ASCO 2018: Survival Outcomes from a Cumulative Analysis from Worldwide Observational Studies on Sequential use of New Agents in mCRPC

Chicago, IL ( In the past decade, it has been demonstrated that cabazitaxel1, abiraterone acetate2, and enzalutamide3 improved overall survival (OS) among men with CRPC who progress after docetaxel chemotherapy. As such, this has increased the number of available second-line therapeutic options, but at the same time, the availability of these new agents has led to the possibility of using them sequentially.  Several small retrospective reports described their activity when sequentially used as second- and third-line after docetaxel failure, which suggests that cabazitaxel-based sequences led to a better OS than sequences based on new hormonal therapies only. 

At the prostate cancer session at ASCO 2018, Dr. Caffo and colleagues presented results of the CASTOR study assessing cumulative survival outcomes according to the different sequence strategies with new agents after first-line docetaxel progression among men with mCRPC. This study was designed as a pooled analysis of individual data from studies published or presented at main international meetings prior to November 30, 2015 on mCRPC patients sequentially treated with first-line docetaxel followed by at least two agents. Among 24 reports identified, all corresponding authors of the published papers meeting study criteria were prompted to provide individual data of the patients evaluated in their work. When possible, updated data were collected. The authors calculated OS from the second-line start by sequence strategy, including three different types of new agent sequences after docetaxel:  
  • One new hormone agent (abiraterone or enzalutamide) followed by cabazitaxel: NHA→CABA  
  • Cabazitaxel followed by abiraterone or enzalutamide: CABA→NHA 
  • One new hormonal agent followed by the other new hormonal agent: NHA→NHA 
For this study, data was collected on 1,099 patients, including 597 patients receiving abiraterone in the second line, 104 receiving enzalutamide, and 398 receiving cabazitaxel: 
Screen Shot 2018 06 02 at 10.22.23 PM

Cumulative OS did not differ significantly among the three different strategies (median cumulative OS ranging 21.1-22.1 month, p = 0.957). Patients treated with new hormonal second-line therapy had a statistically significant longer PFS compared to patients receiving cabazitaxel in the second line (median 6.1, 95%CI 5.7-6.5 vs 5.6, 95%CI 4.9-6.3 months, p < 0.0001). However, in the third-line, cabazitaxel led to a statistically significant prolongation of OS (from the third-line start) compared to new hormonal agents: median OS 12.2 (95%CI 11.2-13.2) vs 9.1 (95%CI 7.3-11.0) months (p = 0.039). In the case of a new hormonal agent-based second-line patients with a longer PFS (> 6 months) were more frequently treated with a new hormonal agent in third-line. In this setting, the sequence NHA→ NHA led to a cumulative OS worse than NHA → CABA: median OS 24.8 (95%CI 21.4-28.3) vs 30.0 (95%CI 27.5-32.5) months (p = 0.022). 

Given that nearly 10 years have passed since the first reporting of clinical trials assessing therapy after progression on docetaxel for men with mCRPC, studies assessing the importance of treatment sequence are important. Recognizing the limits of a retrospective analysis, this study suggests a potential benefit of cabazitaxel in the third-line setting after a new hormonal agent. As per the authors, additional analyses are ongoing to hopefully reduce the biases secondary to the retrospective nature of the study.  

Presented By: Orazio Caffo, Santa Chiara Hospital, Trento, Italy 
Co-Authors: Michel Wissing, Diletta Bianchini, Andre M. Bergman, Frederik Birkebæk Thomsen, Sebastian Schmid, Evan Y. Yu, Evangelos Bournakis, Avishay Sella, Umberto Basso, Ugo De Giorgi, Marcello Tucci, Hans Gelderblom, Luca Galli, Isabella Sperduti, Stephane Oudard, CASTOR study's investigators; Leiden University Medical Centre, Leiden, Netherlands; The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen, Denmark; Department of Urology, Klinikum rechts der Isar, TU München, Munich, Germany; Seattle Cancer Care Alliance, Seattle, WA; Hellenic Group of Young Oncologists (HeGYO), Hellenic Society of Medical Oncology (HeSMO), Athens, Greece; Assaf Harofeh Medical Center, Tzrifin, Israel; Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy; San Luigi Hospital, Orbassano, Italy; Leiden University Medical Center, Leiden, Netherlands; Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy; Bio-Statistics Unit, Regina Elena National Cancer Institute, Rome, Italy; Hopital Europeen Georges Pompidou, Paris, France 

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md  at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

1. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomized open-label trial. Lancet 2010;376(9747):1147-1154. 
2. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005. 
3. 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.

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