Researchers Develop an Accurate Urine Test for Prostate Cancer

It was recently announced that researchers at the Johns Hopkins Kimmel Cancer Center have developed a simple and noninvasive urine test for prostate cancer. This would represent a significant step forward in diagnosis. Researchers have made significant progress toward the development of a simple, noninvasive liquid biopsy test that detects prostate cancer from RNA and other specific metabolic chemicals in the urine. The researchers’ findings appear in the journal Scientific Reports. The investigators emphasize that currently this is a proof-of-principle study for the urine test, and it must be validated in additional, larger studies before it is ready for clinical use.

The researchers used RNA deep-sequencing and mass spectrometry to identify a previously unknown profile of RNAs and dietary byproducts, known as metabolites, among 126 patients and healthy, normal people. The cohort included 64 patients with prostate cancer, 31 with benign prostatic hyperplasia and prostatitis diseases, and 31 healthy people with none of these conditions. RNA alone was not sufficient to positively identify cancer, but the addition of a group of disease-specific metabolites provided separation of cancer from other diseases and healthy people.

“A simple and noninvasive urine test for prostate cancer would be a significant step forward in diagnosis. Tissue biopsies are invasive and notoriously difficult because they often miss cancer cells, and existing tests, such as PSA (prostate-specific antigen) elevation, are not very helpful in identifying cancer,” says Ranjan Perera, Ph.D., the study’s senior author. Perera is also the director of the Center for RNA Biology at Johns Hopkins All Children’s Hospital, a senior scientist at the Johns Hopkins All Children’s Cancer & Blood Disorders Institute and the Johns Hopkins All Children’s Institute for Fundamental Biomedical Research, and an associate professor of oncology at the Johns Hopkins University School of Medicine and Johns Hopkins Kimmel Cancer Center member.

“We discovered cancer-specific changes in urinary RNAs and metabolites that — if confirmed in a larger, separate group of patients — will allow us to develop a urinary test for prostate cancer in the future,” says Bongyong Lee, Ph.D., the study’s first author and a senior scientist at the Cancer & Blood Disorders Institute.

Bill introduced to help VA tackle prostate cancer

Recently, Congressman Neal Dunn, M.D. introduced the Veterans Prostate Cancer Treatment and Research Act. Prostate cancer is the number one cancer diagnosed in the Veterans Health Administration with over 489,000 veterans undergoing treatment.

This new bill will direct the Secretary of Veterans Affairs to establish a national clinical pathway for prostate cancer and a standardized system of care for the treatment of what is the most commonly diagnosed cancer in the veterans’ health system.

“After everything our veterans experience while serving, the last thing they should be faced with is yet another enemy – prostate cancer,” Dunn said. “The key to overcoming prostate cancer is early detection. Veterans deserve a system that streamlines the pathway from early detection to successful treatment. This bill is a solid first-step forward to save fellow veterans lives and defeat this deadly adversary.”

Along with Dr. Dunn, Congressman Joe Cunningham is the lead Democrat co-sponsor of the legislation.

“Prostate cancer is the most common cancer diagnosis among veterans, and more prevalent among African American veterans than anyone else – one of the many health disparities that African Americans face,” Cunningham said. “This bipartisan legislation will go a long way toward improving health care outcomes for our veterans by standardizing treatment options and expanding access to cutting-edge clinical trials.”

It has been shown that veterans who have been in contact with toxins, such as Agent Orange, are at higher risk for prostate cancer. The establishment of a clinical pathway will standardize treatment options and result in improved outcomes for these patients. This bill will also create a real-time registry to track patient progress and will allow patients greater access to cutting edge clinical trials.

“The AUA is proud to support this important piece of legislation, which we believe will standardize treatment options and result in improved outcomes for prostate cancer patients. The VHA – as a national system for healthcare delivery – is perfectly positioned to create this program,” said AUA President Dr. John H. Lynch.

Apalutamide is approved by FDA for metastatic castration-sensitive prostate cancer

In the fall of 2019, the Food and Drug Administration approved apalutamide (ERLEADA, Janssen Biotech, Inc) for patients with metastatic castration-sensitive prostate cancer (mCSPC). Apalutamide was initially approved in 2018 for patients with non-metastatic castration-resistant prostate cancer.

Efficacy was demonstrated in TITAN (NCT02489318), a randomized, double-blind, placebo-controlled, multi-center clinical trial enrolling 1,052 patients with mCSPC. Patients received either apalutamide 240 mg daily or placebo, orally. All patients received androgen deprivation therapy (ADT)—either concomitant gonadotropin-releasing hormone analog or prior bilateral orchiectomy. Patients with both high- and low-volume disease were enrolled in the study.

Statistically significant improvements in both major efficacy outcomes of overall survival (OS) and radiographic progression-free survival (rPFS) were demonstrated. At the time of a pre-specified interim analysis, the hazard ratio for OS was 0.67 (95% CI: 0.51, 0.89; p=0.0053); however, median OS was not reached in either arm. The hazard ratio for the rPFS improvement was 0.48 (95% CI: 0.39, 0.60; p<0.0001). The median rPFS was not reached for the apalutamide plus ADT arm, and was 22.1 months for the placebo plus ADT arm.

The most common adverse reactions (incidence ≥10%) for patients who received apalutamide were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.

The recommended dose of apalutamide is 240 mg (four 60 mg tablets) orally once daily, with or without food. Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

Prostate cancer and the effects on male fertility

Despite the best efforts of surgeons and radiation oncologists, it is nearly impossible for a man to retain his ability to father children through sexual intercourse after initial treatment for prostate cancer.

During a prostatectomy, both the prostate and the nearby seminal vesicles are removed. The seminal vesicles are two small structures that lie at the base of the bladder. Together with the prostate, they provide semen that carries the sperm down the urethra and out the penis during ejaculation. The loss of semen following surgery makes ejaculation impossible, so the sperm cannot physically make it out of the body to reach the woman’s egg for fertilization.

With radiation therapy, fertility is nearly always impaired. Radiated prostate cells and seminal vesicles tend to produce semen that cannot transport the sperm well. In addition, the sperm, which is made and housed in the testicles, can be damaged, but this is seen far less frequently with more accurate dose planning.

Fertility Options After Treatment for Prostate Cancer

For men who wish to father children after treatment for prostate cancer, the best chance for fertility is sperm banking. Semen containing sperm is frozen in liquid nitrogen and, although the cells are technically still alive, all cellular activity ceases. After thawing, up to 50% of sperm will regenerate and can be used for artificial insemination.

As an alternative to banking sperm, extracting sperm directly from the testicles might be an option. After harvesting sperm from testicular tissue, a single microscopic sperm is injected into a single microscopic egg. If an embryo forms, it is implanted into the woman’s uterine wall and allowed to grow.
Although technical advances in assisted reproduction have dramatically improved the conception rates, the success rates for the two procedures combined—sperm extraction followed by injection of the sperm into the egg—is less than 50%.

Apalutamide approved by FDA for metastatic castration-sensitive prostate cancer

The FDA has approved a supplemental New Drug Application (sNDA) for apalutamide (Erleada) for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC).1

The sNDA was processed through the Real-Time Oncology Review Program after the application received a priority review designation when it was submitted in April 2019. Results of the phase III TITAN trial, which were presented at the 2019 ASCO Annual Meeting, were the basis for the sNDA.

“Prostate cancer is more difficult to treat once it spreads, and for patients with castration-sensitive disease, it is clear that androgen deprivation therapy [ADT] alone, is often not enough,” Kim Chi, MD, a medical oncologist at BC Cancer – Vancouver and principal investigator of the TITAN study, said in a statement. “Results from the TITAN study showed that, regardless of the extent of disease, patients with metastatic castration-sensitive prostate cancer have the potential to benefit from treatment with apalutamide in addition to ADT.”

The FDA has noted that the recommended dose for apalutamide is 240 mg or 4 tablets of 60 mg each, given orally once daily with or without food. Additionally, the agency recommends that patients also receive a gonadotropin-releasing hormone analog concurrently with apalutamide or should have received a bilateral orchiectomy.2

The international, randomized, double-blind phase III TITAN trial included 1052 patients with metastatic castration-sensitive prostate cancer across 260 sites, regardless of prior localized therapy, docetaxel treatment, or the extent of their disease. Patients were randomized 1:1 to receive either 240 mg oral apalutamide once daily plus ADT (n = 525) or placebo plus ADT (n = 527). Treatment was given until disease progression, unacceptable toxicity, or the end of treatment was reached.

Patients had a median age of 68 years and 62.7% had high-volume disease whereas the other 37.3% had low-volume disease. A total of 16.4% of patients had undergone a prostatectomy or had received radiotherapy for localized therapy. Previous docetaxel therapy was noted in 10.7% of patients.

The coprimary endpoints of the trial were radiographic progression-free survival (rPFS) and overall survival (OS).

Apalutamide with ADT demonstrated an improvement in OS compared with ADT alone, resulting in a 33% reduction in the risk of death (HR, 0.67; 95% CI, 0.51-0.89; P = .0053). The combination also demonstrated a 52% reduction in the risk of radiographic progression or death (HR, 0.48; 95% CI, 0.39-0.60; P <.0001).1

According to findings presented at the 2019 ASCO Annual Meeting and subsequently published in the New England Journal of Medicine, at 2 years, the rate of OS was 82.4% with apalutamide and ADT compared with 73.5% in the ADT and placebo group (HR, 0.67; 95% CI, 0.51-0.89; P = .005). The 2-year rate of rPFS was 68.2% with the combination versus 47.5% with ADT alone.3,4

Both the median times to prostate-specific antigen (PSA) progression (HR, 0.26; 95% CI, 0.21-0.32) and cytotoxic chemotherapy (HR, 0.39; 95% CI, 0.27-0.56; P <.001) were improved with the addition of apalutamide. In the combination arm, 68.4% of patients demonstrated significant PSA declines to undetectable levels compared with 28.7% in the ADT and placebo group.

Treatment with apalutamide and ADT also resulted in a 34% risk reduction in the median time to second PFS (HR, 0.66; 95% CI, 0.50-0.87).

Grade 3/4 adverse events (AEs) occurred in 42.2% of patients in the apalutamide arm compared with 40.8% in the control arm. Serious AEs occurred in 19.8% of patients versus 20.3% in the 2 arms, respectively. Discontinuations due to AEs occurred in 8% of the apalutamide arm compared with 5.3% in the group receiving ADT alone. There were 10 AE-related deaths in the apalutamide arm versus 16 in the placebo arm.

Grade ≥3 AEs of special interest included rash (6.3% in the apalutamide arm vs 0.6% in the ADT-alone arm), fatigue (1.5% vs 1.1%, respectively), fall (0.8% in each arm), fracture (1.3% vs 0.8%), and seizure (0.2% vs 0).

“Erleada has the potential to change how patients with prostate cancer are treated, regardless of the extent of the disease or prior docetaxel treatment history, by delaying disease progression and prolonging survival,” Margaret Yu, MD, vice president, prostate cancer disease area leader, Janssen Research & Development, LLC, said in a statement. “This milestone highlights Janssen’s commitment to improve the standard of care for patients with prostate cancer as we continue to develop innovative treatments across the disease continuum.”

Apalutamide previously received FDA approval in February 2018 for the treatment of patients with nonmetastatic castration-resistant prostate cancer.
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Reduction of prostate cancer biopsies may be the benefit of a new blood test

The diagnosis of prostate cancer could be significantly improved with a new blood test that looks for circulating tumor cells. Unnecessary biopsies and treatments could also be avoided.

According to a recent study, combining the new test with prostate specific antigen (PSA) results can yield a diagnosis of aggressive prostate cancer that is more than 90% accurate.

This level of accuracy is higher than that of any other biomarker for prostate cancer, according to the study author, who says it could lead to a paradigm shift in the way prostate cancer is diagnosed.

PSA test not enough to diagnose cancer

The prostate produces a protein called PSA. When there is cancer in the prostate, the gland releases more PSA into the blood, and therefore, raised levels of PSA in the blood can be a sign of prostate cancer.

Unfortunately, other prostate conditions, such as inflammation or noncancerous enlargement of the gland, can also raise PSA levels.

In order to confirm the presence of cancer, the patient undergoes a biopsy, which is an uncomfortable procedure where the surgeon removes pieces of the prostate and sends them for tissue analysis.

A biopsy of the prostate is not only invasive but can also have risks such as infection and a high chance of bleeding. And the biopsy results of most men with raised PSA levels come back saying that they do not have cancer.

And when prostate biopsies do reveal the presence of cancer, in most cases, the tumor is not aggressive and will not be fatal if doctors leave it untreated.

Possible new “revolutionary drug” for prostate cancer

Experts say that the first genetically targeted drug for fighting prostate cancer could become a become a revolutionary treatment.

Olaparib is a precision medicine already used by the NHS for ovarian cancer and has been called a game-changer by cancer doctors.

In trials the drug has slowed tumor growth in men with advanced prostate cancer. Researchers hope that this could improve survival for some men. Experts say the drug could be made available to patients in the next couple of years.

Precision medicine

Olaparib, also called Lynparza, works by targeting and killing cancer cells with faulty genetic code, while at the same time sparing normal cells with healthy DNA.

Researchers say that the drug won’t work for everyone with prostate cancer, but it is effective for some men with the disease.

Patients can be tested to see if they have the genetic errors that the drug can attack – faulty DNA repair genes including BRCA1 and BRCA2. This precision approach means that the patients most likely to benefit will be treated, avoiding potential side-effects from other drugs that may not work as well for them.

During the trial, doctors compared Olaparib with two other commonly prescribed prostate drugs (hormone treatments called Abiraterone and Enzalutamide).

It appeared that Olaparib delayed cancer growth by months, which researchers say hopefully means men can survive for longer even when their disease is advanced. The researchers will be monitoring patients to confirm this.

About prostate cancer

One in eight men will be diagnosed with prostate cancer in their lifetime. It mainly affects men over the age of 50 and the risk increases with age.

Not all of these tumors need immediate treatment. If the cancer is at an early stage and not causing symptoms, doctors may instead suggest careful monitoring.

Some cases are more aggressive and need treatment but can be cured if caught early enough.

Other cases may only be diagnosed at a late stage when the cancer has spread and cannot be cured.

All treatments, including Olaparib, can have side-effects. Doctors can talk advise patients about what might be the best treatment for them.

A study from the University of Michigan sheds new light on prostate cancer treatment for African American men

A team of medical researchers led by University of Michigan doctors wanted to answer the question of whether black race associated with worse prostate cancer outcomes after controlling for variables such as access to care.

This question of racial disparity in regard to prostate cancer is important because African American men in the United States are more than twice as likely to die from prostate cancer as Caucasian men. The reason for the disparity, in black and white men with similar stages of prostate cancer disease, is still unclear, especially in regard to the contribution of biological versus non-biological differences.

The University of Michigan conducted an extensive study which concluded that the reason for the prostate cancer outcome disparity isn’t that black men intrinsically and biologically harbor more aggressive disease. The study stated that when provided the same access to treatment and care, black and white men have very similar cure rates.

However, black men get fewer prostate cancer screenings, and are more likely to be diagnosed with later-stage cancer. They are also less likely to have health insurance.

The study from the University of Michigan also suggests that when it comes to African American prostate cancer, health care, and socioeconomic factors play a larger role than genetics.

This study is very important to African American men and also for the physicians who treat them. The key takeaway is that now, more than ever, it is important for African American men to be proactive about their prostate health, and that a good first step in that direction is to initiate a discussion with a primary care physician or a urologist about the benefit of prostate cancer screening.

The University of Michigan study reviewed data on 306,100 men — 54,840 black men — ages 59 to 71 from the Veterans Affairs system and four other clinical trials.

Thanks to this study from the University of Michigan, urologists and other physicians now have evidence that prostate cancer outcomes in African Americans are substantially linked to access to care rather than genetic factors.

After surgery may not be necessary among men with prostate cancer

According to the results of a recent study, there was no difference in disease recurrence among men with prostate cancer when they were given radiation after surgery or not.

The results from the study could mean that men with prostate cancer could be spared having to undergo radiation after surgery. The study found no difference in disease recurrence at five years between those who did and did not utilize the adjuvant therapy.

As an added benefit for patients, these findings could lead to patients experiencing far fewer side effects. The good news could be that in future, many men will avoid the side-effects of radiotherapy. These side effects can include urinary leakage and narrowing of the urethra, which can make urination difficult. Both are still potential complications after surgery alone, but the risk is increased if radiotherapy is used as well.

In the trial, researchers enrolled 1,396 patients after surgery for prostate cancer, and randomized them to receive either postoperative radiotherapy or the standard approach of observation only (in this particular group radiotherapy was only kept as an option if the disease recurred).

After five years at a median follow-up, progression free survival (the time from treatment to disease progression or worsening) was 85% in the radiotherapy group, compared with 88% in the standard care group.

After one year post-surgery, self-reported urinary incontinence was worse in the radiotherapy group (5.3%), compared with those who underwent observation (2.7%).

There is a strong case to be made that observation could be the standard approach after surgery and radiotherapy should only be used if the cancer comes back.

These same findings were also confirmed in a collaborative meta-analysis that included three randomized trials comparing adjuvant radiotherapy with early salvage radiotherapy following prostatectomy for men with localized prostate cancer.

The analysis was comprised of 2,151 men, including 1,074 who were randomized to adjuvant radiotherapy and 1,077 men were randomized to early salvage radiotherapy. Of those randomized to early salvage radiotherapy, only 37% started salvage treatment to date.

Similarly, the analysis did not find a significant difference supporting the use of adjuvant therapy to improve prostaAfter Surgery May Not Be Necessary Among Men With Prostate Cancer
According to the results of a recent study, there was no difference in disease recurrence among men with prostate cancer when they were given radiation after surgery or not.

The results from the study could mean that men with prostate cancer could be spared having to undergo radiation after surgery. The study found no difference in disease recurrence at five years between those who did and did not utilize the adjuvant therapy.

As an added benefit for patients, these findings could lead to patients experiencing far fewer side effects. The good news could be that in future, many men will avoid the side-effects of radiotherapy. These side effects can include urinary leakage and narrowing of the urethra, which can make urination difficult. Both are still potential complications after surgery alone, but the risk is increased if radiotherapy is used as well.

In the trial, researchers enrolled 1,396 patients after surgery for prostate cancer, and randomized them to receive either postoperative radiotherapy or the standard approach of observation only (in this particular group radiotherapy was only kept as an option if the disease recurred).

After five years at a median follow-up, progression free survival (the time from treatment to disease progression or worsening) was 85% in the radiotherapy group, compared with 88% in the standard care group.

After one year post-surgery, self-reported urinary incontinence was worse in the radiotherapy group (5.3%), compared with those who underwent observation (2.7%).

There is a strong case to be made that observation could be the standard approach after surgery and radiotherapy should only be used if the cancer comes back.

These same findings were also confirmed in a collaborative meta-analysis that included three randomized trials comparing adjuvant radiotherapy with early salvage radiotherapy following prostatectomy for men with localized prostate cancer.

The analysis was comprised of 2,151 men, including 1,074 who were randomized to adjuvant radiotherapy and 1,077 men were randomized to early salvage radiotherapy. Of those randomized to early salvage radiotherapy, only 37% started salvage treatment to date.

Similarly, the analysis did not find a significant difference supporting the use of adjuvant therapy to improve prostate cancer from recurring, compared to early salvage radiotherapy. Based on these results, the difference in five-year event free survival is likely only to be around 1%, according to the release.

te cancer from recurring, compared to early salvage radiotherapy. Based on these results, the difference in five-year event free survival is likely only to be around 1%, according to the release.

More data link statins to lower prostate cancer risk; benefits limited to longer duration of treatment

A retrospective cohort study showed that men who used statin drugs had a lower risk of prostate cancer but only with prolonged use or higher doses.

Men who had a history of treatment with statins was associated with a 15% reduction in the relative risk of low-grade prostate cancer and a 46% lower risk of developing high-grade disease. The association, however, was limited to men who took statins for at least 11 months or who had a specific defined daily dose of ≥121. This number is based on a reference dose of 20-mg simvastatin.

According to a report, lipophilic statins appeared to be more protective against prostate cancer than did hydrophilic drugs.

Researchers believe that mechanistically, statins have been found to reduce intracellular and serum cholesterol, and therefore may affect cell membrane organogenesis, steroidogenesis, and proliferation. Growth inhibition in prostate-derived cells lines was observed at clinically relevant statin concentrations.

This study adds to numerous others that preceded it, which collectively showed that statin use is associated with a lower risk of prostate cancer. The cumulative data does suggest only a modest effect on prostate cancer diagnosis.

Statins and Prostate Cancer

Over the past 15 years, statin use has increased dramatically, and as a class, the drugs are among the most widely prescribed medications in the world. It is thought that lowering serum and tissue levels of cholesterol may disrupt cellular lipid rafts, leading to reduced raft-dependent signaling and cell proliferation. And by extension, statins may have chemopreventive effects that reduce carcinogenesis, including prostate cancer carcinogenesis.