High-risk non-metastatic prostate cancer remains a significant cause of mortality and current treatment options are inadequate. A large proportion of men will develop progression after therapy with curative intention. In this stage, before clinically detectable metastases, we believe that intensified therapy could increase survival.
In metastatic prostate cancer, androgen deprivation therapy followed by chemotherapy and newer androgen receptor pathway-targeting therapies have improved survival. However, they also come with elevated toxicity. Precision medicine is the key to identifying patients who could benefit from therapy escalation earlier in the disease course.
Various biomarker panels, including liquid biopsies and imaging, have been proposed for patient stratification. This study will establish a precision medicine platform centered on molecular profiling, imaging, and histology to enhance survival rates for high-risk prostate cancer patients. Our plan involves analyzing retrospective cohorts to identify biomarkers, conducting a multi-center prospective clinical study to validate biomarker algorithms, and further establishing a biomarker-driven adaptive multi-center, multi-arm randomized clinical trial platform. Additionally, we will initiate a drug discovery development program based on targetable pathways identified via continuous profiling of trial participants with poor response to therapy.
To increase survival for patients with locally advanced, high-risk PC, by establishing a precision medicine platform based on molecular profiling, imaging, and histology.
Specific aims are to:
Expand and complete ongoing comprehensive molecular and imaging analysis of large-scale retrospective cohorts to develop decision algorithms for precision medicine.
Start a multi-center prospective non-interventional clinical study to validate and establish the biomarker algorithms in a diagnostic workup.
Transform the established infrastructure from aim 2 into a biomarker-driven adaptive multi-center, multi-arm randomized clinical trial (RCT) platform with metastatic-free survival as the primary endpoint. Biomarker-weighed randomization will stratify patients to standard-of-care (SoC) or treatment escalation arms such as image-guided radiotherapy, addition of docetaxel, novel antiandrogens, PARP-inhibitors, 177-Lu–PSMA radioligand therapy, or novel modalities emerging during the trial period. Quality of Life (QoL) and health economy parameters will be integrated.
Initiate a drug discovery development program based on targetable pathways identified through continuous transcriptomic and genomic profiling of trial participants.
Overall, the project's novelty is defined by its focus on high-risk PC before clinically manifest metastases, where previously no biomarkers have been implemented, and the inclusion of not only genetic but phenotypic and image-based biomarkers compared to the Probio and STAMPEDE trials. In addition, inclusion of metastasis-derived profiling algorithms increases the potential to identify patients with metastasis-prone tumors.
Wikström P, Epithelial and Stromal Characteristics of Primary Tumors Predict the Bone Metastatic Subtype of Prostate Cancer and Patient Survival after Androgen-Deprivation Therapy https://pubmed.ncbi.nlm.nih.gov/37615497/
Gonora M, Characteristics of Patients in SPCG-15-A Randomized Trial Comparing Radical Prostatectomy with Primary Radiotherapy plus Androgen Deprivation Therapy in Men with Locally Advanced Prostate Cancer https://pubmed.ncbi.nlm.nih.gov/35813256/
Schostak M, Practical Guidance on Establishing a Molecular Testing Pathway for Alterations in Homologous Recombination Repair Genes in Clinical Practice for Patients with Metastatic Prostate Cancer https://pubmed.ncbi.nlm.nih.gov/37714762/
Merseburger AS, Apalutamide plus androgen deprivation therapy in clinical subgroups of patients with metastatic castration-sensitive prostate cancer: A subgroup analysis of the randomised clinical TITAN study https://pubmed.ncbi.nlm.nih.gov/37708629/
Thysell E, Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor https://pubmed.ncbi.nlm.nih.gov/31162796/