ASCO GU 2020: Luminal B Subtype as a Predictive Biomarker of Docetaxel Benefit for Newly Diagnosed Metastatic Hormone-Sensitive Prostate Cancer (mHSPC): A Correlative Study of E3805 CHAARTED

San Francisco, California (UroToday.com) The treatment paradigm for metastatic hormone-sensitive prostate cancer has been greatly evolving over the last decade with increasing options for patients and clinicians. Current guidelines include androgen deprivation therapy (ADT), chemotherapy and/or anti-androgens. However, not all men experience treatment benefits from added therapies and patient selection to avoid unnecessary side effects remains a challenge for clinicians. Anis Hamid presented a novel tool to help predict patient response to initial treatment.

The group has previously demonstrated the prognostic abilities of gene expression profiling with the PAM50 classifier in patients with localized disease. Pre-clinical drug response models have demonstrated increased taxane sensitivity in luminal subtypes compared to basal subtypes. Given this fact, the group sought to evaluate the prognostic and predictive value of PAM50 in the metastatic hormone-sensitive prostate cancer setting.

To that end, the group performed whole transcriptomic profiling on formalin-fixed, paraffin-embedded primary prostate cancer (PCa) biopsies from patients enrolled in the E3805 CHAARTED trial. This trial has been previously published and sought to evaluate the effect of androgen deprivation therapy alone versus in conjunction with docetaxel.1 Based on normalized gene expression, subjects were classified as luminal A, luminal B or basal subtype. Multivariable analyses adjusted for ECOG status, de novo metastasis vs prior local therapy and volume of disease. The study was designed to evaluate both overall survival and time to castration resistance.

Successful profiling was completed in 80 percent of specimens (160 out of 198). Half of the patients were classified as luminal B (80), 48% as basal (77) and 2% luminal A (3). High volume disease was equally present in the luminal B and basal subtypes, 79% versus 78% respectively. Despite a similar volume of disease, patients with luminal B subtype experienced a shorter overall survival versus the basal group following androgen deprivation therapy alone (hazard ratio [HR] 1.75, p=0.05). On the other hand, the luminal B subgroup experiences a significant improvement in time to castration resistance and overall survival significantly following docetaxel+ADT. 

time to castration resistance and overall survival

Overall, the authors demonstrated a novel genetic signature that in the future could allow for a better selection of chemotherapy candidates; luminal B demonstrating survival benefit from upfront docetaxel while the basal disease does not portent the same benefit. While exciting, the group acknowledges that the product is not yet ready for mass use and plans to validate these preliminary results in independent trial cohorts.

overall survival differntial benefit from addition of docetaxel

Presented by: Anis Hamid, MBBS, GU Oncology Research Fellow, Dana Farber Cancer Institue, Boston, Massachusetts

Written by: Adrien Bernstein, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Fox Chase Cancer Center, Philadelphia, Pennsylvania at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California 

Reference:

1.Kyriakopoulos, Christos E., Yu-Hui Chen, Michael A. Carducci, Glenn Liu, David F. Jarrard, Noah M. Hahn, Daniel H. Shevrin et al. "Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial." Journal of Clinical Oncology 36, no. 11 (2018): 1080.
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