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ESMO Virtual Congress 2020: Treatment in CARD Eligible Metastatic Castration Resistant Prostate Cancer Patients According to the Status of Germline HRR Mutations: Cabazitaxel vs Enzalutamide/Abiraterone

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(UroToday.com) The CARD trial was a randomized open-label study of cabazitaxel versus the alternative anti-androgen therapy in patients with metastatic castration resistant prostate cancer (mCRPC) who had progressed on docetaxel and also progressed on either enzalutamide or abiraterone within 12 months of therapy initiation. This study showed a statistically significant improvement in radiographic progression free survival and overall survival with cabazitaxel. The PROfound trial, a study of olaparib therapy in men with mCRPC who progressed on at least one anti-androgen therapy and whose tumors possessed certain mutations in homologous recombination repair (HRR) genes, has demonstrated superior radiographic progression free survival and overall survival2 with Olaparib therapy. The authors of this poster hypothesized that the presence of HRR alterations may impact response to cabazitaxel chemotherapy in mCRPC.

To address this question, the authors identified patients recruited to the PROREPAIR-B (NCT03074735) study that met enrollment criteria for the CARD study. PROREPAIR-B is a prospective multicentric study examining the prognostic role of germline deleterious mutations in HRR genes and the efficacy of therapies in mCRPC in the context of these HRR mutations. Of the 419 patients in PROREPAIR-B, 95 met CARD eligibility criteria. Of these patients, 14 had germline alterations in HRR genes. Relative to CARD, the cohort for this study was more likely to have ECOG PS 2 patients who received abiraterone as first line therapy. This cohort, similar to CARD, had prolonged radiographic progression free survival (6 vs 3.7 months, p = 0.03) and PSA50 response (39% versus 17%, p = 0.027) with cabazitaxel over alternative anti-androgen therapy. No overall survival difference was seen in this cohort.

When stratified by germline HRR status, HRR mutation carriers had worse outcomes with regards to overall survival (HR 1.9), radiographic progression free survival (2.4) and clinical progression-free survival (HR 2.6) relative to patients without germline HRR mutations. Using cox multivariate analysis, a significant interaction was observed between germline HRR mutations and response to cabazitaxel for radiographic and clinical progression free survival.

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The authors concluded that their data confirms the superiority of cabazitaxel therapy over alternate anti-androgen therapy, similar to CARD. In this small cohort, patients with germline HRR mutations seemed to not derive benefit from cabazitaxel relative to the alternative therapy, but overall outcomes in this cohort were rather poor. This data should be interpreted in the context of another presentation at ESMO 2020, suggesting that cabazitaxel has efficacy in patients with certain alterations detected in HRR genes by tumor tissue profiling. Additional data may be helpful in determining the optimal sequencing of cabazitaxel versus Olaparib in mCRPC patients who have progressed on docetaxel and at least one anti-androgen therapy. 

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.
2. de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2020 May 28;382(22):2091-2102.
3. Hussain, M., Mateo, J., Fizazi K., Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer N Engl J Med 2020 Sept 20

Presented by: Casilda Llacer Perez, MD, Hospitales Universitarios Virgen de la Victoria y Regional, Malaga, Spain
Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.

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