Ask the Experts – E David Crawford

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?

Answer
During the past several years, we have had 5 new drugs, all with different mechanisms of action, approved for use in advanced prostate cancer. This offers all sorts of opportunities to improve our outcome in men with castration-resistant prostate cancer. These drugs fall into several broad categories, including immunotherapeutics, radiopharmaceuticals, chemotherapy agents, and drugs that interfere with either testosterone production or testosterone action.

Abiraterone is an androgen biosynthesis inhibitor (ABI). Enzalutamide is a third-generation anti-androgen that differs markedly from drugs such as bicalutamide. Both abiraterone and enzalutamide have had remarkable success yet result in modest improvements in survival among men with prostate cancer failing chemotherapy.

Cancer is a collection of genomic changes. The longer it is around, the more that genomic heterogeneity develops and the less responsive it is to therapy. So the natural course of events in the past several years has been to move these drugs into the pre-chemotherapy space. We are going to see these drugs moved up even earlier in the disease process and be used in newly diagnosed metastatic disease in high-risk men with biochemical failure and in men who have high-risk local lesions. These new therapies will be combined with such standard treatments as radical prostatectomy and radiation. I believe the same is true for prostate cancer.

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?

Answer
The fact that survival was only improved on an average of 3 to 5 months postchemotherapy is actually remarkable rather than disappointing. This opened the door to using these drugs earlier. The IMPACT [Immunotherapy for Prostate Adenocarcinoma Treatment] trial showed that sipuleucel-T treatment was associated with significantly prolonged survival among men with lower prostate-specific antigen (PSA) values.¹ Median survival was 13 months for men with a PSA value in the lowest baseline quartile compared with 2.8 months for those in the highest quartile. There are numerous studies ongoing with all of these drugs earlier in the disease process.

Question 3. What have you learned about the differences in tolerability of the newer agents, adverse event profiles, and cost?

Answer
I have learned that these new agents are remarkably well tolerated. Each has its own nuances but, in general, side effects have been minimal.

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?

Answer
We are beginning to see combinations rather than drug sequencing. Every cancer we cure is a result of drug combinations rather than drug sequencing. With lymphomas, for example, several drugs are used: cyclosphosphamide, hydroxydaunorubicin, vincristine, and prednisone or prednisolone. The same is true for testicular cancer. The curative treatment is 3 drugs, not 1. In the future, we will need to focus on therapeutic layering.2 Many clinicians will start out with the least toxic agent and move to an agent with more side effects. What this means is that chemotherapy is delayed in the disease process. We are all aware of CHAARTED [Chemohormonal Androgen Ablation Randomized Trial], which evaluated chemotherapy early, but this was in high-volume, newly diagnosed metastatic disease.3 This group is different from the patients in whom these drugs are being used today. However, it makes sense to move these drugs up early.

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?

Answer
I do not believe there is any question that these drugs will be integrated into first-line therapies. In the future, we may be combining 3 or 4 of these drugs together for a short period of time — for instance 6 months — which is done in many cancers that we control and cure.