A meta-analysis of over 9,500 patients in major prostate cancer trials, including the pivotal VISION and PSMA-4 trials for radioligand therapy, shows significant underrepresentation of Black and Hispanic patients. This creates a critical evidence gap when applying these therapies to diverse real-world populations.

The debate over the STAMPEDE and ENSA-RAD trials stems from a misunderstanding. They aren't contradictory but study different cohorts within the "high-risk" category. STAMPEDE focused on the highest-risk patients, while ENSA-RAD included a broader group. Combining their data could provide a more nuanced treatment approach.

Unlike controlled clinical trial data, real-world evidence is derived from vast, messy, and incomplete data from daily healthcare. This variability is its strength, offering deeper insights into long-term outcomes, drug interactions, and diverse patient populations that clean trial data misses.

While clinical trials raised concerns about falls with enzalutamide, real-world data from the VA’s frail, comorbid population did not show this signal. A possible explanation is that the baseline rate of falls in this vulnerable population is already so high that it masks any drug-specific effect, a key insight for risk assessment.

Even when trials like LITESPARK 022 and Keynote 564 use identical eligibility criteria, outdated staging systems result in patient populations with different underlying risks. This makes direct comparison of outcomes between trials, even for the same drug, an unfair and statistically flawed analysis that ignores the function of a control arm.

Clinical trials for acute leukemia targeting older or chemotherapy-ineligible patients are enrolling a surprisingly high number of younger individuals. This trend blurs the lines of the intended patient population and affects how trial data should be interpreted and generalized to real-world practice.

The clinical definition of "high-risk" prostate cancer is evolving due to improved diagnostics. The move from digital rectal exams to more sensitive MRI for T-staging means more patients meet the criteria for being high-risk. This "stage migration" makes it challenging to apply findings from older clinical trials to a contemporary patient population.

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.

Tarlatamab is being administered to patients who would have been excluded from clinical trials (e.g., lower performance status, brain mets). This real-world population experiences potentially lower efficacy and different toxicity patterns, such as more frequent ICANS, than the pristine data from the drug's approval studies would suggest.