Focal or Radical Therapy: a Lesion-based Molecular Evaluation in Prostate Cancer

Prostate cancer is the leading male cancer in the developed world. However, most prostate cancers are indolent, with only a few being aggressive, or clinically significant (csPCa). Standard radical whole-prostate treatments are effective but result in significant urinary, sexual and bowel side effects. Focal Therapy (FT) is a novel strategy where just the area of csPCa is treated, leaving normal prostate tissue intact, reducing damage to surrounding structures, thus minimizing the morbidity of treatment. This strategy is feasible if the csPCa is early and limited to a lesion of small volume.

However, despite detailed imaging and histological sampling, a significant proportion of patients identified today for FT still experience cancer recurrence. The investigators have recorded a 19.1% csPCa recurrence rate 1 year, and 29.3% (cumulative) 3 years after FT in their NMRC-NIG-funded clinical trial (n=80) despite mapping out csPCa tumors in detail using high resolution (3 Tesla) multiparametric magnetic resonance imaging (mpMRI) and extensive biopsies. Interrogating these failures in their NMRC-TA project, they found that csPCa lesions that recurred had greater transcriptomic risk (genomic classifier \[GC\] score 0.60 vs 0.38, P=0.014), and were more likely to be of a luminal molecular subtype (prostate subtyping classifier luminal proliferative \[PSC-LP\]). The investigators hypothesize that patients with lesions that are high GC, and are PSC-LP should undergo standard radical therapy rather than FT.

FLAME-PC (Focal therapy or radical therapy: Lesion-based Molecular Evaluation in Prostate Cancer), aims to prospectively validate the stratification of csPCa patients to FT or radical therapy based on their genomic risk and molecular profiles. Patients deemed clinically suitable for FT based on imaging and biopsy, will be offered FT if they additionally have a GC score ≤0.5 or non-PSC-LP subtype, whereas those with a GC score \>0.5 and PSC-LP subtype will be offered radical therapy instead.

The investigators Hypothesis is that patients stratified to receive FT in FLAME-PC based on their molecular profiles will have a better cancer outcome than a historical prospective cohort of patients undergoing FT based on clinical criteria only. If proven, this will be transformative as this will be the first evidence for the use of molecular profiling in prostate cancer treatment selection. Additionally, the investigators will gain further insights into the pre-FT molecular profiling (RNA analysis will be supported by and performed in collaboration with industry partner Veracyte, Inc.)

FLAME-PC is the first prospective trial to attempt to stratify early prostate cancer treatment between FT and radical therapy. This will provide the investigators with the opportunity to transform clinical paradigm of primary treatment selection in localized prostate cancer, lead to better patient cancer outcomes with FT, and reduce overall morbidity in patients suffering from prostate cancer.

• 1 year Post-Focal Therapy Infield clinically significant cancer recurrence [Time frame: 12 months after FT]
• 1 year Post-Focal Therapy Outfield clinically significant cancer recurrence [Time frame: 12 months after FT]
• Failure-free survival [Time frame: Over 20 years following enrolment]
• Metastatic Cancer Free Survival [Time frame: Over 20 years following enrolment]
• Cancer-specific Survival [Time frame: Over 20 years following enrolment]
• Overall Survival [Time frame: Over 20 years following enrolment]