November/December 2022

Prostate Cancer Medications
By Mark Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 15 No. 6 P. 22

How Safe Are They?

Prostate cancer is the second most common cancer in American men, behind skin cancer.1 And while most men diagnosed with it today do not die from it, the disease remains second only to lung cancer as the leading cause of cancer death in American men.1 For men diagnosed with prostate cancer, deciding on the most appropriate treatment involves weighing a number of positives and negatives of each available treatment option.2

Despite the FDA’s close evaluation of a medication’s safety profile during its approval process, new safety information sometimes comes to light once a medication becomes more widely used. This is the case for two of the most commonly used oral medications for the treatment of advanced prostate cancer: abiraterone and enzalutamide.

Michigan Medicine Study
In a recent report published in the Journal of the National Cancer Institute, researchers from Michigan Medicine at the University of Michigan found that the treatments abiraterone or enzalutamide may pose a greater risk of serious medical concerns, including metabolic or cardiovascular issues, than was previously understood.3

Study Methods
To gain a greater understanding of the drugs’ safety profiles in real-world settings, researchers designed a study to examine the association between the use of abiraterone or enzalutamide and the risk of metabolic or cardiovascular adverse events in patients undergoing treatment. Men with advanced prostate cancer and using abiraterone or enzalutamide were identified in a 20% sample of the 2010–2017 national Medicare claims. The primary composite outcome was the occurrence of a major metabolic or cardiovascular adverse event, defined as an emergency department visit or hospitalization associated with a primary diagnosis of diabetes, hypertension, or cardiovascular disease. The secondary composite outcome was the occurrence of a minor metabolic or cardiovascular adverse event, defined as an outpatient visit associated with a primary diagnosis of the aforementioned conditions. Risks were assessed separately for abiraterone and enzalutamide using Cox regression. All statistical tests were two-sided.

Increased Safety Concerns
The researchers found that patients taking abiraterone had a 1.77 times greater risk of a major composite adverse event (hazard ratio [HR] = 1.77, 95% confidence interval [CI] = 1.53 to 2.05;
P < .001), including being admitted to the emergency department or the hospital because of diabetes, hypertension, or heart disease, compared with those receiving only hormone therapy. These patients were also at 1.24 times greater risk of minor composite adverse events (HR = 1.24, 95% CI = 1.05 to 1.47; P = .01).

The researchers found that patients receiving enzalutamide had a 1.22 times greater risk of a major composite adverse event (HR = 1.22, 95% CI = 1.01 to 1.48; P = .04) and a 1.04 times greater risk of minor composite adverse event compared with men not receiving abiraterone.

Real-World Use
The study authors note that abiraterone and enzalutamide were found to be relatively safe in clinical trials but that the population of patients treated in the clinical trials was different from those seen in real-life settings. Compared with the preliminary clinical studies utilized for FDA approval, the patients in this study were older and on Medicare. Furthermore, patients in clinical trials are highly selected and may not reflect the broader patient population.

Study Conclusions
The authors suggest that their findings and a better understanding of the risks associated with these life-prolonging cancer treatments in real-life settings can help clinicians and patients make better informed decisions regarding treatment. They emphasized that as approved indications for abiraterone and enzalutamide expand to earlier stages of prostate cancer, a growing number of men will receive these therapies, which in turn will expand the scope of men potentially affected by these adverse events. The researchers concluded that the careful monitoring and team-based management of men taking abiraterone or enzalutamide are critical and that since metabolic and cardiovascular conditions tend to be under the purview of primary care providers, team-based care that involves primary care practitioners for patients with advanced prostate cancer is a way to manage these higher risks.

Cancer Patient Considerations
Patients requiring cancer treatments must consider the chance of a cure, potential short and long-term side effects, the likelihood that cancer will recur after treatment, their chances of living longer with or without treatment, the effect on their quality of life and independence, and their preferences as well as those of their family.4 Thus, health care professionals should embrace the opportunity to help patients and their families not only weigh the increased safety concerns with abiraterone and enzalutamide but also understand how these medications work, the types of prostate cancer they are appropriate to treat, and their potential to prolong life for some patients.

The Role of Androgens
Abiraterone and enzalutamide are types of antiandrogens. Androgens are a group of sex hormones that primarily influence the growth and development of the male reproductive system, with testosterone being the predominant and most well-known. In males, androgens play a role in processes including bone and muscle development, puberty regulation, and the development of primary and secondary sex characteristics. Androgens are also required for the growth and function of the prostate gland. When androgen hormone function is dysregulated, it can cause the abnormal growth of cells in the prostate, leading to prostate cancer. Androgens promote the growth of both normal and cancerous prostate cells by binding to and activating the androgen receptor, which is a protein expressed in prostate cells. Once activated, the androgen receptor stimulates the expression of specific genes that cause prostate cells to grow. While almost all testosterone is produced by the testes, a small amount is produced by the adrenal glands. And although testosterone is not normally made in the prostate cells, some prostate cancer cells acquire the ability to do so.

Types of Advanced Prostate Cancer
It’s important to be aware of the types of advanced prostate cancer for which these medications are approved. (The term “castration” below refers to the lowering of testosterone levels.)

Nonmetastatic castration-resistant prostate cancer (CRPC) is a form that has not spread to other parts of the body and no longer responds to hormone therapy or surgical treatment to lower testosterone.

Metastatic castration-sensitive prostate cancer (CSPC) is a form that has spread to other parts of the body and responds to hormone therapy or surgical treatment to lower testosterone.

Metastatic CRPC is a form that has spread to other parts of the body and no longer responds to hormone therapy or surgical treatment to lower testosterone.

A Closer Look at Abiraterone and Enzalutamide
Both abiraterone and enzalutamide treat prostate cancer by disrupting androgens, but they do this in different ways. The following efficacy data reviewed should not be used to compare the efficacy of these medications to each other as the studies are not head to head.

Abiraterone
Abiraterone acetate, marketed under the brand name ZYTIGA, is FDA-approved for use along with prednisone in advanced prostate cancer, where the cancer has spread to other parts of the body.4 It works by interrupting the androgen-making process at an important step. It inhibits androgen at three sources—the testes, the adrenal glands, and the prostate tumor itself.5

Abiraterone is given with prednisone to replace lost cortisol by the adrenal glands that contributes to side effects including low blood potassium levels, edema, high blood pressure, and irregular heartbeats. The most common adverse reactions (≥10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia.

Severe hypoglycemia has been reported when abiraterone was administered to patients with preexisting diabetes receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide. Blood glucose levels should be monitored closely in patients with diabetes during and after discontinuation of treatment with abiraterone. Antidiabetic dosages may need to be adjusted to minimize the risk of hypoglycemia.

FDA approval was based on clinical studies including more than 3,000 men with metastatic prostate cancer. In clinical studies in men with metastatic CRPC, taking abiraterone with prednisone in addition to standard hormone therapy prolonged life by about 4.5 months.4 For men with metastatic CSPC, drug therapy that included abiraterone lowered the risk of death by 34% over 52 months.6

In a study of men with either metastatic CRPC or CSPC who were starting hormone therapy for the first time, those who took abiraterone had a three-year survival rate of 83%.7 This means they lived for three years after they started taking the drug. Those who received standard therapy had a three-year survival rate of 76%. Also, in this study, abiraterone with prednisone lowered by 37% the risk of death within three years of starting treatment.

Enzalutamide
Enzalutamide, which is marketed under the brand name XTANDI, is FDA-approved to treat advanced forms of prostate cancer that no longer respond to hormone therapy or surgical treatment to lower testosterone and in prostate cancer that’s spread to other parts of the body and responds to hormone therapy or surgical treatment to lower testosterone.8 It works as an androgen receptor inhibitor that acts on multiple steps of the androgen receptor signaling pathway within the tumor cell. Enzalutamide inhibits androgen binding to the androgen receptor, inhibits androgen receptors from entering the nucleus, and inhibits androgen receptor binding to DNA. As a result of these mechanisms, it decreases prostate cancer proliferation, reduces tumor volume, and increases tumor cell death.

In the data from the four randomized placebo-controlled trials, the most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. Lab abnormalities that occurred in ≥ 5% of patients and more frequently (> 2%) in the XTANDI arm compared with placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia.

In a study of 1,150 men with metastatic CSPC, enzalutamide lowered the chance of progression by 61%. The median length of time until cancer progressed was not reached for XTANDI + androgen deprivation treatment (ADT) vs 19 months for ADT alone. Progression was defined as cancer getting worse, as measured by scans, or if the patient died for any reason.

In a study of 1,717 men with metastatic CRPC, enzalutamide lowered the chance of progression by 83%. The median length of time until cancer got worse was not reached for XTANDI + ADT vs four months for ADT alone. Progression again was defined as cancer getting worse, as measured by scans, or if the patient died for any reason.

In a study of 1,401 men with nonmetastatic CRPC, enzalutamide lowered the chance of progression by 71%. The median length of time until the cancer spread was 37 months for XTANDI + ADT vs 15 months for ADT alone. Progression, similarly, was defined as the cancer spreading, as measured by scans, or if the patient died for any reason.

Increasing Prostate Cancer Awareness
In addition to helping patients and families weigh prostate cancer treatment options, health care professionals also play a vital role in assisting patients and families by promoting prostate cancer awareness through education on prostate cancer facts, including key statistics and risk factors that should prompt increased screening and by stressing modifiable risk factors.

Key Statistics
The American Cancer Society estimates that this year there will be about 268,490 new cases of prostate cancer and roughly 34,500 deaths from the disease.1 During their lifetimes, about 1 in 8 men will be diagnosed with prostate cancer. About 1 man in 41 will die of prostate cancer, and more than 3.1 million men in the United States who have been diagnosed with prostate cancer at some point are still alive today.

Prostate Cancer Risk Factors
Nonmodifiable risk factors for prostate cancer include age, race, and family history.

Age
The risk of developing prostate cancer is rare in men younger than 40 (odds 1 out of 10,000) but increases rapidly after age 50. One in 15 men in their 60s will be diagnosed with the disease, with 6 in 10 cases found in men older than 65.7 The average age of men at diagnosis is roughly 66 years.

Race
Black men are about 70% more likely to develop prostate cancer in their lifetimes than are white or Hispanic men. They’re also more likely to develop prostate cancer at a younger age, and it’s more likely their disease will progress to a metastatic state and/or higher grade before clinical diagnosis.

Family History
Gene mutations such as the BRCA1 and BRCA2 gene mutations, as well as other inherited mutations including HOXB13 and DNA mismatch repair genes may explain why prostate cancer runs in families. Having a father or brother with prostate cancer may double a man’s risk, especially if that relative was diagnosed before age 55.

Other Risks
Other risk factors proposed (albeit with conflicting reports in the literature) include a diet high in calcium, obesity, chemical exposure, smoking, prostatitis (inflammation of the prostate gland), sexually transmitted diseases, and vasectomy. Although most studies have not found a direct link between smoking and the development of prostate cancer, there’s evidence that smoking raises the risk of more aggressive prostate cancer and recurrent cancer and also increases one’s chances of dying from prostate cancer.

Prostate Cancer Prevention
While many of the risk factors for prostate cancer are unavoidable, physicians can recommend lifestyle modifications to their patients to help them prevent prostate cancer, including:9,10

• Get regular exercise.
• Maintain a healthy diet to sustain a healthy weight.
• Avoid fat from dairy products and red and processed meats.
• Avoid sugar-sweetened drinks and highly processed food.
• Limit calcium intake to 1,200 mg per day.
• Eat more healthy fats from fatty fish and olive oil.
• Get additional nutrients from tomatoes, broccoli, cauliflower, soy-based foods, and green tea.
• Avoid smoking and heavy use of alcohol.
• Avoid overdosing on multivitamins.
• Avoid vitamin E supplements and folic acid supplements.
• Try to control blood pressure, blood sugar, and cholesterol levels.
• Keep stress levels low.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Key statistics for prostate cancer. American Cancer Society website. https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html. Updated January 12, 2022.

2. Making decisions about cancer treatment. Messino Cancer Centers website. https://messinocancercenters.com/resource/cancer-treatment/making-decision-about-cancer-treatment/

3. Lai LY, Oerline MK, Caram MEV, et al. Risk of metabolic and cardiovascular adverse events with abiraterone or enzalutamide among men with advanced prostate cancer. J Natl Cancer Inst. 2022;114(8):1127-1134.

4. Janssen Pharmaceutical Companies. Highlights of prescribing information. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/ZYTIGA-pi.pdf. Updated August 2021.

5. How ZYTIGA® works. Zytiga website. https://www.zytiga.com/taking-zytiga. Updated September 2021.

6. Metastatic high-risk CSPC LATITUDE study. Zytiga website. https://www.zytigahcp.com/efficacy-and-safety

7. Efficacy in mCRPC: PREVAIL trial. Xtandi website. https://www.xtandihcp.com/efficacy/metastatic-crpc/prevail

8. Xtandi. Xtandi website. https://www.xtandihcp.com/

9. Prostate cancer risk factors. American Cancer Society website. https://www.cancer.org/cancer/prostate-cancer/causes-risks-prevention/risk-factors.html. Updated June 9, 2020.

10. Prostate cancer prevention (PDQ®)–patient version. National Cancer Institute website. https://www.cancer.gov/types/prostate/patient/prostate-prevention-pdq. Updated May 6, 2022.