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Aktuelle Urol 2016; 47(05): 395-401
DOI: 10.1055/s-0042-108533
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Strategien für die Erstlinientherapie des mCRPC

Strategies for First-Line Treatment of mCRPC
K. Miller
1   Urologische Klinik Charité Berlin
,
J. Gschwend
2   Urologische Klinik, Klinikum rechts der Isar, Technische Universität München
,
J.-M. Wolff
3   Urologische Klinik Golzheim
› Author Affiliations
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Publication History

Publication Date:
28 September 2016 (online)

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Zusammenfassung

In der Erstlinientherapie des nicht oder mild symptomatischen, metastasierten kastrationsresistenten Prostatakarzinoms (mCRPC) kommen derzeit vor allem Abirateronacetat und Enzalutamid zum Einsatz. Da beide Wirkstoffe in den jeweiligen Zulassungsstudien eine vergleichbare klinische Wirksamkeit gezeigt haben, spielen bei der Wahl der Therapie zusätzliche Faktoren eine Rolle. Da mCRPC-Patienten im Regelfall mehrere Therapielinien erhalten, könnten zu diesen Faktoren unterschiedliche, zum Therapieversagen führende Anpassungs- und Resistenzmechanismen Hierfür sprechen Beobachtungen aus dem klinischen Alltag und erste Studien zur Resistenz sowie zur Sequenz. Bis zur Bestätigung einer klinischen Relevanz bestimmen jedoch vor allem Nebenwirkungen der Therapie sowie Komorbiditäten des Patienten die Entscheidung, mit welchem Medikament die Erstlinientherapie des mCRPC erfolgt. Auch potentielle Wechselwirkungen mit der individuellen Komedikation und Präferenzen des Patienten sollten berücksichtigt werden. Neben der Wahl des Medikamentes ist in der Erstlinientherapie des mCRPC der Zeitpunkt ihres Beginns Gegenstand aktueller Diskussionen. So gibt es speziell für Abirateronacetat mehrere Hinweise, dass die Patienten womöglich von einem frühen Einsatz im Rahmen der Indikation profitieren. Da die Bestätigung der klinischen Bedeutung unterschiedlicher Resistenzentwicklungen und unterschiedlicher Wirksamkeit verschiedener Sequenzen beim mCRPC ein starkes Argument für Therapieentscheidungen wäre, sollte dies in prospektiven klinischen Studien überprüft werden.

Abstract

At present, abiraterone acetate and enzalutamide are the most commonly used substances in the first-line treatment of asymptomatic or mildly symptomatic metastatic castration-resistant prostate carcinoma (mCRPC). Since the relevant pivotal trials have demonstrated comparable clinical efficacy for both substances, further factors should be considered for the choice of treatment. As mCRPC patients usually receive several lines of treatment, different adaptation and resistance mechanisms leading to treatment failure could be important. This is indicated by daily routine observations and some initial clinical studies on resistance and different sequences of therapy. However, until the clinical relevance has been confirmed, it is mostly adverse events and comorbidities that are taken into account for the choice of first-line therapy. Also potential interactions with comedications and patient preferences should be considered. In the first-line treatment of mCRPC, ongoing discussions not only centre around the choice of medication for first-line mCRPC therapy, but also around the point in time they are started. For abiraterone acetate, for example, there is confirmed evidence that patients may benefit from early use within the approved indication. If the clinical importance of the different resistance mechanisms and differences in efficacy of various sequences could be confirmed, this would be a strong argument for therapy decisions and should therefore be further analysed in prospective clinical studies.

Schlüsselwörter

metastasiertes kastrationsresistentes Prostatakarzinom - Erstlinientherapie - Abirateron - Enzalutamid

Key words

metastatic castration-resistant prostate cancer - first-line treatment - abiraterone - enzalutamide
 

  • Literatur

  • 1 Ryan CJ, Smith MR, Fizazi K et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015; 16: 152-160
    CrossrefPubMedSearch in Google Scholar
  • 2 Beer TM, Armstrong AJ, Sternberg CN et al. Enzalutamide (ENZA) in men with chemotherapy-Naïve metastatic castration-resistant prostate cancer (mCRPC): Final analysis of the phase 3 PREVAIL study. J Clin Oncol 2015; 33 (suppl; abstr 5036)+Poster
    PubMedSearch in Google Scholar
  • 3 Thelen P, Gschwend J, Wolff J-M et al. Mechanisms of resistance in antihormone therapies of advanced prostate cancer. Akt Urol 2016; 47: 79-85
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Liu C, Lou W, Zhu Y et al. Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer. Cancer Res 2015; 75: 1413-1422
    CrossrefPubMedSearch in Google Scholar
  • 5 Bremmer F, Jarry H, Strauß A et al. Increased expression of CYP17A1 indicates an effective targeting of the androgen receptor axis in castration resistant prostate cancer (CRPC). Springerplus 2014; 3: 574
    CrossrefPubMedSearch in Google Scholar
  • 6 Mostaghel EA, Marck BT, Plymate SR et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 2011; 17: 5913-5925
    CrossrefPubMedSearch in Google Scholar
  • 7 Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer 2015; 15: 701-711
    CrossrefPubMedSearch in Google Scholar
  • 8 Yu Z, Chen S, Sowalsky AG et al. Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res 2014; 20: 1590-1600
    CrossrefPubMedSearch in Google Scholar
  • 9 Liu LL, Xie N, Sun S et al. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene 2014; 33: 3140-3150
    CrossrefPubMedSearch in Google Scholar
  • 10 Cheng J, Wu Y, Mohler JL et al. The transcriptomics of de novo androgen biosynthesis in prostate cancer cells following androgen reduction. Cancer Biol Ther 2010; 9: 1033-1042
    CrossrefPubMedSearch in Google Scholar
  • 11 Lorente D, Mateo J, Zafeiriou Z et al. Switching and withdrawing hormonal agents for castration-resistant prostate cancer. Nat Rev Urol 2015; 12: 37-47
    CrossrefPubMedSearch in Google Scholar
  • 12 Joseph JD, Lu N, Qian J et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov 2013; 3: 1020-1029
    CrossrefPubMedSearch in Google Scholar
  • 13 Balbas MD, Evans MJ, Hosfield DJ et al. Overcoming mutation-based resistance to antiandrogens with rational drug design. eLife 2013; 2: e00499
    PubMedSearch in Google Scholar
  • 14 Fenton MA, Shuster TD, Fertig AM et al. Functional characterization of mutant androgen receptors from androgen-independent prostate cancer. Clin Cancer Res 1997; 3: 1383-1388
    PubMedSearch in Google Scholar
  • 15 Bournakis E, Kostouros E, Soupos N et al. Abiraterone Acetate withdrawal in selected m CRPC patients. The European Cancer Congress (ECC) 2015; Abstr. 2559 (Poster Session)
    PubMedSearch in Google Scholar
  • 16 Schweizer MT, Antonarakis ES, Wang H et al. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci Transl Med 2015; 7: 269ra2
    CrossrefPubMedSearch in Google Scholar
  • 17 Azad AA, Eigl BJ, Murray RN et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol 2015; 67: 23-29
    CrossrefPubMedSearch in Google Scholar
  • 18 Brasso K, Thomsen FB, Schrader AJ et al. Enzalutamide Antitumour Activity Against Metastatic Castration-resistant Prostate Cancer Previously Treated with Docetaxel and Abiraterone: A Multicentre Analysis. Eur Urol 2015; 68: 317-324
    Search in Google Scholar
  • 19 Schmid SC, Geith A, Böker A et al. Enzalutamide after docetaxel and abiraterone therapy in metastatic castration-resistant prostate cancer. Adv Ther 2014; 31: 234-241
    Search in Google Scholar
  • 20 Badrising S, van der Noort V, van Oort IM et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer 2014; 120: 968-975
    Search in Google Scholar
  • 21 Bianchini D, Lorente D, Rodriguez-Vida A et al. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur J Cancer 2014; 50: 78-84
    Search in Google Scholar
  • 22 Schrader AJ, Boegemann M, Ohlmann CH et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol 2014; 65: 30-36
    CrossrefPubMedSearch in Google Scholar
  • 23 Cheng HH, Gulati R, Azad A et al. Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel. Prostate Cancer Prostatic Dis 2015; 18: 122-127
    CrossrefPubMedSearch in Google Scholar
  • 24 Caffo O, De Giorgi U, Fratino L et al. Clinical Outcomes of Castration-resistant Prostate Cancer Treatments Administered as Third or Fourth Line Following Failure of Docetaxel and Other Second-line Treatment: Results of an Italian Multicentre Study. Eur Urol 2015; 68: 147-153
    CrossrefPubMedSearch in Google Scholar
  • 25 Badrising SK, van der Noort V, van den Eertwegh AJ et al. Prognostic parameters for response to enzalutamide after docetaxel and abiraterone treatment in metastatic castration-resistant prostate cancer patients; a possible time relation. Prostate 2016; 76: 32-40
    CrossrefPubMedSearch in Google Scholar
  • 26 Suzman DL, Luber B, Schweizer MT et al. Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone. Prostate 2014; 74: 1278-1285
    CrossrefPubMedSearch in Google Scholar
  • 27 Vogelzang NJ, Asmar L, Tang J et al. Abiraterone acetate followed by enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) treated in the US Oncology Community Setting. J Clin Oncol 2015; 33 (15_Suppl) Abstr e16061
    PubMedSearch in Google Scholar
  • 28 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
  • 29 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
  • 30 Maughan BL, Suzman DL, Nadal RM et al. Optimal sequencing of enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2016; 34 (suppl 2S; abstr 308)
    PubMedSearch in Google Scholar
  • 31 Fachinformation Zytiga®, Stand November 2015
    PubMed
  • 32 Fachinformation Xtandi®, Stand Juni 2015
    PubMed
  • 33 Haefeli WE, Seibert-Grafe M.. Kapitel 2: Pharmakokinetische Arzneimittelinteraktionen. In: Haefeli WE, Seibert-Grafe M, Gleiter CH, (Hrsg.). Arzneimittel-Kombinationstherapie. Heidelberg: Universitätsklinikum/Sankt Augustin: Kommissionsverlag Michael Itschert, Gardez! Verlag; 2002; : -
    PubMedSearch in Google Scholar
  • 34 IMS® LRx Co-Medication MAB, Data 02/2015, IMS Health, London, United Kingdom, Data on File
    PubMed
  • 35 Scher HI, Fizazi K, Saad F et al. Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor. J Clin Oncol 2013; 31 (Suppl. 06) Abstract 6
    PubMedSearch in Google Scholar
  • 36 Loriot Y, Miller K, Sternberg CN et al. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial. Lancet Oncol 2015; 16: 509-521
    CrossrefPubMedSearch in Google Scholar
  • 37 Rathkopf DE, Smith MR, de Bono JS et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol 2014; 66: 815-825
    CrossrefPubMedSearch in Google Scholar
  • 38 Beer TM, Armstrong AJ, Rathkopf DE et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424-433 (Suppl App)
    CrossrefPubMedSearch in Google Scholar
  • 39 Miller K, Carles J, Gschwend JE et al. The phase 3 COU-AA-302 study of abiraterone acetate in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: stratified analysis based on pain, prostate-specific antigen and gleason score. EAU-Kongress 2016; 11.–15.3.2016, München: Poster 775
    PubMedSearch in Google Scholar
  • 40 Fizazi K, Flaig TW, Stöckle M et al. Does Gleason score at initial diagnosis predict efficacy of abiraterone acetate therapy in patients with metastatic castration-resistant prostate cancer? An analysis of abiraterone acetate phase III trials. Ann Oncol 2016; 27: 699-705
    CrossrefPubMedSearch in Google Scholar
  • 41 Ryan CJ, Londhe A, Molina A et al. Relationship of baseline PSA and degree of PSA decline to radiographic progression-free survival (rPFS) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302. J Clin Oncol 2013; 31 (suppl; abstr 5010)
    PubMedSearch in Google Scholar
  • 42 ClinicalTrials.gov . Sequencing Abiraterone and Enzalutamide in mCRPC. Im Internet: https://clinicaltrials.gov/ct2/show/NCT02125357 Stand: 12.5.2016
    PubMed