The New mCRPC Drugs: Clinical Practice Trends and Directions
Hospital and Institutional Affiliations
Grover C. Bagby Endowed Chair for Prostate Cancer Research and Deputy Director of the Oregon Health & Science University Knight Cancer Institute in Portland.
Number of Patients Seen in a Month
Question 1.The new anti-androgens have been on the market in the United States for about 5 or 6 years. How does your experience with these medications in clinical practice compare with clinical trial outcomes?
In general, my experience mirrors that of the clinical trial results. However, there are some minor differences. For example, patients who receive different hormonal therapy regimens than were allowed on the clinical trials experience modestly less benefit than the trials reported. We have also gained some more experience with the use of these agents. With enzalutamide, for example, we have seen the benefit of dose reductions for patients with fatigue. We have also come to appreciate that fatigue with these therapies, and particularly enzalutamide, is a real practical issue we need to pay attention to. But for the most part, we see in practice what we expect to see based on clinical trial results.
Question 2. In clinical trials, treatment with the newer agents was associated with a median 4-month improvement in survival compared with placebo. Is there a subgroup of patients who experience substantially better survival? Are there clinical indicators of response?
I would use caution in describing the survival benefit in terms of the median. That is only 1 point on the survival curve. I also think it leads people to believe that their personal benefit will equal 4 months, which is unlikely to be accurate. Individual patients are likely to benefit more or less. But also, importantly, that benefit was seen with considerable crossover, whether within the trials or through access to standard-of-care drugs. Therefore, the overall survival of the study groups reflects not only the treatment assignment in the trial, but also the effects of all subsequent therapies. This almost certainly results in an underestimation of the benefit. Progression-free survival, which has its own limitations, is a more direct measure of the effects of each drug on the behavior of the disease.
The studies were not designed to robustly identify groups that benefit more, and post-hoc subset analyses suggest that treatment benefits all major subsets of patients. That does not mean that there is not significant variation between patients. Patients who respond, as measured by decline in prostate-specific antigen (PSA) and improvements in radiographically evident disease, would be expected to benefit more than those who do not.
Question 3. What have you learned about the differences in tolerability of the newer agents, adverse event profiles, and cost?
Tolerability of the agents is quite good, especially compared with chemotherapy. The side effect profiles in practice largely reflect what we saw in the trial reports, and clinical judgment about susceptibility to various side effects drives our selection of the agent for each patient. As an example, patients with diabetes or other contraindications to steroids might do better starting with enzalutamide while patients with pre-existing severe fatigue may do better with abiraterone. These are not evidence-based suggestions, as the 2 drugs have not been compared head to head, but they do represent day-in/day-out clinical judgment that we exercise in caring for our patients. The cost of these drugs is a significant concern both for patients and for society.
Question 4. Do you have a preferred sequence of agents? Have you found cancer-specific outcomes to be clinically different based on which agent you start with?
There is no one-size-fits-all sequence. As mentioned previously, we tend to consider various side effects when selecting which drug we might start with for an individual patient. At our center, when there is no specific factor driving a choice, we tend to start with enzalutamide. This largely reflects our experience in researching the drug and the fact that many of our patients are treated on clinical trials, and we have focused more of our research on enzalutamide. There is no right or wrong answer on sequence, and when I have discussed this with my colleagues, opinions are divided.
Question 5. Do you think the new androgen receptor-targeted drugs have a place as first-line androgen deprivation therapy in place of traditional agents such as leuprolide?
I see potential for these agents to be given in combination with leuprolide up front. However, this is a question that needs to be answered in clinical trials. It is possible that these agents could also compete head to head with luteinizing hormone-releasing hormone (LHRH) agonists, but I find that to be less likely than the emergence of combination therapy.
1. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433.
2. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol.2017;71:151-154.
3. Higano CS, Beer TM, Taplin ME, et al. Long-term safety and antitumor activity in the phase 1-2 study of enzalutamide in pre-and post-docetaxel castration-resistant prostate cancer. Eur Urol. 2015;68:795-801.