What Is Metastatic Castration-Resistant Prostate Cancer (mCRPC)?

Metastatic castration-resistant prostate cancer (mCRPC) and its precursor, metastatic hormone sensitive prostate cancer (mHSPC), are advanced forms of the condition that don’t respond to initial treatments, such as surgery and hormone therapy, and have started to spread beyond the prostate.

The type mCRPC differs from mHSPC in that the latter disease still responds to standard hormone treatment called androgen deprivation therapy (ADT), even though it has spread to other parts of the body. Specifically, the castration-resistant form mCRPC is particularly dangerous and leads to a very poor prognosis.

The prostate is part of the male reproductive system that surrounds the urethra. The prostate gland produces some of the fluid that carries and protects sperm after ejaculation. Overall, prostate cancer is the second most common cancer in men (skin cancer is the first), with 268,490 new casesand about 34,500 deaths estimated for 2022.

Types of Castration-Resistant Prostate Cancer

Castration-resistant prostate cancers are a class of cancer that do not respond to first-line treatments, which include surgery and/or a standard hormone treatment called androgen-deprivation therapy (ADT). While treatments for mCRPC can be highly effective, especially if the disease is caught early, it is generally incurable. Given that they’re resistant to some therapies, mHSPC and mCRPC represent particularly challenging cases for patients and medical professionals alike.

ADT works by lowering testosterone levels in the body, which can be achieved by either removing the testicles or employing drugs like leuprolide acetate, which lower the production of testosterone. In many prostate cancer cases, this treatment can successfully delay or stop tumor growth.

Whereas mCRPC and mHSPC refer to cases where the cancer cells have started to spread (also known as “metastasis”), nmCSPC is an earlier form that’s confined to the prostate. The difference between the former two of the three conditions is also a matter of progression, with mCRPC being the more advanced and widespread form of the cancer.

Here’s a quick breakdown of these related conditions:

Metastatic Hormone Sensitive Prostate Cancer (mHSPC)

This form of prostate cancer can be an initial diagnosis but more often refers to cases where surgeries or other initial treatments to remove tumors from the prostate haven’t succeeded in stopping its progression.

Notably, too, these cases are defined by metastasis, meaning it has started to spread to other structures in the body, such as bones or the lymph nodes. However, the development of castration resistance is part of the eventual and expected progression of the disease—even while on ADT.

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Basically, mCRPC can be defined as mHSPC that has spread and progressed further, though the exact mechanism of how one leads to the other is not fully understood.

Notably, this type is characterized by the persistence of the disease following ADT, with cancer cells spreading to bone, lymph nodes, and other organs despite the lack of androgen. It’s a more severe, advanced form of cancer and yields a poorer prognosis.

Symptoms of mCRPC/mHSPC    

What’s challenging about some prostate cases is that there’s a chance they can be asymptomatic, especially in their earlier phases. When it comes to mCRPC and mHSPC, symptoms will arise not only in and around the prostate but in those other body systems to which the cancer has spread. These include:

• Frequent urination
• Nocturia (frequent need to urinate at night)
• Difficulty during urination
• Hematuria (blood in the urine)
• Painful urination
• Inability to maintain erection
• Painful ejaculation
• Hematospermia (blood in ejaculate)
• Difficulty emptying bladder

If the cancer has started to spread, it can affect other bodily systems, leading to:

• Severe bone pain (primarily pelvis, vertebrae, hips, femur, or ribs)
• Tingling sensations in the legs or lower back
• Leg weakness
• Urinary/fecal incontinence

If you’ve been diagnosed with prostate cancer, or are experiencing any of these symptoms, seek out medical attention immediately.

Causes

Generally speaking, mCRPC and mHSPC arise as cancer cells start to develop and divide in the prostate and continue to spread despite therapy. Doctors still don’t fully understand the exact mechanism that causes this disease to arise; however, they have been able to localize a range of risk factors and associated conditions. Here’s a quick breakdown:

• Sex: The prostate only exists in males, so females are not at risk.
• Age: Older age is a strong predictor of prostate cancer formation, though seniors typically develop less malignant forms of this disease. This cancer is uncommon in men under 40.
• Race/ethnicity: Incidence of prostate cancer is higher in Black men when compared to White and Hispanic populations. Notably, mortality is also significantly higher among this demographic group.
• Obesity: Among the health effects of being clinically obese is a higher risk of this condition.
• High blood pressure (hypertension): A history of hypertension also increases the chances of developing prostate cancer.
• Genetics: As with all cancers, there’s a strong genetic component to mCRPC and mHSPC. Men with a father or brother who has developed prostate cancer have a doubled risk of developing this disease. 
• Diet: Put broadly, the typical Western diet has been linked with this disease. Advanced prostate cancer risk increases with elevated calcium intake, foods high in saturated fats, dairy consumption, and insufficient amounts of vitamin D. Some studies have linked red meat consumption with this condition, while others noted a vegetarian diet reduces risk. Despite some evidence, more research is needed to confirm these associations.
• Lack of exercise: Likely because this also contributes to obesity and hypertension, lack of exercise has been linked with prostate cancer development.
• Elevated testosterone levels: Higher levels of testosterone (androgen) also increases the chances of developing this disease.
• Race/ethnicity: Incidence of prostate cancer is higher in Black men when compared to White and Hispanic populations. Notably, mortality is also significantly higher among this demographic group.
• Exposure to chemicals: Incidence of advanced prostate cancers have been seen among those exposed to the toxic chemical Agent Orange.
• Prior infections: Those who have or have had chlamydia, gonorrhea, or syphilis have higher rates of developing this cancer. There is some evidence that human papillomavirus (HPV) is linked as well.

Diagnosis

Generally speaking, prostate cancers are graded on a scale that goes from a score of 1, meaning least likely to metastasize to a score of 5, the most severe from. The aim of diagnosis, then, is to assess not only the presence of cancer, but to assess whether it is spreading, and if so, where it’s spreading to. This is typically done using several methods, including physical examination, blood tests, imaging, and core needle biopsy.

Physical Examination

The first step of diagnosis involves a careful review of medical history as well as a physical examination. This entails an assessment of any reported symptoms alongside an evaluation of relevant risk factors.

In addition, the doctor will perform a digital rectal examination (DRE), where they insert a gloved, lubricated finger into the rectum to physically feel for the presence of any tumors. If a potential problem is detected, they will order blood testing. 

Prostate-Specific Antigen (PSA)

The primary blood work done if prostate cancer is suspected is the PSA blood test. This tests for the presence of a specific protein called the prostate-specific antigen. While all men have some PSA, higher levels may indicate the presence of cancer.

The PSA blood test is not definitive, but it can help doctors rule out cases where cancer is unlikely. Elevated levels will indicate the need for further tests.

Core Needle Biopsy

To confirm the diagnosis, a specialized doctor—usually a urologist—will need to perform a core needle biopsy of the prostate. This involves taking samples of prostate tissue and evaluating them for the presence of cancer cells.

In the procedure, a specialized needle is inserted either through the rectum or the skin between the scrotum and anus. The samples are then evaluated by a pathologist.

If there are lesions in the bones or lymph nodes, a specialized doctor—interventional radiologist— may perform a targeted needle biopsy of the lesions.

Imaging

During biopsy and afterward, doctors will rely on imaging approaches, such as transrectal ultrasound, magnetic resonance imaging (MRI), computerized tomography (CT/CAT scan), X-ray, or positron emission tomography (PET scan) to assess the full extent of cancer spread and tumor growth.

The specific approach used is based on the location of the issues; for instance, transrectal ultrasound will focus on the prostate area, while CAT scan is typically best to assess if the cancer has spread to lymph nodes. Since prostate cancer easily spreads to bones, a specialized bone scan X-ray will be needed to fully assess the spread.

Treatment

As highlighted, the tricky thing about mCRPC and mHSPC is that they are, by definition, more aggressive and resistant to initial treatments. That said, there are an increasing number of treatment approaches, improving outcomes for cancer patients. Specific treatment regimens will vary based on individual cases and may include:

• Docefrez/Taxotere (docetaxel): The most frequently prescribed chemotherapy drug to treat mCRPC and mHSPC is the drug Docefrez (docetaxel). This medication functions by targeting microtubules (tubes in cells that help move nutrients and cellular structures) on cancer cells, inhibiting their ability to divide and spread.
• Jevtana (cabazitaxel): Jevtana is another chemotherapy drug that, like Docefrez, binds to microtubules in cells to prevent their functioning and reproduction. 
• Zytiga (abiraterone acetate): Zytiga is a drug that blocks a specific enzyme, cytochrome P (CYP) 17, that’s essential to the synthesis of androgen. Since the presence of androgen boosts cancer growth and activity, this can help prevent the disease from getting worse or spreading.
• Orgovyx (relugolix): Orgovyx is an ADT and the first approved oral GnRH agonist for the treatment of advanced prostate cancer. It works by reducing the amount of testosterone the testicles are able to make. 
• Enzalutamide: Where Zytiga prevents the development of androgen, Enzalutamide is a drug that targets and blocks receptors of this hormone. In effect, this lowers androgen levels and thereby helps rein in cancer.
• Radium-223: For cases where the cancer has spread into the bone, radiation treatment with radium-223 may be indicated.
• Provenge (sipuleucel-T): Approved for use on asymptomatic or minimally-symptomatic cases of mCRPC, sipuleucel-T is a drug that activates the immune system to target cancer cells.
• Olaparib: Olaparib works by inhibiting poly (ADP–ribose) polymerase (PARP), an enzyme associated with cellular repair that becomes overactive in tumor formation. The drug is FDA-approved for gene-mutated mCRPC. Another PARP-inhibitor, Rucapirib, is also now FDA-approved for use in patients with a deleterious BRCA mutation (germline and/or somatic) that's associated with mCRPC.
• Keytruda (pembrolizumab): This drug is part of a class called “check-point inhibitors,” which function by trying to increase the activity of the body's own immune system to fight the cancer. Pembrolizumab is FDA-approved for metastatic prostate cancers that have "microsatellite instability."
• Pluvicto (lutetium Lu 177 vipivotide tetraxetan): Pluvicto is a radioligand that emits radiation to PSMA-expressing cells, causing cell death.
• Nubeqa (darolutamide): Nubeqa is an androgen receptor blocker. By blocking androgen receptors, tumor growth is reduced. In combination with docetaxel, Nubeqa is FDA-approved for treating mHSPC.

As with many cancer cases, more than one treatment approach may be necessary to yield therapeutic results.

Prognosis

Unfortunately, since mHSPC and mCRPC are more aggressive cancers, and since there’s no definitive cure, prognosis is relatively poor. That said, thanks to newly devised therapies and treatments, the numbers are improving.

Keep in mind that the numbers presented here are averages, and there can be a great deal of variation. Among the important measures when discussing cancer is survival rate at five years.

While the outlook for prostate cancers that have not spread is quite positive—if caught in time and treated, the majority of these patients are expected to be alive in five years. For those that have metastasized cancers, like mHSPC and mCRPC, the number is significantly lower—about 31%.

The most challenging question, of course, is the most important one: How long do patients have? There are many factors at play here, and probably the most crucial is timing. The sooner this cancer is discovered, the better the chances of a positive outcome.

Following a diagnosis of mCRPC, the expected prognosis in the past was pretty grim—a median of 11 to 24 months.

Encouragingly, newer therapies have improved the outlook. As these have hit the market, researchers have already started seeing significant changes. 

With a diagnosis of mHSPC, prognosis depends on how the disease responds to ADT treatment. The duration of response is highly variable—some men progress to a castrate-resistant state in less than one year, while others are still responding to ADT more than 10 years later.

In modern trials, men with mHSPC are often treated upfront with ADT in combination with additional drugs such as abiraterone or enzalutamide. Researchers are now seeing median survival times of at least four to five years, even in high-risk patients.

Also, the combination of drugs like Abiraterone with ADT as initial therapy in high risk men which has improved prognosis in mHSPC up to at least four to five years in these cases.

Coping

There’s no doubt that a cancer diagnosis can be incredibly alarming and upsetting. At the end of the day, mHSPC and mCRPC represent advanced stages of a deadly disease, and there’s no doubt that treatment can be disruptive and difficult.

It’s absolutely essential to have a support system in place; though it can be very challenging, it’s helpful to talk to your family about what’s happening. Alongside close friends, they’ll be an essential source of help and support. The better you’re able to communicate, the easier everything will be.

Outside of friends and family, though, you may find the need to seek out professional counseling or a support group to help you cope. Psychiatrists and other mental health professionals can certainly help in this difficult time, so you may find it helpful to ask your oncologist about any services or experts they can recommend.

In addition, there are many support groups and services for those with cancer. In addition to providing clinical information, organizations such as the Cancer Survivor’s Network or the Urology Care Foundation help foster an enriching and supportive community of and for those suffering. The burden of this condition is intense; there’s no reason you should go it alone.

A Word from Verywell

There’s no way around the fact that a cancer diagnosis is a massive, life-altering event. On top of that, most treatment approaches can be very difficult and draining, both physically and emotionally.

As hard as it is, it’s important not to lose hope. While prognosis for mHSPC and mCRPC has been relatively poor, remember that it has been steadily improving as new therapies and approaches have been developed.

Today, people with metastatic prostate cancer, put simply, are in a much better position than they have ever been before. With the right care, and the support of loved ones, you can put yourself in a good position to combat this cancer.