Despite the ASCENT-07 trial failing its primary progression-free survival (PFS) endpoint, an early overall survival (OS) signal emerged. This divergence suggests the drug may confer a survival advantage not captured by the initial endpoint, complicating the definition of a "negative" trial and warranting further follow-up.

The trial allowed patients in the placebo group to receive retifanlimab upon progression (crossover). This common design dilutes the observed overall survival difference. While initial results were not statistically significant, updated data revealed a clinically meaningful 10.6-month median OS improvement.

In trials like ASCENT-4, where over 80% of the control arm received sacituzumab govitecan upon progression, the true overall survival (OS) benefit is obscured. This makes progression-free survival (PFS) a more reliable endpoint for evaluating the drug's first-line efficacy.

The FDA's critique of both CREST and Potomac trials highlights that while event-free survival (EFS) endpoints were met, the lack of improvement in overall survival or prevention of muscle-invasive disease makes the risk/benefit profile questionable for an early-stage cancer, where treatment-related harm is a primary concern.

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.

Praxis Interactive's essential tremor drug succeeded in Phase 3 despite an earlier data monitoring committee (DMC) recommendation to stop for futility. This rare outcome shows that interim analyses on a small fraction of patients can be misleading due to high variance, and continuing a trial against DMC advice can be a winning strategy.

In the CREST trial, the FDA's critique heavily emphasized an overall survival hazard ratio above one. Though statistically insignificant and based on immature data, this single figure created a powerful suggestion of potential harm that overshadowed the positive primary endpoint and likely contributed to the panel's divided vote.

The BREAKAWAY trial's OS data is from a small, crossover-allowed study, making it hard to interpret alone. However, its findings are believable because they align with and reinforce a "building body of evidence" from larger trials like PROPEL and TALA PRO 2, which also show a survival benefit for PARP inhibitor combinations.

Contrary to market convention, a trial delay can be a bullish signal. When an independent data monitoring committee (IDMC) recommends adding more patients, as with Bristol's ADEPT-2 study, it implies they've seen a therapeutic signal worth salvaging, potentially increasing the trial's ultimate chance of success.