The Destiny Breast 11 trial compared a new drug to a chemotherapy regimen (ACTHP) that many US oncologists no longer use. This choice of a less common control arm makes it difficult for them to directly compare the new treatment's efficacy against their own current standard (TCHP), complicating adoption.

The PSMA Addition study, adding lutetium in metastatic hormone-sensitive prostate cancer, showed an RPFS benefit. However, initial data suggested adverse quality of life scores. Upcoming results on pain and skeletal events are critical to determine if the toxicity profile undermines its clinical utility in this earlier disease setting.

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.

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.

The control arm in the EMBARK study was blinded to PSA results, preventing physicians from intervening with standard-of-care AR antagonists at PSA progression. This design likely delayed subsequent effective therapies, making the control arm underperform and potentially exaggerating the overall survival benefit of the experimental arms.

Developers often test novel agents in late-line settings because the control arm is weaker, increasing the statistical chance of success. However, this strategy may doom effective immunotherapies by testing them in biologically hostile, resistant tumors, masking their true potential.

The common practice of switching from one ARPI to another upon disease progression is now considered ineffective for most patients. With the advent of proven alternatives like chemotherapy and lutetium, using an "ARPI switch" as the sole control arm in clinical trials is no longer ethically or scientifically sound.

Clinicians may be biased towards lutetium-PSMA because it causes significant PSA drops, which radium-223 does not. This observable metric may not reflect superior overall efficacy, as radium's survival benefit is proven and it may even have unique synergistic potential with drugs like enzalutamide through different biological pathways.

While the Lidera trial showed a benefit for the oral SERD giredestrant in the adjuvant setting, experts advise caution before changing practice. The trial's control arm (standard endocrine therapy) does not reflect the current standard of care for high-risk patients, which now includes CDK4/6 inhibitors, making a direct comparison difficult.