David R. Wise, MD, PhD

Question 1. What should be the basis for starting non-metastatic CRPC (nmCRPC) patients on one of the novel anti-androgens?

Answer
The basis for starting therapy is to delay metastatic disease in patients with aggressive disease who are likely to tolerate these agents reasonably well. Patients with a PSA doubling time of less than 10 months who are optimized from a cardiovascular and functional standpoint are generally good candidates. Currently, apalutamide and enzalutamide are FDA approved for nmCRPC. The data for darolutamide are promising and we await the FDA approval for this anti-androgen as well. The choice as to which anti-androgen to use is difficult. Anti-tumor activity is similar between all 3 drugs. Based on the phase 3 trial data, key adverse events with these agents—fatigue, falls, fractures—all seem to be most prevalent with enzalutamide followed by apalutamide. Darolutamide seems to have the lowest risk of these 3 F’s and would be my first choice in a patient with known CNS comorbidity, especially a seizure disorder. I believe it is worth exploring darolutamide as a first option because it might be better tolerated, particularly with patients at risk for these critical adverse events. Whether this trend holds true in real world practice is a key unanswered question.

Question 2. What would you advise urologists regarding the management of adverse effects that impair QOL?

Answer
Special attention to patient’s functional status, ability to ambulate, and cognitive status are key for patients on anti-androgens. Deterioration in any of these conditions should prompt holding the drug and a careful workup for the etiology. Significant drug-related toxicity should prompt holding drug until resolution of symptoms. Restarting at a reduced dose level depending on the severity of the adverse event can be considered. Of note, screening for osteopenia and/or osteoporosis is critical in this patient population and patients with these conditions should be on vitamin D, supplemental calcium, and a bisphosphonate or RANKL inhibitor. This is particularly important given the increased risk of fractures in patients treated with enzalutamide and apalutamide.

Question 3. Who should NOT be treated with these medications?

Answer
Patients with non-aggressive appearing prostate cancer (established based on several factors, including PSA doubling times greater than 10 months) with a short life expectancy due to comorbidities should generally not be treated. Patients with poorly controlled cardiovascular disease should not be treated with these agents until their cardiovascular condition is optimized.

Question 4. When men with nmCRPC are placed on one of the novel anti-androgens, what do you think should be the follow-up protocol?

Answer
PSA monitoring every 3 months is appropriate for most patients. Further imaging should be individualized and can generally be reserved for increases in the PSA or for patients with rapid PSA kinetics.

Question 5. If metastatic disease develops, what would be the next step in treatment?

Answer
The next step will depend on the extent of the metastatic disease and the duration of the response to the anti-androgen. Use of subsequent anti-androgens or CYP17A1 blockade will likely be of limited utility given the known cross resistance between these agents. Docetaxel, radium-223, sipuleucel-T, clinical trial, and/or metastasis directed therapy are all reasonable options. Next-generation sequencing of a high risk primary or metastatic biopsy should be considered to evaluate for targeted and/or immunotherapy options.