New insights in the genomic architecture and treatment of high risk and oligometastatic prostate cancer

Prostate cancer (PCa) remains an important health issue as it is the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide. Based on GLOBOCAN 2020 estimates, 1,414,259 new cases of prostate cancer were reported worldwide in 2020, with higher prevalence in the developed countries. PCa patients can be divided into 2 groups: localized or metastatic disease. Patients with localized disease are classically assigned to 3 groups according to D’Amico classification: low, intermediate and high risk. Men with low/intermediate risk disease currently don’t need treatment for their disease or are treated by current standard of care (radical prostatectomy (RP) or radiotherapy + hormonal treatment) with excellent oncological perspectives for their future. Patients with metastatic disease are frequently subdivided into oligometastatic (mostly defined as ≤ 5 metastatic lesions) or polymetastic disease (> 5 metastatic lesions). Men with polymetastatic disease are treated with systemic palliative treatment as no surgical or other loco-regional therapies are meaningful in these cases given the widespread tumor load. The current field of interest in PCa research is the grey zone between high risk localized and oligometastatic disease. The reason why patients with high-risk localized disease have a worse prognosis is partially the fact that many of these patients have micrometastases which are not yet visible on conventional imaging (CT-scan and bone scintigraphy) at time of staging. Despite multimodal therapy, biochemical recurrence occur in 50% of high risk patients and 30% will ultimately die of their disease. Much research is still needed to understand how these patients are best diagnosed and treated. In recent own research (ARNEO trial - NCT03080116) we investigated the effect on minimal residual disease (tumor volume ≤ 0.25 cm3) after radical prostatectomy in high-risk patients treated with neoadjuvant apalutamide (androgen receptor signaling inhibitor) combined with degarelix (LHRH antagonist) compared to degarelix alone. Conclusion from this trial is the fact that patients treated with combination ARSI + ADT had better chance to achieve MRD compared to patients in the monotherapy group. Interestingly, patients who did not achieve MRD under combination treatment had a significantly greater chance of finding PTEN loss in the cancer genome compared to patients who did achieve MRD. This fascinating conclusion opens new doors for further combination treatments to respond to certain deviations in tumor biology. The following aspects will be subject of this doctoral thesis:  1) Continuation of IWT-1 trial in which conventional imaging (CT-scan and bone scintigraphy) is compared to PSMA PET MRI scan to determine whether PSMA PET-CT/MR can be used for more accurate staging and, as a result, could detect smaller metastases at time of initial staging. 2) Set up of a biobank with prostate- and metastatic tissue of primary oligometastatic or oligo-recurrent PCa patients to better understand the tumor biology and heterogeneous treatment response between patients. We will search for alterations in RNA-expressions profiles, copy number aberrations and abnormalities in protein synthesis to find biomarkers that could predict dissemination of a localized tumor. Valuable markers will be validated by immunohistochemistry (IHC). 3) Given the current knowledge from our own research, a new clinical trial will be set up to evaluate new neoadjuvant combination therapies in high-risk PCa patients based on the genomic architecture of the tumor. ...