Washington, DC (UroToday.com) At the 20th Annual Meeting of the Society of Urologic Oncology, Dr. Martin Gleave reviewed findings of the genomic umbrella neoadjuvant study (GUNS) and other biomarker trials. Older neoadjuvant androgen deprivation therapy (ADT) studies showed improved pathologic surrogates (4-8% pathologic cure rate (pCR)) but no difference in PSA recurrence rates.1 Similarly, newer neoadjuvant trials using LHRH with abiraterone or enzalutamide or both showed improved pCR rates, 8%.2 A Clinical Cancer Research (CCR) study evaluated the impact of neoadjuvant docetaxel and ADT on genomics and transcriptomics in high-risk prostate cancer. The study evaluated 52 patients, of which 3 had microfocal residual cancer after treatment, and none had pCR. The investigators found alterations in TMPRSS2-ERG fusion, TP53, PTEN, FOXA1, and SPOP; furthermore, the study demonstrated that androgen receptor (AR) signaling suppression varied among treated tumors, with an upregulation of certain neuroendocrine and plasticity genes. The alterations in this high-risk localized group of patients are distinct and different from those with advanced metastatic castrate resistant prostate cancer mCRPC.
The rationale for biomarker-driven neoadjuvant treatments includes heterogeneity within high-risk localized disease and the ability of genomic sequencing to enable matching of molecularly targeted agents to genomic and molecular aberrations within a given patient’s cancer. Furthermore, despite improved survival associated with chemohormonal therapy (ADT + docetaxel), pCR rates remain low (~8%) when used in the neoadjuvant setting for localized high-risk prostate cancer. Unfortunately, most genetic aberrations in this disease subset arise in a small proportion of patients, making clinical testing with multiple single-agent, single-arm trials difficult.
The genomic umbrella neoadjuvant study (GUNS) is an adaptive, multi-arm, multi-stage trial designed to evaluate targeted therapies in biomarker-pre-selected patients with high-risk localized disease by matching neoadjuvant therapies to baseline genomic alterations. There is a master protocol designed for the first 8 weeks of treatment that includes treatment with LHRH antagonists (LHRHa) and apalutamide. From there, there is an opportunity to add or drop sub-protocols as the study progresses. The primary endpoint is designed to define the conditional lethality of targeted therapy using pCR rate in RP specimens; secondary objectives include AR pathway profiling, discovery of reversion mutations, immune cell infiltration and other alterations that persist after combination therapies (in order to elucidate mechanisms of treatment resistance), assessment of safety and tolerability of combination regimens, and determination of rates of positive margins, extracapsular extension, seminal vesicle invasion and lymph node involvement. Dr. Gleave reviewed some examples of active sub-studies including:
- LHRHa + apalutamide +/- abiraterone/prednisone
- LHRHa + apalutamide +/- docetaxel
- LHRHa + abiraterone +/- PARPI (niraparib)
- PD-L1 inhibitor (atezolizumab) in patients with immunogenic high-risk localized prostate cancer.
In summary, the GUNS trial is an adaptive, biomarker-segmented, multi-arm, multi-stage trial where neoadjuvant therapies are matched to baseline genomic alterations in high-risk localized prostate cancer. The primary endpoint is defining the conditional lethality of targeted therapy using pCR in surgical specimens. Finally, there is utility in genomic profiling after treatment as it may elucidate mechanisms of treatment resistance.
Presented by: Martin E. Gleave, MD, FRCSC, FACS, Executive Director, Vancouver Prostate Centre, Vancouver, Canada.
References:
- Gleave et al. Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. Journal of Urology. 2001 Aug;166(2):500-6; discussion 506-7.
- McKay, R., Ye, H., Xie, W., Lis, R., Calagua, C., & Zhang, Z. et al. (2019). Evaluation of Intense Androgen Deprivation Before Prostatectomy: A Randomized Phase II Trial of Enzalutamide and Leuprolide With or Without Abiraterone. Journal Of Clinical Oncology, 37(11), 923-931. doi: 10.1200/jco.18.01777