Pharmacologic Therapy for Castration-Resistant Prostate Cancer: An Update
David F. Jarrard, MD
Practice Community: Madison, Wisconsin
Hospital and Institutional Affiliations: University of Wisconsin School of Medicine and Public Health in Madison, where he is Professor of Urologic Surgery and holds the John P. Livesey Chair in Urologic Oncology. He also is Associate Director for Translational Research at the University of Wisconsin Carbone Cancer Center.
Number of Patients Seen in a Week: 60 to 70
Practice Niche: Urologic Oncology
At the 2019 annual meeting of the American Urological Association (AUA), Dr Jarrard was a member of the instructional faculty in a session titled “AUA Castration Resistant Prostate Cancer (CRPC) Guidelines and Therapeutic Advances in Metastatic Prostate Cancer.
Question 1. How would you sum up the changes in the management of CRPC that have occurred in recent years?
Answer The field of advanced prostate cancer and CRPC is rapidly evolving, and the 2018 AUA guidelines are undergoing revision. We should have a new set of guidelines available by May 2020. When we think about the management of CRPC, it’s important to differentiate between metastatic symptomatic disease and early non-metastatic, asymptomatic disease. There has been a remarkable change in options for patients with M0 CRPC where previously none existed. These include enzalutamide and apalutamide, which recently received approval in this space. These drugs are now being used earlier in the disease course where previously they were employed in the pre- and post-chemotherapy space only for symptomatic metastatic CRPC.
Question 2. When should the newer oral antiandrogens be used in asymptomatic nonmetastatic CRPC?
Answer Generally, if an individual has a very slowly rising PSA and is asymptomatic in this space, observation is one option. However, if the PSA doubling time is less than 10 months, it’s reasonable to think about treatment with apalutamide or enzalutamide. The risks and benefits need to be discussed. This is clearly an area that urologists need to be involved in and need to be familiar with the application and side effects of these agents.
Question 3. Has the advent of the novel antiandrogens and data supporting their use earlier in advanced prostate cancer changed the role of chemotherapy?
Answer Chemotherapy still has an important role in the management of CRPC. Generally, it’s used in metastatic symptomatic CRPC. Most oncologists would use an oral agent such as apalutamide or enzalutamide before considering chemotherapy, but it remains an option in castration-resistant disease. There are several indications when one might want to consider using it earlier, even before antiandrogens. For example, one might want to use docetaxel as primary therapy for individuals who have very rapidly progressing PSAs and extensive metastases, including large lymph nodes, widespread bony disease, and visceral metastases.
Question 4. What are the patient characteristics that enter into the therapeutic decision-making process?
Answer Quality of life is a very important aspect to consider when we think about the management of patients in the M0 CRPC space. Older patients who have other health issues and have poor performance status may opt for continued observation in this setting. Conversely, someone who has rapidly rising PSA in this castration-resistant space may opt for treatment with either apalutamide or enzalutamide. There are some potential side effects associated with these medicines, but clearly the data demonstrate a marked improvement in radiographic progression-free survival in these patients.
Question 5. At what point is an oncology consult recommended?
Answer Medical oncology is important in the management of these patients. Certainly, I would encourage the urologist to set up lines of communication with medical oncologists. The oral medications are very manageable by practicing urologists, but they need to be aware of the side effects, contraindications, and drug interactions. Generally, when the disease becomes more advanced, and when chemotherapy might be considered an option, it’s worthwhile involving medical oncologists at that point.
Question 6. What follow-up imaging is warranted in the CRPC setting?
Answer Traditional imaging consists of computed tomography scans of the abdomen and pelvis and bone scans. If the PSA is rising rapidly, imaging should be done more often. The advent of newer types of imaging has really changed our management of the disease. Fluciclovine F18 PET scans can help identify metastatic disease in patients with rising PSAs after local treatment. We also have new generation imaging in terms of PSMA PET imaging that looks to be extremely sensitive in picking up small amounts of disease that are outside of the prostate. This is going to change our approach to a lot of these patients. M0 CRPC is potentially going to be a shrinking stage in terms of numbers because newer generation imaging modalities will likely find metastatic cancer in many patients who have a rising PSA in this setting.
Question 7. Which patients with metastatic CRPC would benefit from sipuleucil-T versus antiandrogens?
Answer Sipuleucil-T is indicated for asymptomatic or minimally symptomatic metastatic CRPC. One may want to consider it before an oral antiandrogen. The data clearly indicates that there’s a role for this drug in the modern treatment of patients. Often, we consider using this drug before chemotherapy because it allows us to administer this drug in these relatively asymptomatic patients, when they have a good performance status and may derive the most benefit from this drug compared with much later in the disease. Studies that have looked at optimal use of this approach have indicated that below a PSA of 20 ng/mL is often a good marker for considering use of sipuleucil-T. Sipuleucil-T has side effects that are on the more minor side for the majority of patients. These are often considered flu-like and are usually treated with ibuprofen and rest.
Question 8. What are some important considerations in preserving bone health?
Answer Bone health is a critical aspect of our management of these patients. Often, issues with bone health arise later in the disease. Fractures related to bone density loss can be lethal in elderly patients with advanced prostate cancer. Current recommendations for bone health would be to consider getting a DEXA scan and generating a FRACS score to help determine bone density prior to being placed on androgen deprivation therapy. Most patients will benefit from being placed on vitamin D and calcium supplements. In patients with CRPC who are undergoing therapy, one can also consider, if patients have an at-risk FRACS score, being placed on an agent that prevents bone loss such as denosumab or zoledronic acid. In this situation, denosumab has some advantages in that it is subcutaneous and doesn’t require the individual going to an infusion center.
Question 9. Are there other agents we can consider with unique mechanisms of treatment in CRPC?
Answer Another therapeutic consideration is radium-223, which is indicated for patients with CRPC and symptomatic bone metastases. Contraindications to the use of this drug include visceral metastases. It is an option for patients anywhere along the course of the disease. This is an important discussion to have with patients as well as medical oncologists.
Question 10. What role, if any, do you see for metastasectomy in the setting of metastatic prostate cancer?
Answer With newer-generation imaging, we’re now finding evidence of disease in lymph nodes and other sites that we would never have seen before earlier in the disease. It’s important to realize that metastasectomy in the CRPC setting is considered investigational and not standard of care. Potentially, there are patients who may benefit in selected situations. At the present time, it does not form part of our guidelines-based approach.