Novel Hormone Therapies For Advanced Prostate Cancer: ARPIs

“Once a patient has advanced prostate cancer, and specifically, if they have CRPC [castration-resistant prostate cancer], the treatment algorithm is, we start with ADT … so we have these hormone injections,” Dr. Neha Maithel, a medical oncologist at University of Texas Health – Houston, tells SurvivorNet. “We add on a hormone pill most of the time, and a hormone pill would include something like enzalutamide or darolutamide, or it could be abiraterone.

“There are two mechanisms of action. One is blocking a testosterone [from binding to its receptor]. The other one is blocking CYP17 [enzymes] that are found in the adrenal gland,” she adds. These enzymes are needed to make testosterone everywhere in the body.

Together, these two types of hormone therapy can work together to keep cancer from progressing for longer.

First, The Backbone: ADT

GnRH agonists and antagonists (injections or implants) like leuprolide or degarelix signal the body to reduce testosterone to very low (castrate) levels. They’re time-tested and still the foundation of care for advanced prostate cancer.

A newer option, an oral GnRH antagonist (relugolix), is a once-daily pill that lowers testosterone rapidly without an injection. In a large study (HERO), relugolix kept testosterone suppressed more consistently than leuprolide and it returned to normal more quickly after stopping.

Some analyses also suggested a lower rate of major cardiac events compared with leuprolide, which can be important for men with heart disease. Ask your clinician whether a daily pill, injection schedule, heart history, or other medications makes one approach better for you.

Common ADT side effects include:

• Hot flashes
• Low libido/erectile dysfunction
• Fatigue
• Weight gain
• Loss of muscle
• Mood changes
• Bone thinning

Your team may suggest exercise, calcium/vitamin D, bone-strengthening drugs, and lifestyle changes to reduce these risks.

Androgen Receptor Pathway Inhibitors (ARPIs)

These tablets don’t lower testosterone by themselves; instead, they block the androgen receptor or androgen production inside the tumor.

They’re often added to ADT to “intensify” treatment and are used across several disease states, including:

• Metastatic hormone-sensitive prostate cancer (mHSPC): This is when cancer has spread, but it still responds to testosterone lowering.
• Non-metastatic castration-resistant prostate cancer (nmCRPC): This means PSA is rising despite low testosterone, but scans show no spread.
• Metastatic castration-resistant prostate cancer (mCRPC): In these cases, cancer has spread and is growing despite low testosterone.

The main ARPIs you’ll hear about are:

• Abiraterone acetate (plus prednisone): This blocks a key enzyme (CYP17) that tumors use to make androgens. It’s often combined with ADT in mHSPC and mCRPC. Side effects can include fluid retention, high blood pressure, low potassium, and liver test changes. Your team will monitor labs regularly.
• Enzalutamide: This is a potent androgen-receptor blocker used in mHSPC, nmCRPC, and mCRPC. Side effects can include fatigue, high blood pressure, falls, and rarely seizures; it can interact with other medications, so it’s important to bring a complete medication list to each visit.
• Apalutamide: Similar to enzalutamide, this is used in mHSPC and nmCRPC. Common effects include fatigue, rash, thyroid test changes, and falls/fractures. Bone health strategies are important.
• Darolutamide: This is used in nmCRPC and mHSPC (often with ADT and sometimes with docetaxel). It tends to have fewer interactions with other drugs and may have a favorable side-effects profile for some men.

Real-world and trial data continue to mature; choice among ARPIs often hinges on your other health conditions, drug interactions, convenience, and cost.

These medicines are typically taken daily alongside ongoing ADT. You’ll have periodic blood work (PSA, liver tests, electrolytes), blood pressure checks, and symptom check-ins. Benefits include delaying spread, shrinking or stabilizing tumors, lowering PSA, relieving symptoms, and — importantly — helping men live longer. Your team may also suggest pairing ARPIs with radiation (for selected patients) or chemotherapy, depending on your scan results and overall health.

Combination Approaches With PARP inhibitors

Some advanced prostate cancers carry changes in DNA-repair genes (such as BRCA1 or BRCA2). If present, a PARP inhibitor can be combined with an ARPI to enhance tumor control.

In 2023 the FDA approved talazoparib + enzalutamide for men with mCRPC whose tumors have homologous recombination repair (HRR) gene mutations. These combinations are not “hormone therapy” alone, but they build on hormone-targeting treatment and represent an important advance for many patients. Your care team may recommend genetic testing of the tumor and/or a blood test to see if you’re a candidate.

“There may be a clone or a population of cancer cells that respond to ADT and respond to all our treatments, and there’s a population of cells that are not responding to those. And so with this combination approach, we’re hoping to really capture all the different types of populations of cells that are multiplying and growing really fast,” Dr. Maithel says.

Choosing The Best Treatment Option

Choosing among therapies is personalized.

Your team will weigh several factors, including:

• Your disease state (mHSPC vs nmCRPC vs mCRPC and the number and location of metastases)
• Genetics (tumor and/or inherited, germline, testing for DNA-repair changes)
• Other medical conditions (such as heart disease, seizure risk, diabetes, bone health, kidney/liver function)
• Potential drug interactions and convenience (some ARPIs interact with common meds; relugolix is a daily pill vs injections for others)
• Prior treatments and goals
• Guidelines and evidence

Side Effects & Safety: Practical Tips

Your care team will take several steps to ensure that you are healthy and stable while undergoing treatment with ADT and ARPIs.

This might include doing bone density scans to monitor bone health and recommending weight bearing exercises or supplements

Blood pressure, cholesterol, and blood sugar should also be kept in check. If you have heart disease, discuss whether relugolix or a specific ARPI is preferable.

You should report any new symptoms like dizziness, balance issues, or severe tiredness to your medical team. Side effects like changes in mood or low libido are common — and they are often treatable. Ask early about counseling, medications, vacuum devices/pumps, or penile rehabilitation strategies.

Monitoring & Follow-Up

You’ll typically see your team every 1 to 3 months at first.

Visits often include:

• PSA tests to track response
• Bloodwork for liver enzymes, potassium, complete blood counts, and testosterone levels
• Blood pressure and symptom review
• Imaging (CT, bone scan, or PSMA PET) as needed to check spread or response

Cost & Access

Many of these therapies are branded and can be expensive. Don’t be shy about asking for help — your clinic can connect you with financial counselors, manufacturer copay programs, and foundations. If one ARPI isn’t covered, an equally effective alternative may be. Clinical trials can also provide access to cutting-edge combinations and should be considered at any stage of advanced disease.

Questions To Ask Your Doctor

• Should androgen receptor pathway inhibitors (ARPIs) be part of my treatment plan?
• What side effects should I expect after adding an ARPI?
• How will we monitor if the treatment is working?
• What can I do to prepare for treatment and help mitigate side effects?

Content independently created by SurvivorNet with support from Novartis Pharmaceuticals Corp.

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