As noted in Dr Lowrance’s presentation, the recent guidelines on advanced prostate cancer were developed by the American Urological Association’s Advanced Prostate Cancer Panel in collaboration with the American Society for Radiation Oncology and the Society of Urologic Oncology, with additional representation from the American Society of Clinical Oncology, as well as patient representation. These guidelines very nicely encapsulate the current state of the art in treating these patients. Part I of the guidelines is dedicated to biochemical recurrence without metastatic disease and metastatic hormone-sensitive prostate cancer (mHSPC), while Part II focuses on castration-resistant disease.

The timing of androgen deprivation therapy (ADT) in the absence of overt metastases continues to be an area of uncertainty and shared decision making. For some patients, watching a rising prostate-specific antigen (PSA) over time has a deleterious impact on their quality of life. Ideally, ADT would be initiated early, prior to the development of metastases.

The guidelines note that clinical parameters such as PSA levels and PSA doubling time can be helpful in deciding when to start primary ADT. Additionally, in those without evidence of metastatic disease, next-generation imaging is having an impact. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET), with its sensitivity and specificity, is expected to quickly become widely available in the United States. PSMA PET imaging will increasingly be used for patients with rapidly rising PSA after definitive therapy. Such imaging will allow us to detect metastatic foci and could, perhaps, enable metastasis-directed treatment. By detecting limited recurrence (eg, in the lymph nodes, in so-called oligometastatic disease, or in a solitary or minimal area of bone disease), we may be able to improve outcomes with metastasis-directed therapy. Improved outcomes have not yet been demonstrated, but we are hopeful. Ideally, focal therapy for limited disease outside the prostate bed should be explored in a clinical trial. Although salvage radiotherapy is well studied, with data available from large randomized clinical trials, next-generation imaging may help to better define those radiation fields.

In the mHSPC setting, there has been a change in the standard of care. For many decades, ADT alone was the standard, but the current grade A recommendation is that ADT should be offered in conjunction with either androgen pathway–directed therapy or chemotherapy. Surgical orchiectomy is still an option for primary ADT, although it is not very commonly used today compared with the luteinizing hormone-releasing hormone (LHRH) agonists or antagonists.

LHRH agonists and antagonists both lower testosterone to the castration range. Long-term, there is no evidence of superiority of either type of primary ADT over the other. Short-term, the agonists have the testosterone flare, the clinical significance of which is dubious. From a practical standpoint, the main difference between LHRH agonists and antagonists is that antagonists reduce testosterone levels more rapidly, almost like surgical orchiectomy. This is desirable in cases of urinary retention, bone pain, and impending spinal cord compression. The downside of an LHRH antagonist is the monthly injection, but, if that is a problem, the patient can be converted to an agonist once the testosterone reduction is achieved. Relugolix, an oral antagonist, was recently approved by the US Food and Drug Administration and will likely have a role, but that role is still being defined.

Finally, the guidelines now recommend that, in patients with mHSPC, regardless of age and family history, we offer genetic counseling and germline testing. This was based on expert opinion, and I agree with this recommendation.