Rethinking Long-Term Hormone Therapy for Prostate Cancer

For decades, androgen-deprivation therapy (ADT, or hormone therapy) has been a cornerstone of treatment for men with advanced metastatic prostate cancer and also for many men with localized cancer receiving radiation therapy, particularly those with more aggressive disease. But a recent large-scale study suggests that for many patients, a longer course of ADT may not be better.

Researchers reported that most of the benefits of hormone therapy for prostate cancer occur within the first nine to 12 months. Extending treatment beyond that window appears to offer only modest additional cancer control while significantly increasing the risk of side effects.

“Prostate cancer treatment should not be one-size-fits-all,” says Amar Kishan, MD, a UCLA Health radiation oncologist and co-senior author of the study. “These findings help doctors personalize therapy, balancing cancer control with potential side effects and other health risks.”

What Is Hormone Therapy for Prostate Cancer?

Testosterone is the main androgen, a type of sex hormone that plays a key role in reproductive and overall health. Men and women produce these hormones, but men naturally create more of them. Androgens are responsible for typical male physical traits, such as a deeper voice, increased muscle mass, sperm development, and hair growth on the face, chest, arms, scalp, and genitals.

In some men, androgens also help to fuel the growth of prostate cancer. Working through testosterone suppression, ADT serves as an off-switch of sorts for that hormonal fuel pump. The treatment reduces testosterone levels to near zero, thereby depriving cancer cells of the hormonal fuel they need to grow.

When Is Androgen-Deprivation Therapy Used?

Several treatments are used to manage early-stage prostate cancer that remains confined to the prostate, depending on the cancer’s risk level and grade—i.e., how likely it is to grow quickly and spread aggressively. Curative therapies include surgery to remove the prostate (radical prostatectomy) and radiation therapy, using external-beam radiotherapy (EBRT) or radioactive seed implants (brachytherapy). EBRT also may be used in a salvage capacity for men who show signs of cancer recurrence after radical prostatectomy.

And, for many men with low-risk and some with intermediate-risk cancers, active surveillance is recommended. In this strategy, men are monitored closely and undergo curative treatment only when clinical testing the disease is advancing.

As a standalone therapy, ADT is generally reserved for men with advanced prostate cancer, which has spread outside the prostate. In some instances, it can be added to salvage EBRT treatment after radical prostatectomy, and it can be used to help shrink tumors to make them more amenable to surgical or radiation treatment.

Also, ADT is commonly used in men with intermediate- or high-risk cancers who select EBRT as their initial treatment. Guidelines from the National Comprehensive Cancer Network (NCCN) recommend adding four to six months of ADT to EBRT for men with unfavorable intermediate-risk prostate cancer and 12 to 36 months of ADT for men with high-risk localized prostate cancer.

New Findings About Androgen-Deprivation Therapy

In the recent study, the research team conducted a meta-analysis of 13 international randomized clinical trials examining the use of radiotherapy alone or with ADT among a total of 10,266 men, ages 65 to 74. Researchers compared different durations of ADT and evaluated outcomes including overall survival, cancer-specific survival, and deaths from other causes.

The results suggest that the ideal length of hormone therapy for prostate cancer depends heavily on a patient’s prostate cancer risk level, which is determined using established classification systems based on tumor characteristics. Among the findings:

• Low-risk patientsmay not need ADT at all.
• Intermediate-risk patientsbenefit most from six to 12 months of therapy.
• High-risk patientsachieve most of the survival benefit by 12 months.
• Very high-risk patients (a smaller subset with extremely aggressive disease) may still require longer treatment.

“What pleasantly surprised us was that we were able to see this pattern so clearly in a very large, high-quality dataset,” Dr. Kishan says. “Across studies, the vast majority of benefit was achieved within the first year. …Our findings suggest that very long-term therapy, longer than 12 months, should really be reserved for only the most aggressive cancers.”

The findings could have major implications for men with high-risk prostate cancer, for whom guidelines recommend 18 to 36 months of ADT. The study suggests that most of these men gain nearly all of the benefit within the first year, and that extending therapy longer may allow side effects to outweigh the advantages.

Types of Androgen Deprivation Therapy

ADT usually involves the use of one or more of several classes of medications (see the chart for ADT drug types and examples):

• LHRH agonists. The most commonly used of these medications are luteinizing-hormone-releasing hormone (LHRH) agonists, which are administered as injections or small implants under the skin from once a month to every six months (a once-yearly implant of the LHRH agonist histrelin is available, as well).
• LHRH antagonists. These drugs halt the secretion of luteinizing hormone to stop androgen production in the testicles. Administered as a once-monthly injection (degarelix) or daily pill (relugolix), they can decrease testosterone levels more quickly than LHRH agonists. In a clinical trial involving relugolix, 97% of men taking the drug achieved very low testosterone at four months, compared with 89% of those treated with leuprolide. Men taking relugolix also experienced a quicker recovery of their testosterone level once treatment was stopped.
• Antiandrogens. These medications are taken daily and are most commonly used in combination with other drugs that lower androgen levels.
• Second-generation ADT drugs. Known as androgen receptor axis-targeted (ARAT) therapies or androgen receptor pathway inhibitors (ARPIs), they target other aspects of the androgen pathway. For men with metastatic prostate cancer, these medications are often combined with conventional ADT to help achieve testosterone levels far lower than those achieved with conventional ADT drugs alone.
• Orchiectomy. Another way to achieve the effects of ADT is orchiectomy, or surgical removal of the testicles. Unlike medical therapy, orchiectomy is irreversible.

Side Effects of Hormone Therapy

ADT, especially long-term use, is associated with a wide range of side effects. The treatment can cause reduced sex drive, erectile dysfunction, hot flashes, breast enlargement/tenderness, fatigue, nausea/diarrhea, and decreased strength. Memory problems, depression and liver damage are other potential side effects.

Importantly, ADT has been associated with increased cardiovascular risk and a greater likelihood of metabolic syndrome, a group of risk factors that raise the risk of type 2 diabetes, heart attack, and stroke. In a scientific statement, experts from the American Heart Association recommended that before starting ADT, men should undergo cardiovascular health assessments and, during treatment, be monitored for signs of metabolic syndrome or uncontrolled cardiovascular risk factors, such as high blood pressure, high cholesterol, diabetes, obesity and smoking.

Moreover, because ADT reduces bone density, long-term treatment may increase the risk of osteoporosis and bone fractures. Some experts recommend that men undergo imaging studies before and during ADT to assess and monitor their bone health and fracture risk.

Intermittent vs. Continuous Hormone Therapy

As a way to decrease side effects from hormone therapy, some physicians try intermittent ADT, in which treatment is stopped and restarted for established periods of time or based on the results of clinical tests.

Research comparing intermittent with continuous ADT has produced conflicting findings. Some data suggest no significant survival differences between the two approaches, but some studies have found that men on intermittent ADT may experience improvements in quality of life.

Why the Study Findings Matter

Many men are understandably concerned when they hear they need hormone therapy for prostate cancer, given its impact on energy levels, metabolism, heart health, and quality of life. The recent study findings offer reassurance that shorter courses may be both safer and just as effective for many patients receiving ADT along with radiotherapy.

“ADT improves survival, especially for patients with aggressive cancer,” Dr. Kishan says. “But there is significant room to personalize how long patients actually need to be on it.”

Rather than assuming longer treatment is always better, decisions about ADT duration should account for a patient’s cancer risk, age, overall health, and existing heart or metabolic conditions, as well as personal preferences.

“If you have a diagnosis of prostate cancer and are receiving radiation therapy, the key takeaway is to discuss with your treating team what your true benefits versus risks may be,” Dr. Kishan says. “For many men, a shorter course is likely enough.”