Choosing Therapies in Prostate Cancer

By David Ambinder, MD - September 27, 2022

Multiple considerations come into play when physicians evaluate the best oral hormonal treatment for their patients with prostate cancer. The goals and concerns of the individual patient and his lifestyle also factor into these decisions as does the aim to help patients become active partners in their own care and well-being. In this interview, Catherine Handy Marshall, MD, MPH, serves as our guide to demystifying the complexities of the decision-making process, offering a practical approach that clinicians can apply when thinking through decisions and explain their choices to patients. Dr. Marshall is an assistant professor of oncology in the Department of Oncology, in the Division of Genitourinary Oncology, at the Johns Hopkins University School of Medicine in Baltimore. Her work has been published in such journals as The New England Journal of Medicine, European Urology, Future Oncology, and Prostate Cancer and Prostatic Diseases. Her research focus is on prostate cancer, genetics, and cardiovascular disease.

Dr David Ambinder: There are a wide variety of therapies available for treatment of patients with prostate cancer. What are some of that are associated with significant side-effect profiles?

Dr Catherine Marshall: When I talk with my patients about available medications and their options for therapy, I break down the treatments into a few buckets:

  1. Androgen-deprivation therapy (ADT) – this includes the therapies that suppress testosterone production by the testes which are the LHRH agonists and antagonists.
  2. Oral androgen axis–targeting agents – abiraterone, enzalutamide, darolutamide, apalutamide, and sometimes bicalutamide
  3. Chemotherapy – docetaxel and cabazitaxel mostly. Sometimes also carboplatin is included in this list.
  4. Immunotherapy – sipuleucel-T but also programmed death 1 inhibitors for rare subsets of patients with microsatellite instability-high cancer, or cancer with a high-tumor mutational burden
  5. Radiopharmaceuticals – these include radium-223 and now lutetium-177– prostate-specific membrane antigen-617, better known as 177Lu-PSMA
  6. Everything else – this includes PARP (poly adenosine diphosphate-ribose polymerase) inhibitors for a subset of patients.1

Depending on the patient and state of disease, we might be talking about using therapy from 1 or more of those buckets at a given time.  For example, as a medical oncologist, almost all patients I see will end up requiring ADT at some point in the treatment of prostate cancer. I discuss the potential side effects, which include injection site reaction and the side effects of testosterone suppression. I also break these side effects down into short term (eg, hot flashes, weight gain) and longer term (eg, bone health, metabolic disease) categories which include injection site reaction and the side effects of testosterone suppression. I also break these side effects down into short term (eg, hot flashes, weight gain) and longer term (eg, bone health, metabolic disease) categories.

What are some of the important considerations when deciding how to counsel a patient about a treatment’s side-effect profile before starting them on hormone therapy, i.e, abiraterone?

For the oral androgen axis–targeting agents, I first talk about some of the side effects they share as a drug category, given that they all target the hormonal pathways in some manner. Typically, these effects include fatigue, hot flashes, and cardiometabolic toxicities.  For abiraterone, specifically, I also talk about side effects from prednisone.  This can be particularly important for certain patients who need to monitor their glycemic control.  Then, I talk more about some of the major unique differences between the drugs.  For example, use of abiraterone initially requires regular laboratory monitoring because of the risk of hepatoxicity. Seizures and fatigue are more pronounced with enzalutamide, while rash is more common with apalutamide.

With cytotoxic chemotherapy, I begin by talking about the shared side effects of chemotherapy—primarily docetaxel and cabazitaxel for the treatment of prostate cancer—as well as the logistical differences between receiving chemotherapy compared with one of the oral agents.  Then I talk specifically about the individual side effects of treatment, like neurotoxicity and alopecia with docetaxel. The side effects are usually a major reason why we might not choose chemotherapy when there are alternative options available.

Sipuleucel-T side effects are mainly around the time of reinfusion of the cellular product and most often include infusion reactions and chills, fevers, and flulike symptoms. For patients who need a central venous catheter, I also discuss possible side effects related to the catheter, like infection and clotting. If I’m using PD-1 inhibitors for the subset of patients with MSI-high disease or high tumor mutational burdens, I discuss the spectrum and time course of auto immune toxicities that can arise.

The radiopharmaceutical treatments can cause cytopenias, and in patients who have baseline cytopenias related to chemotherapy or the disease, this is a common reason why I do not prescribe these. 177Lu-PSMA has the unique side effect of dry mouth because of PSMA expression in the salivary glands. Radium-223 also causes more gastrointestinal side effects like nausea and diarrhea.

For the PARP inhibitors, olaparib is approved for use in men with alterations in one of 15 genes in the homologous recombination repair pathway who have disease that has progressed after one oral therapy, while rucaparib is approved for men with BRCA1 or BRCA2 gene alterations who have disease that has progressed after treatment with an oral agent and a taxane. Those differences in the approval are one of the main reasons why I choose one over the other as the side effects of the class are similar. Fatigue, cytopenias, and gastrointestinal toxicities are the most common. Studies with rucaparib also reported elevated transaminases which should be monitored on therapy.

Are there any considerations specifically related to side-effect profiles that you weigh before choosing one type of hormone therapy over another?

Absolutely! Fluid retention and the requirement for concomitant use of prednisone sometimes leads me away from choosing abiraterone.  If a patient has seizures or significant fatigue at baseline from ADT, I tend to not select enzalutamide.  For patients very worried about side effects, or in whom I’m very worried about side effects, I will sometimes start treatment at a low dose and monitor for side effects for the first 1 to 3 months.  If there are no significant side effects, then I will consider titrating up to the recommended dose after the first few months.

Are there any important adjuncts (medications, supplements, holistic approaches) that can help mitigate the side effects of oral hormonal agents?

Exercise! I suggest exercise for all of my patients taking hormonal agents. Exercise really does help offset many of the side effects of the medication, but it can be harder to get patients to begin exercise programs after treatment has started. I still recommend calcium and vitamin D supplements for all of my patients receiving ADT, although that may change in the future after the large trial recently published in The New England Journal of Medicine did not find that supplementation lowered the risk of fractures among people without vitamin D deficiency or low bone mass or osteoporosis.

How often do you screen your patients on hormone therapy for side effects? Are there any particular lab tests that should be done routinely?

I see each patient at least once every 3 months.  If they have other comorbidities, I may ask them to come in sooner than that—usually about 4 to 6 weeks after starting a new drug.  Now that it is easy for some patients to communicate with me through their electronic medical record, I also encourage them to use it to report any new symptoms or to ask questions as they arise.  With the expansion of telemedicine during the COVID-19 pandemic, I do some of these visits as telemedicine visits as well.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology