ESMO Virtual Congress 2020: Cabazitaxel Activity in Men with Metastatic Castration Resistant Prostate Cancer with and without DNA Damage Repair Defects

(UroToday.com) Up to 30% of metastatic castration-resistant prostate cancer (mCRPC) men harbor DNA damage repair defects and may benefit from poly-ADP ribose polymerase (PARP) inhibitors after abiraterone/enzalutamide and docetaxel failure. Cabazitaxel was recently shown to improve overall survival in this population,1 though benefit by DNA damage repair status is unknown. At the prostate cancer session during the European Society of Medical Oncology – 2020 Virtual Congress (ESMO), Dr. Mihaela Aldea and colleagues reported outcomes of their assessment of cabazitaxel activity in men with mCRPC according to their DNA damage repair status.


In this retrospective multicenter study (15 centers from two European countries), mCRPC patients who received cabazitaxel were included if their DNA damage repair profile from tissue was available. Gene panels included at least BRCA1/2, ATM, CDK12 CHEK1/2, FANCA/FANCL, PALB2, RAD51. DNA damage repair positive patients could have had any deleterious germline or somatic DNA damage repair. For each DNA damage repair positive patient, DNA damage repair negative patients were randomly selected after matching for the same molecular test and institution, in a 1:1 ratio. PSA decline, radiological progression-free survival (rPFS) and overall survival were assessed.

There was a total of 190 patients included, 95 DNA damage repair positive and 95 DNA damage repair negative. DNA damage repair positive patients were younger than DNA damage repair negative (66 vs 69 years, p=0.026). The Gleason score was ≥8 in 66% and 55%, metastases were found at diagnosis in 51% and 41%, respectively. The molecular profile for DNA damage repair positive patients was as follows:

ESMO2020_CabazitaxelmCRPC_with_and_without_DDRD_1.png

At cabazitaxel start, patients had received a median of two prior life-prolonging agents, visceral metastasis in 24% and 26%, ECOG ≤1 in 78% and 80%, and a median PSA of 91 and 77 ng/ml, respectively. Among DNA damage repair positive patients, 40 (42%) had BRCA defects and 43 (45%) received a PARP inhibitor. A 50% PSA decline was achieved with cabazitaxel in 29 (32%) and 33 (36%) in DNA damage repair positive and DNA damage repair negative patients (p=0.64). Further analyses are as follows:

ESMO2020_CabazitaxelmCRPC_with_and_without_DDRD_2.png

Median rPFS was 5.33 months (95% CI 4.34-7.04) for DNA damage repair positive patients and 5.75 months (95% CI 4.67-7.27) (p=0.55) for DNA damage repair negative patients, Median overall survival (OS) was 15.4 months (95% CI 12.16-26.6) for DNA damage repair positive patients and 11.5 months (95% CI 9.76-14.4) (p=0.036) for DNA damage repair negative patients. An ECOG≥2 and visceral metastases were independently associated with shorter overall survival. The analysis of cabazitaxel outcomes according to previous or subsequent use of PARP inhibitors is as follows:

ESMO2020_CabazitaxelmCRPC_with_and_without_DDRD_3.png


Dr. Aldea concluded with the following take home messages:

  • Cabazitaxel is active in mCRPC patients, regardless of the DNA damage repair status (PFS response, rPFS)
  • The efficacy of cabazitaxel in DNA damage repair positive patients may be lower in men treated with a PARP inhibitor, but this requires validation
  • The overall survival of DNA damage repair positive patients treated with cabazitaxel was greater than that of DNA damage repair negative patients, likely due to post-cabazitaxel treatments including PARP inhibitors and carboplatin
  • The main limitation of this study is the retrospective nature of the study and the use of various molecular tests to assess the DNA damage repair status

References:
1. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med 2019 Dec 26;381(26):2506-2518.

Presented by: Mihaela Aldea, MD, PhD, Medical Oncology, Institut Gustave Roussy, University of Paris Saclay, Villejuif, France

Co-Authors: L. Lam2 , C. Llacer Perez 3 , M. Saint-Ghislain 4 , G. Gravis Mescam5 , A. Fléchon 6 , G. Roubaud 7 , P. Barthélémy 8 , F. Ricci 9 , F. Priou 10 , Z.M. Neviere 4 , M. Beaufils 11 , C. Helissey 12 , R. Ratta 13 , C. Pobel 14 , E. Castro Marcos 15 , A. Thiery-Vuillemin 16 , G. Baciarello 17 , E. Orillard 18 , K. Fizazi 1

Author Affiliations:
1 Medical Oncology, Institut Gustave Roussy, University of Paris Saclay, Villejuif, France, 2 Biostatistics and Epidemiology, Institut Gustave Roussy, University of Paris Saclay, Villejuif, France, 3 Medical Oncology Department, Hospital Universitario Virgen de la Victoria, Malaga, Spain, 4 Medical Oncology, Centre Francois Baclesse, Caen, France, 5 Medical Oncology, Institute Paoli Calmettes, Marseille, France, 6 Department of Medical Oncology, Centre Léon Bérard, Lyon, France, 7 Medical Oncology, Institute Bergonié, Bordeaux, France, 8 Department of Medical Oncology, Les Hôpitaux Universitaires de Strasbourg/ Institut de Cancérologie Strasbourg Europe, Strasbourg, France, 9 Medical Oncology, Institut Curie, Paris, France, 10 Medical Oncology, CHD Vendee - Hopital Les Oudairies, La Roche Sur Yon, France, 11 Medical Oncology, Institute Paoli Calmettes, Marseille, France, 12 Medical Oncology, Bégin Military Teaching Hospital, Saint-Mandé, France, 13 Medical Oncology, Hôpital Foch, Suresnes, France, 14 Medical Oncology, Hôpital Européen Georges-Pompidou, Paris, France, 15 Medical Oncology, Hospital Universitario Virgen de la Victoria; Instituto de Investigación Biomédica de Málaga, Málaga, Spain, 16 Medical Oncology Department, University Hospital Jean Minjoz, Besancon, France, 17 Medical Oncology, Institut Gustave Roussy, University of Paris Saclay, Villejuif, France 18 Medical Oncology Department, University Hospital Jean Minjoz, Besancon, France

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020 

Related Content:
The Clinical Implications of The Efficacy and Safety in Older Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel versus Abiraterone or Enzalutamide In The CARD Trial - William Oh and Stephen Freedland
CARD Study Demonstrates Cabazitaxel Improves Pain and Health-Related Quality of Life Analysis in Patients with mCRPC - Karim Fizazi 
Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer - Beyond the Abstract

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