Standard guidelines for treating metastatic prostate cancer are based on conventional imaging (CT/bone scan). The panel argues that PSMA PET-positive biochemical recurrence represents a different, earlier disease state. This necessitates new treatment paradigms, like definitive therapy durations, not covered by current guidelines.

The effectiveness of radioligand therapy is counterintuitive: as tumors shrink and PSMA binding sites decrease, less radiation is delivered to the cancer. The VISION trial showed the first two doses delivered more radiation to the tumor than the subsequent four, questioning the value of a fixed, prolonged treatment schedule.

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.

The future of advanced prostate cancer treatment may involve combining ADCs with bispecific T-cell engagers. This strategy could use ADCs for a short duration to deliver a potent hit, followed by immunotherapy to achieve durable remission, potentially reducing toxicity and enabling earlier use.

For an older patient population, the ultimate goal in prostate cancer treatment might not be a traditional cure, but rather turning it into a quiescent, chronic disease manageable with well-tolerated therapy, similar to HIV. This reframes success as long-term control until a patient dies of other causes.

The patient population in pivotal trials like EMBARK, defined as non-metastatic by conventional imaging, is being re-evaluated. A UCLA study showed that over 80% of a similar patient group would have been positive on a PSMA PET scan, suggesting the "M0" classification is largely an artifact of older imaging technology and that these patients likely have micrometastatic disease.

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.

For patients with oligometastatic disease who achieve a deep PSA response (e.g., to zero), oncologists consider finite treatment durations (e.g., 18-24 months) followed by observation. This "do less harm" approach challenges the standard of continuous therapy until progression, aiming for long-term treatment-free intervals.

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.