Ask the Experts – Amar U. Kishan, MD

Question 1. ADT plus abiraterone and ADT plus docetaxel are the current standard-of-care for mCSPC, and apalutamide in September received FDA approval for this disease state. How would you decide which medication to use in patients with mCSPC?

Answer
Assessing the “burden of disease” may be important in this context. Patients with “high-volume” disease have either visceral metastases and/or 4 or more bone metastases with at least 1 outside of the vertebral column and pelvis. Early data from the CHAARTED [Chemo Hormonal Therapy versus Androgen Ablation Randomized Trial in Extensive Disease] trial suggested that the benefit of docetaxel was restricted to patients with “high-volume” disease.¹ In contrast, abiraterone and apalutamide have both shown benefits in patients with high-volume disease. Recently presented and published data from the STAMPEDE [Systemic Therapy in Advanced and Metastatic Prostate Cancer Evaluation of Drug Efficacy] trial suggest that docetaxel may indeed be beneficial regardless of disease volume.² Notably, STAMPEDE included predominantly patients with de novo disease, whereas CHAARTED include more patients with recurrent disease. This may account for the difference in the importance of disease volume.

That said, traditionally, our practice has been to recommend abiraterone for patients with low-volume disease, and either abiraterone or docetaxel for patients with high-volume disease. Abiraterone recently has gone generic, and that has influenced our practice patterns. We do try to obtain apalutamide for patients who experience toxicity (generally, progressive hypertension) with abiraterone. Enzalumatide, and, for low-volume disease, prostate-directed radiotherapy, are also options.

Question 2. How do you decide the optimal time to begin treatment for metastatic castration-sensitive prostate cancer (mCSPC)?

Answer
Our practice has been to begin first-generation ADT early, and then reserve some time to discuss the optimal sequencing of other systemic therapies and/or local radiation therapy to the primary.

Question 3. What do you consider the major challenges in the management of metastatic PCa?

Answer
The biggest challenges in the mCSPC space, in my opinion, relate to the lack of ability to predict the course of disease. Some patients may have a great prognosis and respond well to therapy. For these patients, it is critical to consider the quality of life impact of intensifying therapy. Others will have a poor prognosis and will progress rapidly. For those patients, early intensification of treatment would be ideal. For patients with metastatic castration-resistant prostate cancer, of course, the big challenge relates to improving outcomes in general. As a radiation oncologist, a particular challenge for me is to determine what role radiation has to the primary and/or to metastatic sites.

Question 4. What do you see as the next big step forward in the pharmacotherapy of metastatic PCa?

Answer
The next big step will be in utilizing biomarkers to determine how to rationally sequence treatments. Much of the sequencing is guided by clinical practice patterns. There are intriguing data to suggest that biomarkers, such as the presence of the constitutively active androgen-receptor splice variant 7 (AR-V7), may predict resistance to certain therapies. In the case of AR-V7, advanced ADT may not be useful. Data from the metastatic castration-resistant prostate cancer space suggest that the presence of DNA repair gene mutations might predict treatment response to PARP inhibitors, and the presence of mismatch repair may portend a benefit to immunotherapy. Biomarker development and validation strategies will help rationally guide treatment.

Question 5. To what extent does the cost of the novel antiandrogens affect treatment decisions?

Answer
The financial toxicity of cancer care is a real problem. I think it must always be considered and currently plays a role in the choice of agent (eg, preferring abiraterone as a first pass in low-volume disease).