The negative ANSA-RAD trial, when contrasted with the positive STAMPEDE trial, demonstrates that patient selection is paramount in adjuvant therapy. The difference in outcomes was driven by risk definition, not the drug. This reinforces that "negative" trials are clinically vital for defining which patient populations do not benefit, preventing widespread overtreatment.

A key hypothesis for why docetaxel showed better overall survival than lutetium in the PLUTO trial is that patients treated with lutetium upfront may become unfit for subsequent chemotherapy. This highlights a critical factor in trial design: the planned therapeutic sequence and a patient's ability to receive later-line treatments significantly impact survival outcomes.

Lutetium faces criticism for its fixed 6-cycle regimen, which may be suboptimal as the PSMA target diminishes with ADT. However, this critique is rarely applied to other drugs like PARP inhibitors, which are given until progression. This highlights a double standard and the tension between using a fixed regimen for regulatory approval versus finding the optimal dose in practice.

With highly active agents yielding 30% complete response rates, the immediate goal should be to cure more patients by exploring potent combinations upfront. While sequencing minimizes toxicity, an ambitious combination strategy, such as ADC doublets, offers the best chance to eradicate disease and should be prioritized in clinical trials.

Data from the CAPItello trial showed a significant number of patients with PTEN deficiency experienced radiological progression without a corresponding PSA increase. This challenges the standard reliance on PSA for monitoring in high-risk prostate cancer and suggests a need for more frequent, personalized imaging protocols to detect progression earlier.

The FDA is predicted to approve new PARP inhibitors from trials like AMPLITUDE only for BRCA-mutated patients, restricting use to where data is strongest. This contrasts with the EMA's potential for broader approvals or denials. This highlights the diverging regulatory philosophies that create different drug access landscapes in the US and Europe.

Perioperative enfortumab vedotin-pembrolizumab (EV-Pembro) is surprisingly well-tolerated on a per-cycle basis compared to the traditional GEMSYS chemotherapy regimen. This challenges preconceived notions about the toxicity of this powerful combination, though cumulative toxicity over longer durations remains a key factor.

High relapse rates (~70%) in surgery-alone arms of recent trials suggest most patients with muscle-invasive bladder cancer (MIBC) already have micrometastatic disease. This reframes the disease, prioritizing early systemic therapy over immediate surgery to achieve control and potential cure.

Three 2025 trials (AMPLITUDE, PSMA-addition, CAPItello) introduced personalized therapy for metastatic hormone-sensitive prostate cancer. However, significant benefits were confined to narrow subgroups, like BRCA-mutated patients. This suggests future success depends on even more stringent patient selection, not broader application of targeted agents.