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Enzalutamide for Metastatic Castration-Sensitive Prostate Cancer: Andrew J. Armstrong, MD, MSc

Andrew J. Armstrong, MD, MSc.

The FDA recently added a new approval of enzalutamide (Xtandi®, Astellas Pharma Inc.) for the treatment of metastatic castration-sensitive prostate cancer, based on data from the ARCHES and ENZAMET trials. In this interview with i3 Health, Andrew J. Armstrong, MD, MSc, lead researcher of the phase 3 ARCHES trial, discusses the approval's significance and compares the variety of options that are now available for the treatment of metastatic hormone-sensitive disease.

What are the greatest challenges involved in treating patients with metastatic castration-sensitive prostate cancer?

Andrew J. Armstrong, MD, MSc: When I see a man who has metastatic disease and is just starting on treatment, there's quite a range of possible options now resulting in better outcomes which are discussed with the patient. These decisions are based on the volume of his metastatic disease (such as the pattern of spread), his other health conditions, and his preferences; the decisions also depend on whether he's had prior therapy to his prostate, such as surgery or radiation. Now, with the approval of enzalutamide, abiraterone, and apalutamide as well as the availability of docetaxel, we have really good news that men are living longer while maintaining a high level of quality of life. However, treatment decisions have become more complex and expensive, and they illustrate the need for attention to side effects and a holistic approach to care.

The good news is that men are doing better. Their disease is being more optimally controlled by these improved and more potent systemic therapies, with longer-lasting remissions of the prostate cancer. We also have new data that some men with metastatic disease should have their prostates treated with radiation, which can further extend survival. The enzalutamide approval, based on the ARCHES and ENZAMET trials, adds another agent to several that have demonstrated improved outcomes for these patients, giving us another weapon to discuss with our patients and another choice, which is always good for patients.

Can you comment further on the significance of the enzalutamide approval for metastatic hormone-sensitive disease?

Dr. Armstrong: Now we have four agents that have demonstrated improved survival in this setting of what we call metastatic hormone-sensitive prostate cancer (mHSPC), which means men who, on standard imaging, have metastatic disease outside the prostate, and either their disease is either still responding to hormone therapy, or they have not even started hormonal therapy. Enzalutamide is the latest approval, but as I mentioned earlier, we also have docetaxel, abiraterone, and apalutamide. All of these agents are effective, but they do differ based on their side effects.

How does enzalutamide compare with the other treatments for mHSPC in terms of adverse events?

Dr. Armstrong: Enzalutamide and apalutamide are very similar in structure and in the way in which they work, but obviously, docetaxel is very different from these hormonal therapies. A major distinguishing factor of chemotherapy versus hormonal therapy is that chemotherapy is intravenous. Chemotherapy has side effects on the bone marrow, hair loss, significant fatigue, negative impacts on quality of life over a six- to 12-month period, and additional side effects such as neuropathy and nausea that really are not seen with these hormonal therapies, which are really pills.

These pills do differ from each other. For example, abiraterone requires prednisone, but apalutamide and enzalutamide do not. Prednisone can have its own list of side effects, and many patients with prostate cancer have issues with their weight, diabetes, metabolic syndrome, and cholesterol, where prednisone may cause increases in cardiac risk, electrolyte imbalance, or liver problems that could be avoided by avoiding abiraterone/prednisone. However, abiraterone/prednisone is well tolerated overall and is a good option for many patients.

Enzalutamide is a very potent inhibitor of the androgen receptor. Because of that, it works throughout the body, as do all of these agents. Apalutamide is very similar. The main side effects are fatigue and hot flushes, hypertension, and muscle loss. These medications do also reduce bone density, so there is a higher risk of fracture. This emphasizes the need for bone density monitoring and management of bone loss. The good news is that seizures, which have been rarely observed with enzalutamide, are seldom seen in this setting.

The main side effects have been largely those of fatigue due to the effects on muscle, so it's important when you're starting these kinds of drugs to emphasize to patients the need to continue to exercise or to stay fit, to watch their diet, to avoid gaining weight, and to really monitor blood pressure. Hypertension is a side effect of all of these hormonal therapies, and cardiac risk for these older men is still a major issue over long periods of time because men are living longer now, so other things can start to cause problems over time.

For a patient who has preexisting hypertension, would you still prescribe enzalutamide?

Dr. Armstrong: Absolutely. Hypertension is relatively easy to control if recognized, and treatment of high blood pressure can prevent heart disease and stroke. Some patients may require several antihypertensives, and you have to follow patients closely. I do recommend home blood pressure monitoring for these patients who are starting any of these hormonal therapies, and you have to be proactive and monitor and manage the hypertension. That could be done by the patient's primary care doctor or cardiologist, or most medical oncologists feel very comfortable with doing that. Working as a team to manage that patient's cardiac risk is really important.

You mentioned the small seizure risk with enzalutamide. Would this drug be contraindicated in a patient with a history of seizure?

Dr. Armstrong: Patients with a history of seizure or epilepsy or who take medications that lower the seizure threshold still can be safely treated with enzalutamide, but the risk of seizures would be a bit higher. Still, the risk is low, at under 5% even in high-risk patients. In those patients, I would tend to favor abiraterone or docetaxel, which really have no seizure risk.

About Dr. Armstrong

Andrew J. Armstrong, MD, MSc, a medical oncologist, is a Professor of Medicine and Surgery and an Associate Professor of Pharmacology and Cancer Biology at Duke University School of Medicine. In addition, he is a Member of the Duke Cancer Institute (DCI) and is Director of Research for the DCI Center for Prostate and Urologic Cancers. He is involved in clinical and translational research in drug development and biomarker studies for prostate and kidney cancer, with a focus on prognostic and predictive biomarkers, circulating tumor cell biology, and metastasis. He oversees multiple clinical trials of hormonal therapies, chemotherapies, immunotherapies, and molecularly targeted agents.

For More Information

Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al (2019). ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol, 37(32):2974-2986. DOI:10.1200/JCO.19.00799 (2019). A study of enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT in patients with metastatic hormone sensitive prostate cancer (mHSPC) (ARCHES). NLM identifier: NCT02677896.

Davis ID, Martin AJ, Stockler MR, et al (2019). Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med, 381:121-131. DOI:10.1056/NEJMoa1903835 (2018). Enzalutamide in first line androgen deprivation therapy for metastatic prostate cancer (ENZAMET). NLM identifier: NCT02446405.

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