DOI: 10.25934/pr00011690
title: Training and Validation of PSA and Pain as Biomarkers and Causal Mediators in Metastatic Hormone Sensitive Prostate Cancer

description: Prostate cancer is the most common cancer in the North American male population. In 2023, the American Cancer Society estimates about 288,300 new cases of prostate cancer and about 34,700 deaths from prostate cancer. Of note, it is the second leading cause of cancer death in men in the U.S. after lung cancer. In about 3/4th of these patients, cancer remains limited within the prostate gland at diagnosis. Majority of them receive curative local therapy including removal of the prostate or radiotherapy to the prostate. This is often combined with testosterone suppression as testosterone acts like a fuel for the prostate cancer cells and thus suppressing the testosterone inhibits growth of the cancer. Despite these treatments, some of them progress to a phase where the cancer spreads to organs outside the prostate. Additionally, about 1/4th of patients are diagnosed when the cancer has already spread to other organs. As long as the cancer is responsive to testosterone suppression (lowering testosterone levels), metastatic prostate cancer patients are treated with testosterone suppression in combination with other drugs such as docetaxel which is a chemotherapy agent (a type or mixture of drugs that work by killing cancer cells), novel hormonal agents (drugs that work to slow or stop cancer growth by effecting hormone levels), or both. Novel hormonal agents are first line treatment for these patients with metastatic hormone sensitive prostate cancer (mHSPC) after they were found to be the effective in a succession of randomized controlled trials which are a type of scientific experiment where people are randomly assigned to either a treatment group or a control group that doesn't receive the treatment. Darolutamide, Apalutamide, and Abiraterone are such novel hormonal agents, when added to testosterone suppression with or without docetaxel, a chemotherapy drug, was found to improve overall longevity in randomized controlled trials which are clinical studies where one treatment strategy is compared to the other in a large number of patients to choose the best strategy. Prostate specific antigen is a marker for prostate cancer and increase or decrease in this marker, as detected by serial blood tests, corroborate with disease progression or regression in men with prostate cancer. However, it remains unknown if early PSA response plays a causal mediation role in the treatment effect on overall longevity. Similarly, longitudinal change in pain, as reported by patients, has been reported to be associated with outcome in metastatic prostate cancer. However, it remains unknown if pain progression could also play a causal mediating role in the treatment effect on overall longevity. We plan to pool data from the three randomized trials (LATITUDE, TITAN, ARASENS, ENZAMET, and ARCHES) to determine if early drop in PSA or early worsening of pain could affect the survival benefit of new hormone treatments plus testosterone suppression, with or without docetaxel. In other words, we would like to determine if PSA drop and pain progression could be some of the pivotal factors through which the combination of darolutamide, testosterone suppression, and docetaxel exerts its effect on OS. If found to be mediators, this information will help us determine the possible outcome of patients early in the disease course and thereafter personalize their treatment accordingly.