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Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED study

  • A A Hamid,
  • H-C Huang,
  • V Wang,
  • Y-H Chen,
  • F Feng,
  • R Den,
  • G Attard,
  • E M Van Allen,
  • P T Tran,
  • D E Spratt,
  • R Dittamore,
  • E Davicioni,
  • G Liu,
  • R DiPaola,
  • M A Carducci,
  • C J Sweeney

Background 

The phase III CHAARTED trial established upfront androgen deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined.

Patients and methods 

Whole transcriptomic profiling was performed on primary prostate cancer (PC) tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVA) adjusted for age, ECOG status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration resistant prostate cancer (ttCRPC).

Results 

The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared to localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower AR activity (AR-A) and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT+D (OS: HR 0.45, p=0.007), in contrast to basal subtype which showed no OS benefit (HR 0.85, p=0.58), even in those with high volume disease. Higher Decipher risk and lower AR-A significantly were associated with poorer OS in MVA. Additionally, higher Decipher risk showed greater improvements in OS with ADT+D (HR 0.41, p=0.015).

Conclusion

This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof-of-concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

Commentary by Prof. Igor Tsaur

As demonstrated in the CHAARTED and STAMPEDE trials in the field of metastasised hormone-sensitive prostate cancer (mHSPC), docetaxel was the first compound to yield survival benefit when combined with androgen deprivation therapy (ADT) compared to ADT alone as the “evergreen” backbone in the mHSPC treatment paradigm. Later, agents inhibiting androgen signalling, i.e. abiraterone acetate, apalutamide and enzalutamide, further expanded the therapeutic arsenal in this disease. However, tailored disease management is still challenging since biomarker-guided selection of either treatment approach is not established, which leads to decision-making mostly based on comorbidities and a patient’s preferences, but also costs and availability issues.

Hamid and co-authors present a whole transcriptomic assessment of the primary tumour (biopsy or prostatectomy specimen) of mHSPC patients enrolled in the CHAARTED trial prior to systemic therapy. The highest-grade tumour focus was selected for RNA extraction. Based on defined prognostic discriminative abilities in localised prostate cancer, the PAM50 (luminal-basal subtypes) classifier, the Decipher genomic classifier (GC), and androgen receptor activity (AR-A) were tested in the analytic cohort of 160 patients to independently associate with time to castration-resistant prostate cancer (ttCRPC) and overall survival (OS) as well as to identify transcriptomic subgroups benefitting from specific treatment.

The analytic cohort comprised 88% de novo metastasised and 78% high-volume disease. The median follow-up was 4 years. The distribution of luminal-basal subtypes (basal 50%, luminal B 48%, luminal A 2%) was unique in mHSPC in comparison with published data on localised or castration-resistant prostate cancer (PCa). Median GC score and the rate of males with lower AR-A was higher in this cohort than in localised PCa. AR-A and GC score, but not luminal-basal subtypes, were prognostic for OS and ttCRPC. Luminal B subtype showed an inferior OS on ADT mono as compared to basal subtypes while men with luminal B classification significantly benefitted from the addition of docetaxel in contrast to the basal group. Related to OS, patients with higher GC scores experienced the most pronounced advantage from the combination treatment, whereas AR-A status did not favour one treatment over the other.

This investigation demonstrates that gene expression profiling of the primary PCa tumour is promising for the prognostication of the outcomes of ADT and the prediction of the benefit from the upfront chemohormonal treatment even in a metastasised setting. Despite the limited sample size of the studied analytic cohort and the well-known molecular heterogeneity between primary PCa and its metastatic lesions, the findings of the study indicate a feasibility of transcriptional profiling of the primary tumour as an auspicious tool for tailored therapeutic decision-making. Since tumour material is mainly available either through a prostate biopsy or a radical prostatectomy outside of clinical trials, the reliability of this specimen in a gene expression analysis is of high clinical relevance. Data from the transcriptional profiling of patients treated with androgen signalling inhibitors are eagerly awaited in order to provide individualised medicine for men with mHSPC in the nearest future.