NEW DEVELOPMENTS IMPROVE THE OUTLOOK FOR MEN WITH PROSTATE CANCER
By Daniel Dupuis
There has never been a good time to get prostate cancer, but innovative developments in a number of sectors has improved every phase of treatment, which includes testing, procedures, and new medications in development.
Patients, however, will have to take a proactive approach to avail themselves of these new innovations. While physicians generally have the best of intentions, they will often develop habits that become standard practice and are often slow to adopt new innovations.
The PSA blood test is still used in great numbers, but has a reliability that is only slightly better than flipping a coin (see below). Armed with this information physicians will often order an invasive biopsy that can have life-altering implications. There is a wide array of new screening processes currently available that are far superior to a PSA and they are very affordable. If a patient encounters a scenario where a PSA test leads to a biopsy they should not only seek a second opinion, but never return to the first office.
Additionally, new medications in development may offer comparable efficacy, but substantially fewer side effects than the currently available standard of care medications. This is of special significance to African American men as they have a much higher incidence of prostate cancer and are twice as likely to die from the disease. Fortunately, the reasons for this imbalance have been identified and newer drugs in development may target the specific genetic anomalies that are common to African American men that are stricken with prostate cancer.
HOW COMMON IS PROSTATE CANCER?
Other than skin cancer, prostate cancer is the most common cancer in American men. The American Cancer Society’s estimates for prostate cancer in the United States for 2019 are as follows:
- There will be about 174,650 new cases of prostate cancer.
- This will result in 31,620 deaths from prostate cancer.
- About 1 man in 9 men will be diagnosed with prostate cancer during their lifetime.
- About 1 in 41 will die of prostate cancer.
- African-American men are 76 percent more likely to be diagnosed with prostate cancer than White men.
- African American men are twice as likely to die of the disease.
WHAT ARE THE SYMPTOMS?
Prostate cancer usually shows no symptoms in its early stages and many of the subsequent symptoms are often ignored or mistaken for other, less serious conditions, such as a urinary tract infection, prostatitis, or most commonly, BPH (benign prostate hyperplasia or enlarged prostate).
As the disease progresses it can lead to difficulty starting urination, a weak stream, more frequent urination (especially at night), partial impotence, and painful urination and/or ejaculation. In its later stages it can lead to blood in the urine and bone pain in the spine, hips, and ribs and cause substantial leg weakness.
HOW OFTEN SHOULD MEN GET SCREENED?
The U.S. Preventive Services Task Force recommends that men 55 to 69 may be screened for prostate specific antigens, a simple blood test that can indicate the possible presence of cancer in the prostate. Many doctors will recommend this as part of a regular physical exam for men. A digital rectal exam can be performed as well to feel for any abnormalities in the prostate. The American Cancer Society recommends screening for: men 50 and older who are expected to live 10 or more years; men 45 and older who are at high risk (African Americans, men who have had a close relative with prostate cancer under age 65); and men 40 and older who are at very high risk (those who had a first-degree relative with prostate cancer at an even younger age).
This is the component where a patient needs to gather as much information as possible. A PSA test is still the first step in a diagnosis, but the results are far from definitive and too often lead straight to a biopsy. A patient will need to insist on further testing to gain more information and only after exhausting all options should they allow for a biopsy, which present safety risks and can often cause both short and long term side effects that can be life changing (further information regarding biopsies is provided below).
Many physicians may be unaware of some of the following tests so patients may have to be proactive with both urologists and insurance companies to avail themselves of these innovations.
PSAs are generally the primary diagnostic tool and can provide the first indication of prostate cancer, but the accuracy is estimated to be as low as 52%.
The worst scenario is, unfortunately, not uncommon; a physician receives results that indicate an elevated PSA and immediately proceeds to ordering a biopsy. The PSA, however, is known for false positives and higher PSA levels can often be caused by far less serious illnesses. This is especially problematic as these very same illnesses have symptoms that are similar to early stage prostate cancer. Additionally, some people simply have higher PSA levels that are not indicative of poor health.
Perhaps even more problematic, however, is that 15% of people that do have prostate cancer do not have elevated PSA levels. This may be why the U.S. Preventive Service Task Force gave PSA screening a grade of D in 2012. They said the harm it brings outweighs the benefits.
PHI (Prostate Health Index)
This blood test measures and combines into a single score the levels of three different blood chemicals: regular PSA, so-called “free” PSA, and a precursor PSA compound known as [-2]proPSA. Its maker claims it is 3 times more accurate than a PSA alone, while others report that it has an accuracy level of 71%. It can also help identify if the cancer may or may not be of a more aggressive type. This is especially important as a physician may adopt a “wait and see” approach as less aggressive prostate cancers progress slowly and may not warrant attention in older patients. The developers claim it can reduce unnecessary biopsies by 26%.
The PHI costs about $80 and is covered by most insurance companies. A patient can suggest one after a positive PSA test, but should probably suggest the PHI as the first test simply because of its improved accuracy.
The 4Kscore Test is the current gold standard for prostate cancer testing that can be done with a blood test and it is the most useful tool currently available to avoid unnecessary biopsies.
The 4Kscore Test combines four prostate-specific kallikrein assay results with clinical information in an algorithm that calculates the individual patient’s risk, while also identifying if they have a more aggressive type of cancer. With the 4Kscore Test, physicians can more confidently choose to place a low-risk patient under active monitoring or perform a biopsy on a high-risk patient based on their clinical evaluations, in addition to the 4Kscore Test results.
The prostate cancer antigen 3 gene (PCA3) test is used to help determine a patient’s risk of prostate cancer. It can be done after a positive result from one of the tests listed above or after a biopsy has found no cancer but there are still symptoms and/or elevated PSA levels.
A PSA3 Test is not influenced by prostatitis, BPH or urinary tract infections so it can confirm prior results.
Multiparametric MRI (mpMRI) offers two advantages over the diagnostic pathway that can result in a biopsy. First, mpMRI has excellent sensitivity in detecting prostate cancer that is aggressive enough to warrant biopsy and probably treatment; mpMRI can therefore rule the need for a biopsy in or out.
This is not a common practice among urologists and patients may have to search for a physician that is familiar with this procedure. It is done in a hospital or laboratory setting and will be a costly procedure and will generally not be covered by insurance.
NEW TESTS ON THE HORIZON
New tests are in development that are focusing on gene expressions that is common to prostate cancer.
The TMPRSS2:ERG fusion is a simple urine test that looks for an abnormal merging of two genes found in some prostate cancers and rarely found in cells of men free of the disease. Researchers are still trying to determine its value in the clinical setting.
PCS, or Prostate Cancer Subtype. Though far from ready-for-prime-time yet, a team of researchers have identified three distinct patterns of gene activation in tumor cells, which they’ve dubbed PCS1, PCS2, and PCS3. One type in particular, PCS1, is strongly associated with poorer outcomes. It may be applicable for both blood testing and/or as a component of a biopsy.
A BIOPSY MAY BE NEEDED
A biopsy should be carefully considered and a comprehensive discussion of all of the variables should be completed by all patients. To perform a prostate biopsy a doctor inserts a needle into a portion of the prostate and removes small samples of tissue from the prostate to test for cancer.
A second opinion is often warranted as a biopsy can have serious ramifications.
The reasons for this are due to the problems associated with biopsies.
- Over 1 million US men per year have prostate biopsies due to elevated PSA, but only 25% actually have cancer.
- Prostate biopsies can have complications such as fever, infection, bleeding, urinary problems, and pain, which may require hospitalization.
- Over treatment due to prostate cancer misdiagnosis often causes lasting damage, including erectile dysfunction, urinary or bowel incontinence, and serious surgical complications.
- It is estimated that for every life saved by PSA screening, 48 men suffer harm from treatment due to the damage and health risks often associated with biopsies.
A patient that gets a biopsy should know there are associated side effects that may include:
- Bleeding at the biopsy site; rectal bleeding is common after a prostate biopsy.
- Blood in the semen that may persist for weeks.
- Blood in the urine.
- Difficulty urinating which may necessitate that a Foley catheter is inserted.
MRI-GUIDED TARGETED BIOPSY
This is a newer, less invasive method for a biopsy. This type of biopsy would generally follow a Multiparametric MRI biopsy (see above) and is indicated based on the MRI interpretation. An MRI-guided real-time biopsy, done in the bore (tunnel) of the MRI equipment, can greatly reduce the risk of infection or hitting critical structures while also increasing diagnostic accuracy. While a learning curve would still be involved for a radiologist in training, an MRI-guided targeted biopsy is highly unlikely to put sexual function at risk and greatly minimizes the risk of infection since the biopsy involves fewer needles than a standard prostate biopsy.
TESTS AFTER A BIOPSY
Unfortunately, a biopsy, while problematic, is not foolproof. Subsequent tests may be necessary if a patient still has symptoms or an elevated PSA after a biopsy is negative or after a patient is deemed to be cancer free.
PCA3 is a gene that is over-expressed in prostate cancer cells. After a digital rectal examination (DRE), PCA3 can be measured in a simple urine sample.
PCA3 is far more specific for prostate cancer than prostate-specific antigen (PSA). Unlike PSA, PCA3 is not influenced by conditions such as benign prostatic hyperplasia (BPH), prostatitis, medical procedures, or injury.
The Progensa PCA3 test is a very sensitive, gene-based urine test. The test is approved by the FDA to help a doctor decide if a repeat biopsy is necessary.
This genetic test checks normal-appearing prostate tissues for cancerous changes in DNA. Biopsies are able to sample, at best, only 1 percent of the entire prostate, and doctors frequently worry that some patients may harbor cancer that the needle has simply missed.
ConfirmMDx looks for tell-tale epigenetic changes, such as the silencing of key tumor suppressor genes, which can signal cancer even when a biopsy looks completely clean under the microscope. For guys who are truly clean, this test lets them off the hook for more prostatic pin-cushioning. This test is covered by Medicare.
A Polaris Test uses the tissue gathered from a biopsy and identifies the aggressiveness of the cancer. This can help a patient and physician adopt a more efficient treatment protocol or even decide to postpone treatment and take a wait and see approach. It is covered by Medicare.
NEW DRUGS ON THE HORIZON
There are a number of new combination therapies already in use and many more are in development. They are all designed to find a better balance between efficacy, safety and side effects. The known side effects of most current medications for prostate cancer are extensive and life altering and, depending on the type of treatment, can include painful urination, hair loss, impotence, chills, nausea, diarrhea, breast pain, rash and seizures. This is in addition to increasing the risk of a heart attack.
The list of combination drugs in development is almost endless, but two medications are unique in that they may offer comparable, or superior, efficacy, while significantly reducing side effects. Interestingly, they accomplish this with completely different mechanisms of action.
Darolutamide is a new oral therapy that will be utilized in combination with what is known as an ADT (androgen deprivation therapy), which is a commonly prescribed medication for non-metastatic castration-resistant prostate cancer (nmCRPC).
It is an oral medication that has been fast-tracked by the FDA and should be available by late 2019. It offers efficacy that is comparable or superior to current therapies, but with a dramatically improved side effect profile. Another important feature is that unlike many cancer medications, it does not interact with commonly prescribed drugs for hypertension, cholesterol control and/or cardiac medications.
In layman’s terms, nmCRPC is cancer that has not spread beyond the prostate region, in which PSA levels are elevated despite treatment with hormone therapy. Men in this stage of nmCRPC generally feel well and do not have symptoms. The unmet medical need is for treatments that achieve disease control and delay the spread of the cancer without impacting their daily lives or increasing the burden of disease with treatment side effects.
While the current treatments in this space are effective in delaying onset of metastases, the side effects can be unpleasant and disruptive to men’s lives; particularly cognitive issues, seizures, impact on balance which may lead to falls and bone fractures, rash and hypertension.
Darolutamide has the potential to be the first novel androgen receptor (AR) antagonist to delay metastases and extend survival, while allowing patients nmCRPC to continue their day-to-day life without adding any burden.
Phase III trial results showed a significant improvement of 40.4 months of metastasis-free survival (MFS) with darolutamide plus androgen deprivation therapy (ADT), an improvement of 22 months versus ADT in combination with placebo. These results are highly clinically relevant and are equivalent to a 59% reduction in the risk of metastases or death.
Of even greater importance, however, is that darolutamide does not cross the blood brain barrier. This means that there are no central nervous system side effects and in trials darolutamide plus ADT did not increase rates of critical adverse events including seizures, falls, fractures, rash, cognitive disorder, mental impairment or hypertension. Patients with a history of seizure were not excluded from the study.
The importance of providing a CRPC treatment with a favorable side effect profile cannot be understated. A lot of these men may be on treatment for three or four years, and even low-grade side effects can become problematic over a long period of time. If approved, darolutamide has the potential to fulfill critical treatment goals for men with CRPC: to achieve disease control and delay the spread of the cancer without impacting their daily lives with potential falls or seizures.
Aneustat is a unique drug formulation that has been the subject of numerous studies that have examined its viability as an effective agent against prostate cancer cells as both a stand-alone medication and as a combination therapy with the most commonly prescribed medications currently in use for the treatment of prostate cancer.
In contrast to darolutamide, Aneustat does cross the blood brain barrier, but is non-toxic, so in addition to having no affect on the central nervous system, it has a side effect profile that could best be described as negligible (incidence of nausea no greater than common supplements).
It has had extraordinary results in pre-clinical trials that utilized human prostate tumors and has the potential to offer substantial efficacy, yet have a negligible side effect profile while presenting no known safety risks.
Aneustat is also unique in that it has been shown to normalize protein levels, which may affect the action of what are known as SNPs that are common to people with prostate cancer. African Americans simply have more of these SNPs and also possess specific genetic mutations that can allow for prostate cancers that can best be categorized as more lethal. These anomalies may explain why they are 76% more likely to contract the disease and twice as likely to die from it.
The fact that Aneustat demonstrates a distinct mechanism of action that may influence the specific elements that are common among African Americans with prostate cancer would indicate that a clinical trial that included a substantial African American patient population is warranted.
The fact that prostate cancer is among the most prevalent cancers, and will only increase as the population ages, will lead to a number of developments that will hopefully allow for a new treatment protocol.
Physicians now have more exact testing procedures at their disposal that can reduce the number of biopsies. Additionally, drug companies have a wide array of medication in development that will increase efficacy, while dramatically decreasing, or eliminating, life changing side effects.
As stated earlier, there is no good time to get prostate cancer, but when compared to just ten years ago, a patient’s experience can be substantially different and less invasive.