatment of mCRPC curs. Patients with a previous response to first-line is currently under evaluation. Because of the multi- docetaxel can be challenged anew with the same tude of these agents, it will take some time to show docetaxel regimen and, in a retrospective study, a a survival benefit and surrogate markers are neces- PSA response rate of 48% and a median survival of sary to make an informed decision and speed up 16 months were observed.12 treatment development.8 Another chemotherapeutic option that can be considered after first-line docetaxel is a treatment with Conclusion MP. However, PSA response rates were lower (6-20%) The treatment outcome of mCRPC has experienced than when patients were first treated with MP fol- an important improvement in recent years with lowed by docetaxel-based chemotherapy (20-33%).13 the development of first- Table( 1) and second-line Recently, cabazitaxel-prednisone was compared treatment options (Table 2). The standard first-line to MP as second-line treatment in patients with chemotherapeutic treatment in fit patients is the mCRPC. There was an improvement in OS from docetaxel-prednisone combination. In second-line 12.7 months in the MP arm to 15.1 months in treatment, cabazitaxel-prednisone has shown a sur- the cabazitaxel arm with similar beneficial effects vival benefit over MP but other treatments such as on QoL. However, more patients were dying from abiraterone acetate or dendritic cell therapy have treatment-related complications in the cabazitaxel also shown clinical activity.8 Patient selection is of arm within 30 days after administration of the last the utmost importance to the selection of treatment. chemotherapy. This indicates the importance of patient selection and an adequate response to treatment-related complications.14 Based on this study, References cabazitaxel-prednisone can be considered to be 1. Heidenreich A, Aus G, Bolla M, Joniau S, Matveev VB, Schmid HP, et al. the standard second-line chemotherapy in patients European Association of Urology. EAU guidelines on prostate cancer. Eur with mCRPC. Urol 2008;53:68-80. In addition to this, several other chemotherapeutic 2. Goodin S, Rao KV, DiPaola RS. State-of-the-art treatment of metastatic agents have been tested in the second-line setting.8 hormone-refractory prostate cancer. Oncologist 2002;7:360-70. Satraplatin, an oral platinum derivative was evaluat- 3. Kühn MW, Weissbach L, Hinke A. Primary therapy of metastatic pros- ed in a phase III trial. It showed an improvement in tate carcinoma with depot gonadotropin-releasing hormone analogue gos- disease-free survival (DFS) but not in OS and was erelin versus estramustine phosphate. The Prostate Cancer Study Group. not further developed.15 Urology 1994;43:61-7.

Belgian Journal of Medical Oncology volume 5, issue 6, 2011 231 6 Review oncology

4. Newling DW, Fossa SD, Tunn UW, Kurth KH, de Pauw M, Sylvester R. 11. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Mitomycin C versus estramustine in the treatment of hormone resistant et al. Docetaxel and estramustine compared with mitoxantrone and prednisone metastatic prostate cancer: the final analysis of the European Organization for advanced refractory prostate cancer. N Engl J Med 2004;351:1513-20. for Research and Treatment of Cancer, genitourinary group prospective 12. Eymard JC, Oudard S, Gravis G, Ferrero JM, Theodore C, Joly F, randomized phase III study (30865). J Urol 1993;150:1840-4. et al. Docetaxel reintroduction in patients with metastatic castration-resistant 5. Benson RC Jr, Gill GM. Estramustinee phosphate compared with docetaxel-sensitive prostate cancer: a retrospective multicentre study. BJU diethylstilbestrol. A randomized, double-blind, crossover trial for stage D Int 2010;106:974-8. prostate cancer. Am J Clin Oncol 1986;9:341-51. 13. Berthold DR, Pond GR, de Wit R, Eisenberger M, Tannock IF. TAX 327 6. Fizazi K, Le Maitre A, Hudes G, Berry WR, Kelly WK, Eymard JC, et Investigators. Survival and PSA response of patients in the TAX 327 study al. Meta-analysis of estramustine in Prostate Cancer (MECaP) Trialists’ who crossed over to receive docetaxel after mitoxantrone or vice versa. Ann Collaborative Group. Addition of estramustine to chemotherapy and sur- Oncol 2008;19:1749-53. vival of patients with castration-refractory prostate cancer: a meta-analysis of 14. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, individual patient data. Lancet Oncol 2007;8:994-1000. et al. TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for 7. Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, et al. metastatic castration-resistant prostate cancer progressing after docetaxel Chemotherapy with mitoxantrone plus prednisone or prednisone alone for treatment: a randomised open-label trial. Lancet 2010;376:1147-54. symptomatic hormone-resistant prostate cancer: a Canadian randomised 15. Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero trial with palliative end points. J Clin Oncol;14:1756-64. JM, et al. Multinational, double-blind, phase III study of prednisone and 8. Schrijvers D, Van Erps P, Cortvriend J. Castration-refractory prostate either satraplatin or placebo in patients with castrate-refractory prostate cancer: New drugs in the pipeline. Adv Ther 2010;27:285-96. cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol 9. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. 2009;27:5431-8. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008;26242-5. 10. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Related articles in the BJMO TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus - Tombal B, Stainier A. Hormone therapy in the management of prostate prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12. cancer: treating the cancer without hurting the patient. BJMO 2008;2:205-11.

Belgian Journal of Medical Oncology volume 5, issue 6, 2011 232