Aktuelle Therapiekonzepte bei kastrationsresistenten Prostatakarzinom

 

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Zusammenfassung

Das metastasierte kastrationsresistente Prostatakarzinom (mCRPC) wird als Voranschreiten der malignen Erkrankung trotz Androgenablation definiert. Während bis vor wenigen Jahren lediglich für das Taxan Docetaxel ein lebensverlängernder Effekt nachgewiesen werden konnte, stehen heute verschiedene weitere therapeutische Optionen mit unterschiedlichen Wirkmechanismen zur Verfügung: So nutzen der CYP17-Inhibitor Abirateron und das Antiandrogen Enzalutamid den Androgenrezeptor-Signalweg, der auch bei CRPC eine entscheidende Funktion behält. Cabazitaxel – ein semisynthetische Taxanderivat – führt als bislang einzige Zweitlinienchemotherapie zu einer signifikanten Verlängerung des Gesamtüberlebens. Der Alphastrahler Radium-223 besitzt calciummimetische Eigenschaften und stellt eine sinnvolle Behandlungsoption für Patienten mit symptomatischer, ossärer Metastasierung dar. Mit Sipuleucel-T wurde 2013 erstmalig in Europa eine Immuntherapie zur Behandlung des CRPC zugelassen.

Im Rahmen dieses Übersichtsartikel werden die verschiedenen Behandlungsoptionen bei CRPC aufgezeigt, Überlegungen zu den möglichen therapeutischen Sequenzen angestellt, sowie ein Ausblick auf neue Medikamente gegeben.

Abstract

Metastasized castration-resistant prostate cancer (mCRPC) is defined by disease progression despite androgen depletion therapy (ADT). While until recently a life-prolonging effect could only be demonstrated for the taxane docetaxel, various alternative therapeutic options based on different mechanisms of action are available today: CYP17-inhibitor abiraterone and antiandrogen enzalutamide target the androgen receptor-signaling pathway, which maintains a crucial role in mCRPC. Cabazitxel – a semisynthetic taxane derivate – is the only second line chemotherapy, which results in a prolongation of overall survival to date. Alpha emitter Radium-223 has the ability to mimic calcium and target bone metastases. Thus, it is a reasonable therapeutic alternative for patients suffering from symptomatic bone metastases. In 2013, Sipuleucel-T was the first immunotherapy approved for CRPC in Europe. In this review we introduce the different therapeutic options to the reader, reflect the possible therapeutic sequences and give a perspective on novel pipeline medications.

• Literatur

• 1 Armstrong AJ, Tombal B, Sternberg CN et al. Primary, secondary, and quality-of-life endpoint results from PREVAIL. J Clin Oncol 2014; 32 abstr 5007
  PubMedSearch in Google Scholar
• 2 Bahl A, Oudard S, Tombal B et al. Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial. Ann Oncol 2012; 24: 2402-2408
  PubMedSearch in Google Scholar
• 3 Beer TM, Armstrong AJ, Rathkopf DE et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424-433
  CrossrefPubMedSearch in Google Scholar
• 4 Caffo O, Facchini G, Gasparro D et al. Activity of subsequent new drugs (NDs) in post-docetaxel (DOC) failure for metastatic castration-resistant prostate cancer (mCRPC) patients (pts). J Clin Oncol 2014; 32 (Suppl. 05) abstr 5089
  PubMedSearch in Google Scholar
• 5 Chi KN, Hotte SJ, Yu EY et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2010; 28: 4247-4254
  CrossrefPubMedSearch in Google Scholar
• 6 de Bono JS, Oudard S, Ozguroglu M et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment. Lancet 2010; 376: 1147-1154
  CrossrefPubMedSearch in Google Scholar
• 7 Fizazi K, Carducci M, Smith M et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer. Lancet 2011; 377: 813-822
  CrossrefPubMedSearch in Google Scholar
• 8 Flaig TW, Ng Y, Todd MB et al. Treatment evolution for metastatic castration-resistant prostate cancer (mCRPC) with recent introduction of new oral agents. J Clin Oncol 2014; 32 (Suppl.) abstr e16010
  PubMedSearch in Google Scholar
• 9 Harris WP, Mostaghel EA, Nelson PS et al. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol 2009; 6: 76-85
  CrossrefPubMedSearch in Google Scholar
• 10 http://www.rki.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2013/krebs_in_deutschland_2013.pdf
• 11 Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90
  CrossrefPubMedSearch in Google Scholar
• 12 Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411-422
  CrossrefPubMedSearch in Google Scholar
• 13 Kantoff PW, Schuetz TJ, Blumenstein BA 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: 1099-1105
  CrossrefPubMedSearch in Google Scholar
• 14 Kellokumpu-Lehtinen PL, Harmenberg U, Joensuu T et al. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer. Lancet Oncol 2013; 14: 117-124
  CrossrefPubMedSearch in Google Scholar
• 15 Kwon ED, Drake CG, Scher HI et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043). Lancet Oncol 2014; 15: 700-712
  CrossrefPubMedSearch in Google Scholar
• 16 Levine GN, D'Amico AV, Berger P et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk. Circulation 2010; 121: 833-840
  CrossrefPubMedSearch in Google Scholar
• 17 Logothetis CJ, Basch E, Molina A et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer. Lancet Oncol 2012; 13: 1210-1217
  CrossrefPubMedSearch in Google Scholar
• 18 Loriot Y, Bianchini D, Ileana E et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol 2013; 24: 1807-1812
  CrossrefPubMedSearch in Google Scholar
• 19 Loriot Y, Massard C, Gross-Goupil M et al. The interval from the last cycle of docetaxel-based chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer. Eur J Cancer 2010; 46: 1770-1772
  CrossrefPubMedSearch in Google Scholar
• 20 Mita AC, Denis LJ, Rowinsky EK et al. 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 tumors. Clin Cancer Res 2009; 15: 723-730
  CrossrefPubMedSearch in Google Scholar
• 21 Mohler JL, Gregory CW, Ford OH et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res 2004; 10: 440-448
  CrossrefPubMedSearch in Google Scholar
• 22 Mottet N, Bellmunt J, Bolla M et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2011; 59: 572-583
  CrossrefPubMedSearch in Google Scholar
• 23 Mulders PF, Molina A, Marberger M et al. Efficacy and safety of abiraterone acetate in an elderly patient subgroup (aged 75 and older) with metastatic castration-resistant prostate cancer after docetaxel-based chemotherapy. Eur Urol 2014; 65: 875-883
  CrossrefPubMedSearch in Google Scholar
• 24 Noonan KL, North S, Bitting RL et al. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013; 24: 1802-1807
  CrossrefPubMedSearch in Google Scholar
• 25 Parker C, Nilsson S, Heinrich D et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213-223
  CrossrefPubMedSearch in Google Scholar
• 26 Pili R, Haggman M et al. Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer. J Clin Oncol 2011; 29: 4022-4028
  CrossrefPubMedSearch in Google Scholar
• 27 Scher HI, Fizazi K, Saad F et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187-1197
  CrossrefPubMedSearch in Google Scholar
• 28 Schrader AJ, Boegemann M, Ohlmann CH et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol 2014; 61: 30-36
  PubMedSearch in Google Scholar
• 29 Small EJ, Schellhammer PF, Higano CS et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24: 3089-3094
  CrossrefPubMedSearch in Google Scholar
• 30 Smith DC, Smith MR, Sweeney C et al. Cabozantinib in patients with advanced prostate cancer. J Clin Oncol 2013; 31: 412-419
  CrossrefPubMedSearch in Google Scholar
• 31 Smith MR, Halabi S, Ryan CJ et al. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases. J Clin Oncol 2014; 32: 1143-1150
  CrossrefPubMedSearch in Google Scholar
• 32 Sternberg CN, Molina A, North S et al. Effect of abiraterone acetate on fatigue in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy. Ann Oncol 2013; 24: 1017-1025
  CrossrefPubMedSearch in Google Scholar
• 33 Sweeney C, Carducci MA, Liu G et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa). J Clin Oncol 2014; LBA2
  PubMedSearch in Google Scholar
• 34 Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502-1512
  CrossrefPubMedSearch in Google Scholar
• 35 Zhang T, Dhawan MS, Healy P et al. Clinical benefit of docetaxel or enzalutamide after progression on first-line abiraterone acetate and prednisone in men with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol 2014; 32: abstr e16031
  PubMedSearch in Google Scholar
• 36 Ryan CJ, Smith MR, de Bono JS. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138-148
  CrossrefPubMedSearch in Google Scholar
• 37 Fizazi K, Scher HI, Molina A et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer. Lancet Oncol 2012; 983: 983-992
  PubMedSearch in Google Scholar