The treatment of metastatic castration-resistant prostate cancer (mCRPC) involves a combination of therapies, including chemotherapy, hormone therapy, immunotherapy, and different medications that target bone metastases.

The treatment plan can vary due to genetic mutations and other factors that can make some drugs effective in some people but not others. With appropriate treatment, people with this advanced form of prostate cancer can enjoy a better quality of life and longer disease-free survival.

Treatment Goals and Strategies

Castration-resistant prostate cancer (CRPC) is an incurable form of prostate cancer that no longer fully responds to treatments used to lower testosterone.

It is classified as metastatic (mCRPC) because the cancer has spread from the primary (initial) tumor to distant parts of the body, most commonly the nearby lymph nodes and bones, as well as the bladder, rectum, liver, lungs, and possibly the brain.

With mCRPC, androgen deprivation therapy (ADT)—also known as “chemical castration”—can no longer sufficiently suppress testosterone, the hormone that fuels tumor growth. While most people with mCRPC will continue to use ADT (as it can still control some prostate cancer cells), other therapies will need to be added to the treatment plan.

The treatment for mCRPC is personalized, using genetic tests and biomarkers that help determine which therapies are most effective against the specific cancer individual has. These tests can identify gene mutations that direct which treatments can and cannot be used.

With mCRPC, the goals of treatment are not curative but rather to:

• Alleviate cancer-related pain and symptoms
• Extend survival times
• Improve the overall quality of life

Chemotherapy

Chemotherapy (“chemo”) is one of the main treatment options for mCRPC. The drugs are designed to kill fast-replicating cancer cells. They can also damage fast-replicating normal cells in the gastrointestinal (GI) tract, hair, and bone marrow (accounting for chemo side effects).

Delivered intravenously (within a vein) over 10 or more cycles, the drugs commonly used include:

• Docetaxel: Considered the first-line treatment for mCRPC
• Jevtana (cabazitaxel): Used when docetaxel is no longer effective

Other chemotherapy drugs like etoposide, paclitaxel, and vinblastine may also be added to the treatment plan.

Hormone Therapy

In addition to ADT, other hormone therapies can help suppress testosterone. Known as androgen receptor signaling inhibitors (ARSIs), these drugs prevent testosterone from binding to and activating androgen receptors (proteins on cell surfaces) that stimulate prostate cancer growth.

Two ARSIs are currently approved for the treatment of mCRPC:

• Xtandi (enzalutamide): Taken by mouth once daily with or without food
• Zytiga (abiraterone): Taken by mouth once daily without food

Side effects are relatively mild. Hot flashes, diarrhea, and fatigue are common with Xtandi, while fluid retention, muscle aches, and upset stomach are common in Zytiga.

Targeted Therapies

Targeted therapies are medications that recognize and attack genetic “targets” on cancer cells. Because the assault is focused, other cells are largely untouched, resulting in fewer severe side effects compared to chemo.

Genetic tests are needed to establish whether your cancer has the specific genetic mutations, including BRCA mutations, that the drugs target.

The approved targeted drugs for mCRPC, taken by mouth once or twice daily, include:

• Rubraca (rucaparib): Used if the cancer has spread after chemotherapy
• Talzenna (talazoparib): Typically used in combination with Zytiga
• Lynparza (olaparib): Typically used in combination with Xtandi, or sold as a two-in-one drug called Akeega (niraparib and abiraterone)

Common side effects include:

• Cough
• Diarrhea
• Fatigue
• Loss of appetite
• Nausea
• Shortness of breath
• Vomiting

Immunotherapy

Immunotherapy involves medications that help your immune system fight cancer more effectively. It does so in part by helping the body better recognize cancer cells, which can often evade immune detection.

Despite its effectiveness in treating conditions like breast cancer, immunotherapy has not yet been proven as effective with prostate cancer. While some studies have shown that immunotherapy can improve survival times, there is no evidence that it can make prostate cancer tumors smaller.

Immunotherapies sometimes used for advanced prostate cancer include:

• Provenge (sipuleucel-T): A therapeutic vaccine, delivered in three intravenous doses, that is created from a person’s own immune cells
• Keytruda (pembrolizumab): A lab-made monoclonal antibody that is given intravenously every three weeks for up to two years to block the PD-1 protein that makes immune cells “blind” to cancer cells

As with targeted therapies, immunotherapies also require genetic testing to determine if a person is a candidate for the drug.

Side effects of Provenge tend to be mild, often causing chills, fever, and fatigue, while Keytruda can cause a wider range of symptoms affecting the lungs, kidneys, livers, skin, and hormones.

Radiation

For early-stage prostate cancer, radiation therapy is used for curative purposes. It is less commonly used for mCRPC as the condition is incurable, but it may be recommended if the tumor is large and causing pain or other symptoms. In such cases, radiation can help ease symptoms, slow disease progression, and possibly extend life expectancy.

A small study published in Radiation Oncology reported that radiation therapy used in combination with Xtandi or Zytiga resulted in a median survival time of around 47 months. This is well in excess of the roughly 25-month survival time commonly reported in people with mCRPC.

Symptoms vary by the radiation dose but may include:

Treatment of Bone Metastases

Bone metastasis, which is the spread of cancer to the bones, is common in mCRPC. It accounts for roughly 85% of all metastases. The extent of bone metastasis—how much or little there is in the hip, spine, ribs, or other parts of the body—can determine survival rates.

Because of this, cancer specialists will prescribe different drugs to slow the progression of metastasis or prevent it altogether if the bones are not affected.

These include:

• Radiopharmaceuticals: Intravenous infusion of drugs like Xofigo (radium-223) and Metastron (strontium-89) that deliver radioactive matter that settles in the bone, killing cancer cells
• Bisphosphonates: Drugs like Zometa (zoledronic acid) that are given intravenously every three to four weeks to prevent the excessive breakdown of bone, easing pain and reducing the risk of fractures
• Prolia (denosumab): A monoclonal antibody given by injection every one to six months that may be used if bisphosphonates are no longer effective in preventing bone breakdown
• Corticosteroids: Drugs like prednisone and dexamethasone, taken by mouth, to temper inflammation and help ease pain caused by bone metastasis

In addition to these medications, bone metastases may also be treated with ablation therapy if the tumors are small and few. This involves the use of electricity (radiofrequency ablation), extreme cold (cryoablation), or ultrasound (high-intensity focused sound waves) to destroy cancer tissues.

Complementary and Alternative Therapies

No complementary or alternative therapies can alter the course of mCRPC, but some can help manage symptoms or alleviate treatment side effects. This includes cancer-related stress, anxiety, and depression that many people experience with an incurable disease.

Those shown to offer the greatest benefit include:

• Glutamine: This amino acid, available as a supplement, may help reduce damage to the gastrointestinal tract during chemotherapy and radiation, lessening side effects.
• Lycopene: Some studies report that this organic pigment found in tomatoes and other red fruits may modestly lower prostate-specific antigen (PSA) levels with prolonged use. PSA is elevated in prostate cancer.
• Mind-body therapies: Practices like guided imagery and progressive muscle relaxation (PMR) have been shown to relieve stress and improve the quality of life of people with advanced prostate cancer during chemotherapy.

Some natural remedies may be harmful. This includes green tea and high-dose vitamin C, which may increase PSA levels in people with advanced prostate cancer. Others, like selenium and calcium, may increase the risk of a high-grade tumor (one that has highly abnormal cells and may be more aggressive).

Clinical Trials

The outlook for metastatic prostate cancer has changed dramatically, with the five-year survival rate increasing by 65% between 2005 and 2020. This is largely due to advances in treatment, for which clinical trials play a central role.

Even if your current treatment options are limited, speak with your oncologist (cancer specialist) about clinical trials that actively recruit participants. Many new and emerging treatments are in the drug development pipeline for mCRPC, including:

• Radioactive ligand therapy: Combining a radioactive agent and targeted therapy
• Antibody-drug conjugates: Combining chemotherapy and targeted therapy
• CAR-T therapy: A method of genetically altering immune cells (called T-cells) to better fight cancer
• Cytokine-based therapies: A form of immunotherapy involving lab-made immune signaling proteins called cytokines

Supportive and Palliative Care

Maintaining quality of life and building a solid support network is crucial for people living with mCRPC. This includes the implementation of palliative care, a form of care focused on reducing pain, symptoms, and stress caused by serious illness.

If you have mCRPC, you are likely to already be under palliative care. If not (or you are unsure), speak with your cancer care team. Most health insurance plans, including Medicare and Medicaid, cover part or all of palliative care received in a hospital, outpatient clinic, or skilled nursing facility.

Unlike hospice, where insurance benefits last for six months, palliative care is covered by most comprehensive insurance plans for the duration of your severe illness.

To find practical and social support, speak with a clinical social worker (available at most cancer treatment centers) about financial, travel, housing, or legal assistance programs. Your care team can also link you to in-person and online support groups for people living with metastatic cancer.

This includes the Prostate Cancer Foundation’s Metastatic Prostate Cancer Support Group Facebook page and the in-person support group locator offered by ZERO Prostate Cancer.

Summary

The treatment of metastatic castration-resistant prostate cancer (mCRPC) is different from other types of prostate cancer because it is neither curable nor fully responsive to androgen deprivation therapy (ADT), which is commonly used to treat the disease.

The treatment of mCRPC is personalized, using biomarkers and genetic tests to select the most effective combination of therapies. These may include chemotherapy, hormone therapy, targeted therapy, immunotherapy, radiation therapy, and bone-targeted therapies.