The patient has developed castrate resistant disease, and given that he has no visceral metastases and no bone pain, you should continue ADT, start a bone protective agent (such as zoledronic acid or denosumab) and start enzalutamide or abiraterone with prednisone. However, given that enzalutamide interferes with warfarin, you should recommend abiraterone plus prednisone in this case.
The definition of castration resistance is progression of disease marked by 3 consecutive rises in the PSA above the PSA nadir or clinical progression in the setting of castration (a circulating testosterone < 50 ng/dl). Clinical progression includes the development of new metastases or progression of existing disease. When patients develop castrate-resistance, you should continue ADT. Despite their progression, testosterone is likely to remain a potent growth factor for the disease and discontinuing ADT will result in recovery of testosterone and may spur on disease progression. For patients with no visceral metastases who have developed castrate-resistance, the NCCN Guidelines recommend continuing ADT and starting a bone protective agent (zoledronic acid or denosumab) and one of the following:
- Enzalutamide
- Abiraterone with prednisone
- Docetaxel x 6 cycles
- Clinical Trial
- Other secondary hormonal therapy
The PREVAIL Trial (Beer et al., Eur Urol 2017) demonstrated a progression-free and overall survival benefit to enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer. Enzalutamide reduced the risk of radiographic progression or death by 68% (p < 0.0001) and the risk of death by 23% (p = 0.0002). The median overall survival was 35.3 months in the enzalutamide arm and 31.3 months in the placebo arm. Note that enzalutamide can cause seizures and affects warfarin.
Abiraterone with predinose was established as a category 1 recommendation after demonstrating a survival benefit in men with castrate resistant disease who had not received chemotherapy (Ryan et al., N Engl J Med 2013). The double-blind study randomized 1,088 patients to abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The authors reported the following significant improvements in the abiraterone-prednisone arm
- Median radiographic progression-free survival (16.5 months vs. 8.3 months, p < 0.001).
- Overall survival (median not reached, vs. 27.2 months, p = 0.01)
- Time to initiation of chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status.
Clinical Pearl: Men with newly diagnosed castrate resistant, metastatic prostate cancer should be continued on ADT. For those with bone metastases and no visceral metastases, treatment should include a bone protective agent (e.g. denosumab or zoledronic acid) and second line therapy with enzalutamide, abiraterone plus prednisone, chemotherapy or clinical trial. Enzalutamide can cause seizures (~1-2% of patients) and can affect warfarin levels.
