What If Prostate Cancer Hormones Stop Working?

Hormone treatment, also known as androgen deprivation therapy (ADT), is a cornerstone of treatment for advanced prostate cancer. Hormone treatment decreases prostate cancer growth by lowering testosterone levels in the body via medicine or surgery.

For most prostate cancers, hormone treatment eventually becomes ineffective, at which point the prostate cancer is considered “castration-resistant.”

Therapy options available for castration-resistant prostate cancer (CRPC) include secondary or more intensive hormone medicines, chemotherapy, immunotherapy, and radiation-related agents. These treatments are not cures but can potentially improve symptoms and prolong life.

Why Hormone Therapy Stops Working

Prostate cancer is unique in that it relies on testosterone for survival and growth. Testosterone is an androgen and the primary sex hormone in males.

Hormone therapy starves, or deprives, prostate cancer cells of testosterone, thereby shrinking tumors within the prostate gland or elsewhere if the disease is metastatic (when the cancer spreads to other parts of the body).

Castration via hormone therapy can be achieved medically or surgically:

• Medical castration (more common) entails taking a drug, either a luteinizing hormone-releasing hormone (LHRH) agonist or an LHRH antagonist. These drugs block testosterone production within the testicles.
• Surgical castration (less common) is when the testicles are removed (orchiectomy) by a surgeon. The testicles are the dominant site of testosterone production in males.

The majority of prostate cancers eventually stop responding to hormone therapy. At this time, the cancer is termed castration-resistant prostate cancer (CRPC).

Multiple factors contribute to the timing of when hormone therapy stops working, which, for mCRPC, is around two to three years after starting treatment.

One factor is that the genetic makeup of prostate cancer cells can change over time, allowing them to produce more androgen receptors (binding sites for testosterone).

Remarkably, prostate cancer cells can start producing testosterone themselves to combat the effects of hormone therapy. They may also develop other ways to stay alive and thrive despite very low testosterone levels in the body.

Progression of CRPC

Specific features influence the timing of when a castration-sensitive prostate cancer transitions to being castration-resistant.

These features include:

• The presence of metastatic disease predicts a faster progression to castration-resistant prostate cancer.
• The higher the Gleason score (grading scale to assess aggressiveness) at diagnosis, meaning the more abnormal the cancer cells appear under a microscope, the higher the chance that the cancer will progress to CRPC.
• A higher prostate-specific antigen (PSA) blood level at diagnosis increases the risk for a faster progression to CRPC. PSA is a protein made by both healthy and cancerous prostate cells.
• Specific changes in PSA levels during hormone therapy—for example, the risk of CRPC progression increases as the time to nadir (TTN) decreases. TTN is the time it takes for the PSA level to reach its lowest point once hormone therapy has been initiated.

Signs Hormone Therapy Is Not Working

While undergoing hormone therapy, a person’s cancer care team will monitor them regularly to see if the cancer is progressing.

One key sign that hormone therapy isn’t working is a continuous rise in PSA blood levels despite a very low blood testosterone level, specifically one that is less than 50 nanograms per deciliter (ng/dL).

Another sign is the spread of the cancer to different parts of the body, as revealed on imaging tests, such as:

• A computed tomography (CT) scan visualizes internal body structures using computer technology and a series of sophisticated X-ray images.
• A magnetic resonance imaging (MRI) test utilizes a strong magnetic field and radio waves to generate two- or three-dimensional images of the organs and tissues within the body.
• A positron-emission tomography (PET) scan uses radioactive glucose (sugar) to create computerized images of the inside of your body. Cancer cells generally take up more glucose than healthy cells, so the test can help detect the spread and location of cancer.

Lastly, a person may begin experiencing new symptoms, which could indicate cancer progression. These symptoms could include:

What Does It Mean for Treatment?

Various therapies are available for castration-resistant prostate cancer, intending to reduce symptoms and help a person live longer.

The precise treatment regimen for a person with CRPC depends on whether the cancer is nonmetastatic or metastatic, as well as other factors like potential side effects and patient preference.

Androgen Receptor Blockers

An androgen receptor blocker may be added on if an LHRH agonist, LHRH antagonist, or orchiectomy is no longer working well by itself, as evidenced by cancer progression.

Androgen receptor blockers are intended to “intensify” androgen deprivation since some prostate cancer cells may still be responsive. These medicines are taken by mouth as a pill and block testosterone from binding to sites within prostate cancer cells.

They include:

• Casodex (bicalutamide)
• Eulexin (flutamide)
• Nilandron (nilutamide)

Newer androgen receptor blockers that may be used when the ones above are no longer working include:

• Erleada (apalutamide)
• Nubequa (darolutamide)
• Xtandi (enzalutamide)

All of the above can be used to treat nonmetastatic castration-resistant prostate cancer. Xtandi can also be used to treat metastatic castration-resistant prostate cancer.

Androgen Synthesis Inhibitor

If an LHRH agonist, LHRH antagonist, or orchiectomy is also no longer effective, the androgen synthesis inhibitor Zytiga (abiraterone) can be added.

Taken as pills each day, Zytiga blocks testosterone production within prostate cancer cells and the adrenal glands. The adrenal glands, which are located on top of the kidneys, serve as an additional site of testosterone production in the body.

Chemotherapy

Chemotherapy agents, most commonly docetaxel, may be used when hormone treatments stop working and a person has metastatic CRPC. Chemotherapy kills rapidly dividing cells, like cancer cells.

If docetaxel stops working, Jevtana (cabazitaxel) might be tried as a next step.

Both agents are administered intravenously, which means they are injected within a vein at an infusion center or hospital.

Targeted Therapy

Poly (ADP-ribose) polymerase (PARP) inhibitors block a protein that prostate cancer cells need to repair damaged DNA.

PARP inhibitors are pills or capsules that are effective in treating prostate cancers with specific gene mutations, which are changes in the DNA sequence.

They can be used in the treatment of both metastatic castration-sensitive prostate cancer and metastatic castration-resistant prostate cancer, assuming the cancer cells carry the appropriate genetic mutation.

Tumor biopsies (taking samples of the prostate cancer cells to analyze in the lab) are performed to check for these mutations.

PARP inhibitors include:

• Lynparza (olaparib) 
• Rubraca (rucaparib)
  
• Talzenna (talazoparib)
• Zejula (niraparib) plus Akeega (abiraterone)

Immunotherapy

A cancer vaccine called Provenge (sipuleucel-T) uses a person’s own immune system cells to launch an attack against the prostate cancer cells.

Provenge is prescribed to treat mCRPC that causes minimal to no symptoms. This uniquely tailored vaccine is manufactured in a laboratory by combining a person’s white blood cells (infection-fighting cells) with a protein derived from prostate cancer cells.

Radiopharmaceuticals

Radiopharmaceuticals, including Pluvicto (lutetium Lu-177 vipivotide tetraxeta) and Xofigo (radium 223 dichloride), may be used to treat mCRPC, as follows:

• Pluvicto is used in people with prostate-specific membrane antigen (PSMA)-positive cancer, as it releases radiation that binds to PSMA (a protein found in some prostate cancer cells) to kill the cells.
• Xofigo is only used in people with mCRPC that has spread only to the bones.

Xofigo releases radiation that accumulates in areas of bone undergoing increased bone turnover, and also where bone metastases manifest. The radiation aims to kill the cancer cells within the bone.

Treatment Advancements

Multiple new therapies and regimens (how therapies can be combined) are being tested in clinical trials against castration-resistant prostate cancer.

In addition, clinical trials are ongoing regarding the role of genetics in prostate cancer and how drugs that target prostate cancer cells with specific genes may slow the growth of the tumor or extend survival.

Advancements are also being made in prostate cancer screening, diagnosis, and the early identification of more aggressive cancers.

The ample research going into prostate cancer provides hope and promise for the future care of this complex and highly variable disease.

Life Expectancy

Prostate cancer that becomes unresponsive to hormone therapy portends a poor prognosis (disease outcome).

Specifically, once prostate cancer has progressed to a castration-resistant state, the chances of dying from prostate cancer are higher than dying from any other cause.

The median survival time for a person with mCRPC is approximately 22 months.

Coping With End-of-Life Concerns

If you have been recently diagnosed with and/or are undergoing treatment for castration-resistant prostate cancer, it’s normal to feel overwhelmed and experience some sense of unease or worry.

While the therapies mentioned above can ease symptoms and extend life, they also have potential side effects. As such, it is essential to carefully discuss personal goals and desires with your cancer care team and family and weigh the risks vs. the possible benefits of all therapies.

Moreover, even though treating cancer may be a dominant focus, it’s also important to address quality-of-life issues and advanced directives so that your end-of-life wishes are honored.

 Summary

Prostate cancer cells require androgens, namely testosterone, to stimulate their growth. Hormone therapy is a standard treatment strategy for combating prostate cancer, as it works by depriving the cancer cells of testosterone.

Unfortunately, within a few years, most prostate cancers become resistant to hormone therapy, at which point they are deemed “castration-resistant.”

Therapies used to treat castration-resistant prostate cancer include regimens that intensify or prolong androgen deprivation, as well as medicines that target prostate cancer cells with specific gene mutations and a cancer vaccine. Some radiotherapeutic agents target prostate cancer metastases, like those in the bone.

Coping with advanced prostate cancer is challenging. It requires support from loved ones and a dedicated discussion about goals and expectations of care, quality of life, and potential risks vs. benefits of treatment.