Even if radioligand therapies like Lutetium-PSMA are approved for first-line metastatic prostate cancer, their real-world adoption will be significantly hampered by logistics. Most U.S. patients are treated in community practices that lack the infrastructure for these therapies, creating a major access and bandwidth problem that will temper uptake.
Despite guidelines and trial data suggesting low-volume patients may not benefit from chemotherapy, some oncologists offer it to a select subset. This decision is based on factors like young age, fitness, and genomic alterations in tumor suppressor genes, reflecting a personalized, biology-driven approach in an area where consensus is lacking.
The definition of high-volume disease, a key factor in chemotherapy decisions for prostate cancer, has changed across major trials like CHARTERED and STAMPEDE. This evolution, including variations in bone metastases counts and inclusion of Gleason score, complicates cross-trial analysis and highlights its weakness as a surrogate for true disease biology.
The ASPIRE trial design was altered due to pushback from patient advocates who felt it was unethical to randomize metachronous low-volume disease patients to a chemotherapy arm. This led to the exclusion of that subgroup, demonstrating how advocate consensus can override a purely biology-based trial design in favor of perceived patient benefit.
The innovative Triple Switch trial treats all patients with a doublet therapy and then uses their PSA response at six months to guide further treatment. Patients whose PSA fails to reach a nadir are then randomized to receive docetaxel chemotherapy, testing a strategy of early intensification based on a real-time biological response rather than upfront risk stratification.
The ongoing Alliance ASPIRE trial is one of the first to use tumor biology, specifically alterations in suppressor genes like P10, P53, and RB1, as a primary stratification factor. This marks a significant move away from relying on imaging-based volume criteria (high vs. low) to determine prognosis and predict who may benefit from chemotherapy.
Intensive treatments like ADT plus an ARPI can suppress a patient's PSA so effectively that it becomes an unreliable marker of disease status. Patients may show radiographic progression on scans even while their PSA remains low and they feel clinically well. This discordance necessitates periodic imaging to avoid missing actual disease progression.
While PSMA PET scans are more sensitive, they create a clinical dilemma because pivotal trials defining treatment efficacy were based on conventional imaging (CT/bone scans). This forces oncologists to either re-image patients with older technology to match trial criteria or make treatment decisions based on PET data that lacks a clear evidence-based framework for response assessment.