2024

Background

Oligometastatic prostate cancer (omPC) designates the status of having 3 to 5 metastatic lesions at diagnosis with an untreated primary or a similar extent of spread at recurrence after primary therapy. Metastasis directed therapy (MDT) focuses radiation to those several lesions. This situation is increasingly prevalent due to the more frequent use of PSMA PET imaging and in 2018 the incidence of hormone sensitive metastatic PC prostate cancer (mHSPC) at diagnosis was 8.2% (Vandenberg et al. Prostate Cancer and Prostatic Diseases, 2023), occurring mainly in men with high-risk cancer. Metastatic hormone sensitive PC can be found in men studied by PET imaging whose PSA is rising following primary therapy, converting non-metastatic HSPC to metastatic hormone resistant PC (mHRPC).

In their study of 200 men with rising PSA values after primary therapy before hormone intervention, PSMA PET scans identified metastases beyond the prostate in 55% of men, pelvic nodal disease in 20% and local recurrence in 24% (ibid). Studies comparing the genomics of denovo mHSPC with recurrent mHRPC have found — likely due to the delay in diagnosis allowing time for mutations to develop — that the cancer in the recurrent state is more aggressive.

Focal radiation therapy (e.g. with CyberKnife radiation) achieves >95% local control of oligometastatic lesions, but the major deficiency of MDT is the subsequent emergence of un-imaged polymetastatic disease. Metastatic prostate cancer is biologically heterogeneous with some metastatic sites remaining indolent and others rapidly progressing to polymetastatic spread. The current research challenge is to identify biologic markers and molecular signatures to predict metastatic behavior and guide therapy based on which men would benefit from MDT.

Three treatment options for oligometastatic prostate cancer were reviewed in PCa Commentary Vol. #182. In brief, MDT without ADT, MDT with ADT, and MDT combined with intermittent Xtandi. All had improved overall survival as compared to ADT only. However, in those studies patients were selected based on CT and technetium bone scans, not the more sensitive PSMA PET imaging, which detects metastases earlier at diagnosis and at recurrence. Current patient selection is based arbitrarily on the number and location of treatable metastatic lesions.

Conventional Predictors of Progression Following MDT for Oligometastatic Prostate Cancer

Analysis of early trials comparing MDT with no ADT (Deek, JCO 2022) found that men with mutations in the DNA damage repairs genes, i.e. BRCA 1, 2 and ATM, were at high risk for early failure. Radiographic progression-free survival for those without deleterious mutations compared to those with mutations was 22.6 months vs 10 months, respectively.

Another analysis found that the size, location of metastatic lesions and PSA doubling time in men with oligorecurrent disease affected outcome (Franzese, Clin & Experimental Metastases, 2022). In their study with PSMA PET imaging the median size of metastatic lesions was 4 cm.

Local control at 1 and 2 years was 94% and 92%; progression-free survival at 1 and 2 years, 80% and 69%, with a median time to progression of 33.7 months. The best outcomes were associated with pelvic nodal disease, followed by extra-pelvic nodal spread or metastases to bone. The take-away from these data is the need for more accurate predictors based on molecular features to guide selection of men who will benefit most from MDT.

Liquid Biopsy

The current quest is to identify a molecular signature to predict the aggressiveness of oligometastatic lesions to determine the likelihood of rapid progression to polymetastatic disease.

Tumor cells circulate (CTC) in the blood pre-diagnosis and increasingly as the disease progresses. Cell Search, an FDA approved test, has established that 5 or more CTC in 7.5 cc of blood augers a poor prognosis and less than 4 is associated with a better prognosis. Sophisticated genomic sequencing – usually referred to as ‘next generation sequencing,’ can analyze the DNA and identify the associated mutations of these circulating cells. The analysis of DNA debris from these cells – referred to as circulating tumor DNA (ctDNA) summarizes the contribution of ctDNA of the entire malignant population, an advantage since the genomes of various metastatic lesions may differ, rendering a biopsy of one site a limited representation of the overall metastatic burden.

Most circulating free DNA is shed from normal cells; in cancer patients only 0.01 – 5% of the circulating free DNA is derived from tumor cells. After the primary prostate tumor has been removed or treated, ctDNA characterizes the totality of micro- or macro metastases – and it is this ctDNA that is being evaluated for clues as to the aggressiveness of the oligometastatic lesions to guide the appropriateness of MDT.

A Major Effort

“Stratification of Oligometastatic Prostate Cancer by Liquid Biopsy: Clinical Insights from a Pilot Study,” Colosini, Triggiano et al, Biomedicines, 2022. In their earlier abstract (GU Cancers Symposium, 2018) they described the background of their study: “oligometastatic prostate cancer (OPC) may represent the initial stage of an unfavorable, rapid progression to a polymetastatic state, or the expression of a real oligometastatic phenotype related to a condition of stable disease for a long time.” They studied 28 men with hormone naive OPC, imaged with 11C-Choline PET CT, sequencing a panel of 37 prostate cancer relevant genes in circulating free DNA and microRNA. The genomic analysis was repeated frequently to evaluate the evolution to disease progression. The commonest adverse mutations were ATM, 50%, BRCA2, 39% and BRCA1 21%.

Having established the pre-MDT genomic characteristics of the men, their goal is in the subset follow-up to relate the molecular biomarker to outcome. The study is immature for analysis, but it is hoped that the outcome will provide guidance for patient selection to MDT.

BOTTOM LINE

Metastasis directed therapy prolongs survival in men with oligometastatic prostate cancer. It is hoped that genomic analysis with liquid biopsy will provide guidance for improved patient selection.