The advent of highly sensitive PSMA PET imaging identifies metastases in many patients previously considered to have only biochemical relapse (BCR). However, experts argue against a knee-jerk reaction to treat. Many of these patients, particularly those with slow PSA doubling times, can be safely observed, challenging the assumption that visible disease always requires immediate intervention.

Unlike bladder cancer, prostate cancer has highly effective androgen-pathway inhibitors (ARPIs) that extend survival. This success has pushed chemotherapy and, by extension, ADC development to later treatment lines as clinicians prioritize other novel mechanisms of action first.

The EMBARK trial showed that enzalutamide monotherapy was superior to standard ADT monotherapy for metastasis-free survival. This suggests potent AR antagonism may be a more effective strategy than simply depleting the testosterone ligand, challenging the long-held dogma of ADT being the fundamental building block for systemic prostate cancer therapy.

After years of successfully intensifying hormonal therapy, the focus in prostate cancer is shifting toward de-intensification. Researchers are exploring intermittent therapy for top responders and developing non-hormonal approaches like radioligands to spare patients the chronic, life-altering side effects of permanent castration.

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.

An NCI working group coined "PSMA positive BCR" to classify patients with biochemical relapse (BCR) who have findings on a modern PSMA PET scan. This formally recognizes this group is distinct from both conventionally-defined metastatic patients and traditional BCR patients, necessitating unique clinical trial designs and treatment strategies.

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.

Even when testing drugs in heavily pre-treated patients, clinical trials incorporate subtle biological selection criteria. For instance, the COMPASS trial excludes patients with visceral metastases, a tactic to enrich for a population more likely to respond and avoid the most aggressive disease subtypes.

For biochemically recurrent (BCR) prostate cancer, which is often indolent, trials should not wait years to study treatment reduction. The NCI group universally agreed that de-escalation strategies—such as intermittent therapy—should be the default design from the outset, prioritizing quality of life and avoiding overtreatment.