Recent studies summarized on this website on December 30th, 2015 and November 7th, 2016 concluded that hormonal therapy of prostate cancer was linked to an increase in dementia and Alzheimer’s disease. Now a recent study published in the Journal of Clinical Oncology and summarized in the February 6th, 2017 e mail issue of Prostate Cancer News Today has concluded the opposite, namely that prostate cancer patients receiving androgen deprivation therapy (ADT) are not at increased risk of dementia or Alzheimer’s disease.
Cognitive impairment is a known side effect of declining testosterone, in general, so it is naturally of concern with ADT. However the study authors noted that “there is a significant difference between cognitive limitations and the biological mechanisms associated with dementia.” Because ADT is so often given to older men, very careful statistical analysis is required to assert a causal relationship.
Using data from the United Kingdom’s Clinical Practice Research Datalink (CPRD), researchers analyzed the medical records of 30,903 patients diagnosed with nonmetastatic prostate cancer over 27 years. During a mean follow-up of 4.3 years, 799 patients were diagnosed with dementia. Researchers did not find a link between ADT and the condition. Secondary analyses — assessing whether the risk varied with the type of ADT or length of use — also failed to show a connection. There are side effects to every medication. The authors note that “if patients believed that ADT doubled their risk of Alzheimer disease they may be reluctant to take it for their cancer. Thus, our analysis should be welcome news for men whose prostate cancer is being controlled with ADT.”
ODM-201 (also known as BAY-1841788) is a non-steroidal, oral anti-androgen (specifically a full and high-affinity antagonist of the androgen receptor (AR), that is under development by Orion and Bayer Healthcare for the treatment of advanced, hormone-resistant prostate cancer. [An antagonist is a drug (blocking agent) that binds to the cellular receptor for a hormone (e.g. testosterone) thus blocking the effect of the hormone without producing any physiologic effect itself.] Bayer HealthCare and Orion Corporation have begun to enroll patients in a Phase III trial with ODM-201. The study, called ARAMIS, evaluates ODM-201 in men with hormone-resistant prostate cancer (CRPC) who have rising Prostate-Specific Antigen (PSA) levels and no detectable metastases. The trial is designed to determine the effects of the treatment on metastasis-free survival (MFS). The trial is being conducted at 502 locations in the US. For enrollment and location information see the following clinicaltrials.gov link.
The ARAMIS trial is a randomized, Phase III, multicenter, double-blind, placebo-controlled trial evaluating the safety and efficacy of oral ODM-201 in patients with non-metastatic CRPC who are at high risk for developing metastatic disease. About 1,500 patients are planned to be randomized in a 2:1 ratio to receive 600mg of ODM-201 twice a day or matching placebo. Randomization will be stratified by PSA doubling time (PSADT < 6 months vs. > 6 months) and use of osteoclast-targeted therapy (yes vs. no). In men with progressive non-metastatic CRPC, a short PSA doubling time has been consistently associated with reduced time to first metastasis and death.
The primary endpoint of this study is metastasis-free survival (MFS), defined as time between randomization and evidence of metastasis or death from any cause. The secondary objectives of this study are overall survival (OS), time to first symptomatic skeletal event (SSE), time to initiation of first cytotoxic chemotherapy (such as taxotere), time to pain progression, and characterization of the safety and tolerability of ODM-201.
A Phase II clinical trial conducted in patients with progressive metastatic castration-resistant prostate cancer assessed the efficacy and safety of three dose levels of ODM-201 (100mg, 200mg and 700mg given twice a day) in 124 patients. The study included patients who were treated previously with abiraterone and/or chemotherapy as well as patients who were chemotherapy-naïve. The results showed that ODM-201 provided disease suppression and had a favorable safety profile. The results were presented at the international ECCO oncology congress at the end of September 2013 and published in June 2014 in The Lancet Oncology.
Relative to enzalutamide (MDV3100 or Xtandi) and apalutamide (ARN-509), two other recent non-steroidal antiandrogens, ODM-201 shows some advantages. ODM-201 appears to negligibly cross the blood-brain barrier. This is beneficial due to the reduced risk of seizures and other central side effects that tends to occur in non-steroidal antiandrogens that are structurally similar to enzalutamide. Moreover, in accordance with its lack of central penetration, ODM-201 does not seem to increase testosterone levels in mice or humans, unlike other non-steroidal antiandrogens. Another advantage is that ODM-201 has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently-identified clinically-relevant F876L mutation that produces resistance to enzalutamide and ARN-509. ODM-201 has been studied in phase I and II clinical trials and has thus far been found to be effective and well-tolerated with the most commonly reported side effects including fatigue, nausea and diarrhea. No seizures have been observed. As of July 2015, ODM-201 is in phase III trials for CRPC. For more specific information, see the following link.
A new study published in the Journal of Urology suggests that anxiety may prompt prostate cancer patients to opt for potentially unnecessary treatments.
The research included more than 1,500 men newly diagnosed with localized prostate cancer. They were more likely to choose surgery and radiation therapy than active surveillance. Active surveillance — also known as “watchful waiting” — is when the patient is monitored closely, but not treated.
“Men’s level of emotional distress shortly after diagnosis predicted greater likelihood of choosing surgery over active surveillance,” said the researchers from the University at Buffalo and Roswell Park Cancer Institute in Buffalo, N.Y.
“Importantly, this was true among men with low-risk disease, for whom active surveillance may be a clinically viable option and side effects of surgery might be avoided,” they noted.
Though the study found an association between anxiety and more aggressive treatment, it didn’t prove cause and effect.
“Emotional distress may motivate men with low-risk prostate cancer to choose more aggressive treatment,” said study author Heather Orom, an associate professor of community health and health behavior at the University at Buffalo.
“If distress early on is influencing treatment choice, then maybe we help men by providing clearer information about prognosis and strategies for dealing with anxiety. We hope this will help improve the treatment decision-making process and ultimately, the patient’s quality of life,” Orom said in a university news release.
Study co-author Dr. Willie Underwood III, an associate professor in Roswell Park’s department of urology, said that to help men and families through this difficult process, “it is helpful for physicians to better understand what is motivating men’s decisions and to address negative motivators such as emotional distress to prevent men from receiving a treatment that they don’t need or will later regret.” Overtreatment is a concern because surgery and radiation therapy can cause side effects such as erectile dysfunction and incontinence. These problems can be avoided in men with low-risk prostate cancer by choosing active surveillance, the researchers said.
This report appeared in the January 27th, 2017 Medline Plus, published by the U.S. National Library of Medicine.
The National Institutes of Health (NIH) of the Department of Health and Human Services (DHHS) sponsors clinical trials related to many diseases and conditions including prostate cancer. (The National Cancer Institute, NCI, is the largest of all the institutes comprising NIH). The director of the NIH, Dr. Francis Collins recently discussed accessing information about these trials on their website, clinicaltrials.gov. The new NIH rules makes it easier for the public to access purposes of the trials, enrollment requirements, location, and especially summary results. I encourage you to view the following link to the short video by Dr. Collins who was a pioneer in the sequencing of the total human genome a few years ago.
The Prostate Cancer Foundation (PCF) just published an e mail review entitled “When Treatment Stops Working, Blame Resistance.” It describes multiple ways of treating advanced prostate cancer including androgen receptor blockers such as enzalutamide and abiraterone, chemotherapy, targeted drugs such as PARP inhibitors (olaparib and rucaparib), immunotherapy including checkpoint inhibitors, bipolar hormonal therapy, SBRT radiation, liquid biopsy and radiopharmaceuticals. See this link.
Patients with newly diagnosed metastatic, hormone-sensitive prostate cancer gained a dramatic survival benefit with simultaneous initiation of two drugs, rather than delaying the second drug until the cancer began to worsen, according to results of a clinical trial recently published in The New England Journal of Medicine (2015; doi:10.1056/NEJMoa1503747).
Patients who underwent six cycles of treatment with docetaxel® (taxotere) along with a hormone blocker survived for a median of 57.6 months, more than 1 year longer than the median 44-month survival for men who received only the hormone-blocker. The immediate combination also prolonged the period before the cancer began to worsen, to a median of 20.2 months vs 11.7 months with the single agent.
The multicenter, phase III trial, involving 790 patients, “is the first to identify a strategy that prolongs survival in men [with] newly diagnosed with metastatic, hormone-sensitive prostate cancer,” said Christopher J. Sweeney, MBBS, of Dana-Farber’s Lank Center for Genitourinary Oncology in Boston, Massachusetts. He said the results of the multicenter phase III trial should change the way doctors have routinely treated such patients since the 1940s.
Sweeney had reported initial results of the trial in June 2014 at the annual meeting of the American Society of Clinical Oncology (ASCO), and they were so favorable that the new regimen has been adopted by some physicians. Since then, confirmatory data from the STAMPEDE trial were presented at the 2015 ASCO meeting, and those results, along with the new publication in the New England Journal of Medicine, are the final pieces “required for treatment guidelines to be updated around the globe,” Sweeney said.
The standard practice for decades has been to treat this group of prostate cancer patients with hormone blockers; chemotherapy is withheld until the hormone blockers become ineffective, which they do, on average, in approximately 3 years.
The new trial was designed and conducted by the ECOG-ACRIN Cancer Research Group to test Sweeney’s hypothesis that adding chemotherapy to hormone treatment from the start would impair the tumor cells’ ability to repair damage, delaying the development of resistance.
Madison Vaccines Incorporated (MVI, see the linked news release), has begun a Phase 1 clinical trial for MVI-118 (pTVG-AR) in men with metastatic prostate cancer who are initiating androgen deprivation (hormonal) therapy (ADT). MVI-118 targets the human androgen receptor, the critical biological target responsible for driving prostate cancer progression and, in many cases, resistance to current therapies. MVI-118 is intended to provide persistent activation of immune system CD8+ T-cells that target the androgen receptor, a key tumor cell protein that is frequently and highly overexpressed as resistance to ADT emerges. MVI-118 is being developed to prolong the duration of disease control gained from standard androgen deprivation therapies thus delaying resistance to ADT. The trial will be conducted at the University of Wisconsin – Madison Carbone Cancer Center and two additional Medical Centers including Rutgers Cancer Institute in New Jersey. For an overview see the link in the Nov. 7th Prostate Cancer News Today.
This is MVI’s second prostate cancer vaccine, along with MVI-816 (pTVG-HP), MVI’s lead vaccine that has demonstrated clinical evidence of safety, immune activation and biological signals (PSA changes) of activity. Both MVI-816 and MVI-118 are plasmid DNA vaccines that differ from other vaccines because they can be rapidly and inexpensively manufactured, can be administered by simple intradermal injection, and are relatively more stable in storage.
MVI’s lead vaccine, MVI-816, is in a Phase 2 clinical trials in patients with early biochemically recurrent prostate cancer intended to delay the onset of metastatic disease after primary therapy. MVI-816 is also in a second clinical trial in advanced metastatic, hormone-resistant cancer that began this past summer pairing it with an immunomodulatory PD-1 inhibitor which enhances the immune system’s activity against cancer cells but does not work alone in prostate cancer. Final Phase 2 data on MVI-816, the lead vaccine, is expected in 2018. Both MVI-816 and MVI-118 are intended to address the anticipated surge in prostate cancers over the next two decades as “Baby Boomers” reach the age when men are most commonly diagnosed with the disease.
For MDI-118 clinical trial details concerning enrollment and other criteria, see the following link to the National Institutes of Health (NIH) ClinicalTrials.gov. Patients in the Phase 1 trial of MDI-118 must have metastatic prostate cancer (clinical stage D1 or D2 disease), with previously documented lymph node, soft tissue and/or bone metastases as evidenced by radiographic imaging (including CT (or MRI) of abdomen and pelvis and bone scans). Patients must have started androgen deprivation therapy at least one month (4 weeks) prior to enrollment and no more than six months (24 weeks) prior to enrollment. Patients must continue the androgen deprivation therapy throughout the study period, and patients are not permitted to change the type of androgen deprivation therapy during the course of investigational therapy.
It isn’t often that a research finding appears in 4-5 e mail or other publications but such is the case herein. Researchers at Stanford University School of Medicine published a study entitled “Association Between Androgen Deprivation Therapy and the Risk of Dementia” in the journal Journal of the American Medical Association Oncology. They reported that men treated with testosterone-lowering drugs for their prostate cancer are more than twice as likely to develop dementia as those not receiving such treatment, according to a study that reviewed the medical records of nearly 10,000 patients. But, the study only found an association between ADT and dementia risk, not cause and effect. The researchers advised however that men undergoing androgen therapy shouldn’t stop the treatment based on these findings because more studies are needed to verify this potential link.
Last year, the research team at Stanford discovered that testosterone-lowering treatment was linked to a higher risk of developing Alzheimer’s disease. Since Alzheimer’s is commonly confused with vascular dementia, the team decided to explore if the association held true when including all types of dementia.
They identified medical records of 9,272 men with prostate cancer who had been treated between 1994 and 2003, of which 1,829 received testosterone-lowering treatment. To make sure results became as robust as possible, they first removed all patients who had dementia at prostate cancer diagnosis. Then, they matched treated and untreated patients with the same disease stages, to make sure the comparisons were valid.
The team discovered that within five years, 7.9 percent of those receiving testosterone-targeting treatment had developed dementia. Among patients not receiving such treatment, the number was 3.5 percent.
The risk is real and, depending on the prior dementia history of the patient alternative treatment treatment may be considered, particularly in light of a recent prospective study from the U.K., which showed that prostate cancer patients had the same chances of survival within a 10-year time frame, whether they received aggressive treatment or active monitoring. Only 1% of men died during the 10 years, suggesting that monitoring may be as good as treatment, without causing side effects.
According to an article in the Oct. 13th MedlinePlus published by the U.S. National Library of Medicine, one possible explanation is that androgens like testosterone are believed to be very important for neuron [brain cell] health. In the brain, the ability of neurons to repair themselves and not die off, those are at least partially regulated by androgens. A very reasonable theory would be if you don’t have those androgens around to have that protective effect, you would be more susceptible to developing dementia.
Based on the findings, researchers argue it makes sense to identify those at risk for dementia before considering testosterone-lowering treatment. Researchers, however, underscored that the data are derived from medical records, and that prospective clinical trials ultimately are needed to remove any doubts that testosterone-lowering treatments may trigger cognitive decline.
A slightly more extensive article for health professionals was published in the October 21st issue of Cancernetwork, home of the journal Oncology.
In a study published online on Oct. 20th in the Journal of the American Medical Association (JAMA) Oncology, more than 90 percent of men in Sweden who have very low-risk prostate cancer choose close monitoring rather than immediate treatment — and more American men should use that option, researchers say.
In a study of nearly 33,000 Swedish men with very low-risk (stage T1) prostate cancer diagnosed between 2009 and 2014, the number choosing what is called active surveillance increased from 57 percent to 91 percent during that time frame.
“For men who are diagnosed with low-risk prostate cancer, it is important to know that active surveillance is an accepted way to manage the cancer,” said lead researcher Dr. Stacy Loeb, an assistant professor in the departments of urology and population health at NYU Langone’s Perlmutter Cancer Center in New York City.
“There is no rush to get treatment — low-risk prostate cancer can be safely monitored,” she added. “Some men will eventually need treatment, but others will be able to preserve their quality of life for many years.”
In the United States, the majority of men with low-risk prostate cancer get treatment upfront, which can have side effects, such as urinary and erectile problems, Loeb said.
Active surveillance isn’t wait-and-see, she explained. It involves regular blood tests and regular biopsies to gauge the growth of the tumor. When the tumor grows to a point where treatment is needed, then it’s time for curative surgery or radiation.
A recent British trial showed that 10 years after diagnosis, the risk of dying from prostate cancer was the same whether men initially had surgery or radiation or opted for monitoring, Loeb added.
“We found that most men in Sweden with low-risk cancers are now opting for surveillance rather than upfront treatment,” Loeb said. “Hopefully, this study can increase awareness among patients in the U.S. and other countries that deferring treatment is an accepted option for low-risk prostate cancer.”
There is a lot of controversy about prostate cancer screening, Loeb noted. “Prostate cancer has no symptoms until it is advanced, so screening is actually very important to find life-threatening cancers in time for cure,” she said.
Patients with high-risk cancer do need treatment right away, and that treatment can be lifesaving, Loeb said. “However, many other men are diagnosed with low-risk cancers that have a very good prognosis without any treatment, and deferring upfront treatment can allow them to preserve their quality of life longer,” she said.
About 181,000 American men will be diagnosed with prostate cancer in 2016, and most of those will be in the earliest stages, according to the U.S. National Cancer Institute (NCI). Approximately 26,000 men will die from prostate cancer in 2016, the NCI estimates. The five-year survival rate for prostate cancer is nearly 99 percent, the NCI says.
“This [study] is more evidence of active surveillance becoming a standard of care,” said Dr. Matthew Cooperberg, an associate professor of urology, epidemiology and biostatistics at the University of California, San Francisco and author of an accompanying journal editorial.
Sweden has been far ahead of the United States in terms of active surveillance, but it is becoming more accepted here, Cooperberg said. About 40 percent to 50 percent of men with low-risk prostate cancer are choosing surveillance, “so we still have some catching up to do,” he said.
Adoption of active surveillance has been slow in the United States for several reasons, Cooperberg added. Among these are the financial and legal incentives to treat patients.
“In addition, culturally Americans have been uncomfortable with the idea of not treating cancer, because of the psychology that comes with the ‘C’ word,” he said. “But things are changing; it’s not such a foreign concept.”
Cooperberg said the future of active surveillance is refining it based on an individual’s cancer, so that tests and biopsies aren’t done on an arbitrary schedule, but on a schedule based on the characteristics of the patient’s tumor.
“Prostate cancer decision-making — from PSA testing on through treatment — really needs to be personalized,” he said.
As always, if this information pertains to your specific diagnosis, it should be discussed with your personal health care provider before taking any action. This report appeared in the October 20th issue of MedlinePlus, published online by the National Institutes of Health U.S. National Library of Medicine. This information also was posted on-line by Prostate Cancer News Today on October 31st (see link).
A large database analysis showed that the addition of external beam radiotherapy (RT) to androgen deprivation therapy (ADT) significantly improves overall survival (OS) in men with metastatic prostate cancer.
“As advances in systemic therapy for metastatic prostate cancer have improved OS and the control of metastatic disease, a greater interest has emerged in therapies to promote local control of the primary prostatic tumor,” wrote study authors led by Chad G. Rusthoven, MD, of the University of Colorado School of Medicine in Aurora. There is relatively limited data so far, though, on the use of external beam RT in these patients.
The study analyzed outcomes from 6,382 men diagnosed between 2004 and 2012 included in the National Cancer Data Base (NCDB), all of whom received ADT. Of these men, 538 (8.4%) also received prostate RT. The results of the analysis were published in the Journal of Clinical Oncology and linked herein.
Those who received RT were younger, had better comorbidity scores, lower prostate-specific antigen levels, and higher T stage, and were more likely to have n0 disease, to be treated at a community facility, and to have private insurance.
After a median follow-up of 5.1 years, the addition of RT was associated with a longer median OS of 53 months, compared with 29 months without RT. The 3-year OS rates were 62% with RT and 43% without RT; at 5 years, these rates were 49% and 25%, respectively, and at 8 years, the rates were 33% and 13%. A subgroup analysis showed that the biggest benefit of RT was gained in patients with Gleason scores of 8 or below, and for T1–3 tumors compared with T4 tumors. Higher RT dose was also associated with better OS compared with lower doses.
The analysis has limitations inherent to retrospective cohort studies, including the possibility of selection biases and imbalances. The authors noted that performance status and extent of metastatic disease burden could not be controlled for, and the sites of metastatic spread were unavailable.
Still, they concluded, “In this large contemporary analysis, men receiving prostate RT plus ADT lived substantially longer than men treated with ADT alone. Randomized trials to evaluate the impact of local therapy for men with metastatic prostate cancer appear warranted and several trials are ongoing.”