The NCI working group concluded that neither metastasis-directed therapy (MDT) nor systemic hormonal therapy should be required as a control arm in trials for biochemically recurrent (BCR) prostate cancer. This facilitates testing novel non-hormonal agents and reflects that surveillance is often a reasonable standard of care.

While PCWG4 advocates for using Patient-Reported Outcomes (PROs), it doesn't mandate specific analysis methods. This flexibility creates a risk where researchers can explore numerous permutations of the data post-hoc to find a result that supports their desired conclusion, whether positive or negative.

The NCI working group asserts that PSA doubling time, especially a rate under six months, remains the key indicator of high-risk biochemically recurrent (BCR) prostate cancer. This biological marker of aggressiveness is considered more prognostically significant than the presence of lesions on a highly sensitive PSMA PET scan.

The PCWG4 imaging committee is comprised of at least 50% non-US experts. This reflects the reality that significant expertise in advanced imaging like PSMA PET resides outside the US, particularly in Australia and Germany, making global collaboration crucial for creating relevant standards.

The influential "2+2 rule" on bone scans, which accounts for treatment "flare," wasn't an arbitrary threshold. It was proposed as a working hypothesis to be tested and validated through numerous clinical trials. This exemplifies the data-driven, iterative process behind the PCWG criteria.

Experts believe molecular tests like Decipher and PTEN status are superior to simply counting bone lesions for guiding treatment. While not yet standard practice for all decisions, this represents a significant shift towards using underlying tumor biology to determine therapy, like adding docetaxel.

The NCI Working Group argues against equating PSMA PET-positive biochemically recurrent (BCR) prostate cancer with traditional metastatic disease. They propose the term "PSMA positive BCR" to emphasize that traditional prognostic factors still apply and the natural history is distinct and often more indolent.

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.

Clinical trials use arbitrary, time-based definitions (e.g., relapse within 2 years) for endocrine resistance. This isn't a perfect biological classification but a practical necessity to create homogeneous patient groups for testing, which may not fully reflect the diverse patient population in clinical practice.