Prostate Cancer Drugs
Men treated with ADT more likely to experience impaired cognitive performance
Men treated with androgen deprivation therapy (ADT) for prostate cancer were more likely to demonstrate impaired cognitive performance within 6 months and for up to 12 months after initiation of ADT, a new study published online early in the Journal of Clinical Oncology has shown.
For the study, researchers at Moffitt Cancer Center in Tampa, Florida, sought to determine the effect of ADT on cognitive performance identify predictors of impaired performance. Researchers enrolled 58 patients with prostate cancer whom they assessed before or within 21 days of starting ADT and 6 and 12 months afterwards.
Participants were compared with matched controls with prostate cancer treated with prostatectomy as well as men with without prostate cancer.
Results showed that participants that received ADT had higher rates of impaired cognitive performance over time compared with all controls.
Researchers found that those who received ADT were more likely to exhibit impaired performance within 6 and 12 months versus the other two groups despite no differences in baseline characteristics.
Exploratory genetic analyses showed that GNB3 single-nucleotide polymorphism rs1047776 was associated with higher rates of impaired cognitive performance over time in patients treated with ADT.
The findings may result in changes to patient education regarding the benefits and risks of ADT.
Source : Oncology Nurse Advisor (July 2015)
Long-Term Survival of Participants in Prostate Cancer Prevention Trial Detailed
In the NCI-sponsored Prostate Cancer Prevention Trial (PCPT), initial findings from a decade ago showed that the drug finasteride significantly reduced the risk of prostate cancer, but among those who did develop prostate cancer, paradoxically, the drug was associated with an increased risk of high-grade disease. New findings reported in NEJM on August 15, 2013, based on follow-up of trial participants for up to 18 years, showed that survival of the men on finasteride was equivalent to men who did not take the drug and the reduction in risk of prostate cancer persists. Among nearly 19,000 eligible men who underwent randomization, prostate cancer was diagnosed in 10.5 percent of those in the finasteride group and 14.9 percent of those in the placebo group, a 30 percent reduction in risk. For the men diagnosed with prostate cancer, 10-year survival from time of diagnosis was equivalent between study groups overall (78 percent), in those with low-grade cancers (82 percent), and in those with high-grade cancers (73 percent) providing reassurance that the small excess of higher grade tumors in the men in the finasteride arm of the study did not translate into an increased risk of death.
Previous studies based on the original 2003 analysis had already suggested that the increase in high-grade disease may have been due to prostate gland shrinkage and increased sensitivity in detecting higher grade cancers. In fact, the PCPT was not designed specifically to address the question of high-grade disease. Since 2011, drugs such as finasteride have had to carry a warning that they may increase the risk of high-grade prostate cancer; they have never been approved for the prevention of the disease. Specifically, there was concern that the increase in high-grade cancers detected among men receiving finasteride would result in more deaths. This new analysis was undertaken, in part, to understand if such concern was warranted.
Source : Newswise
Link to Source
Insight: New doubts about prostate-cancer vaccine Provenge
Prostate cancer vaccine Provenge has long incited passions unlike any other cancer therapy.
Doctors who raised doubts about it received death threats. Health regulators and lawmakers faced loud protests at their offices. A physician at the American Cancer Society was so intimidated by Provenge partisans that he yanked a skeptical discussion of it from his blog.
The vitriol dissipated in April 2010, when the U.S. Food and Drug Administration approved Provenge for advanced prostate cancer, satisfying investors in manufacturer Dendreon and patients who for years had demanded it be put on the market.
But the bell on Round Two sounded when Marie Huber, a trained scientist and former hedge-fund analyst, made it her mission in the last year to analyze what she believes are deadly flaws in the studies that led to the approval of Provenge by the FDA.
She argues that the main reason Provenge seemed to extend survival - a crucial factor in the FDA's decision - was that older men in the study who did not receive Provenge died months sooner than similar patients in other studies.
She raises the possibility the "placebo" they received was actually harmful and made Provenge, known scientifically as sipuleucel-T, look better by comparison.
As Huber gains traction, most notably with a February paper in the prestigious Journal of the National Cancer Institute, she, too, is receiving threats. One post on an investors' message board last month suggested that "somebody smack her with a rubber hose." An email said "don't think you will be unscathed in this battle you waged on Provenge."
Provenge is Dendreon's only product and the company's stature with investors has waned with disappointing sales. In 2011, product revenues totaled $213.5 million, far from the $400 million Dendreon initially projected.
The company insists Huber's analysis is flawed and that Provenge has helped thousands of men with prostate cancer.
"I'm looking forward to getting this to patients around the world," said President and Chief Executive John Johnson.
FIRST CANCER VACCINE
Since it won FDA approval two years ago, Provenge has been Exhibit A for the idea that a patient's immune system can control or cure cancer. The first therapeutic cancer vaccine to reach the market, Provenge tries to engineer white blood cells, part of the immune system, to vanquish prostate cancer, which killed an estimated 33,720 men in the United States last year.
ts path to approval has all the features of a heavyweight healthcare fight - desperate patients demanding access to a promising therapy, a very expensive drug that extends life only a few months and efficacy data open to interpretation.
The FDA declined to approve the drug in 2007, when a clinical trial failed to show it slowed tumor growth. That incited protests, lawsuits and death threats against physicians on the FDA advisory panel who did not recommend approval, breaking with the 13-4 majority in favor.
"Provenge came along when we didn't have much to offer for prostate cancer," said Dr. Len Lichtenfeld of the ACS. "The advocacy community was bursting at the seams for something that worked. When you have that situation, it inflames passions and that can overtake the science."
In the pivotal trial called IMPACT, published in July 2010, but shared with the FDA months earlier, Provenge extended median survival by 4.1 months to 25.8 months from 21.7 months. That was sufficient for FDA approval. The vaccine costs $93,000 and patients also incur physician and other charges. Medicare agreed to cover Provenge last year, as have private insurers, but doctors initially balked at a long wait for reimbursement.
Huber had long been "utterly intrigued" by Provenge and its "huge promise of harnessing the immune system to battle cancer," she said in an interview.
In documents JNCI requires authors to sign, she declared no financial conflicts of interest. Neither she nor her former firm nor anyone else she is connected to stands to benefit financially from her analysis, she said.
Instead, she says she is motivated to help "vulnerable and desperate patients" - so much so that she gave up her job, salary and health insurance. Arguing that Provenge is harming these men,
She called "the whole thing utterly horrific. The company got away with hiding data and doctors making $7,000 per prescription won't even engage in discussion" about whether it helps their patients.
After receiving degrees in biochemistry and bioscience enterprise from Cambridge University, Huber began working as an analyst for a hedge fund in 2007. A Thomson Reuters analysis of securities filings confirmed her former firm has not held any positions in Dendreon.
LACK OF EVIDENCE
Each dose of Provenge is custom-made. A nurse or technician withdraws white blood cells from a man's arm in a three-to-four hour procedure called leukapheresis.
The cells are shipped to a Dendreon manufacturing facility, where for two days they are incubated with a "fusion protein:" One protein that stimulates the cells' growth and maturation and another called PAP, or prostatic acid phosphatase. PAP is an antigen that studs prostate cancer cells like antennae, pieces of it sticking out of the cells' surfaces.
Dendreon says the patients' white blood cells take up the antigen and within hours their surfaces bristle with fragments of the telltale molecule. The cells are then shipped back to the physician and infused into the patient. A full treatment includes three such procedures, two weeks apart.
Back inside the body, Dendreon claims the modified cells trigger the immune system to produce T cells that kill any cell sporting the PAP antigen — namely, prostate cancer cells.
In principle, that should eliminate the cancer, but Provenge does not shrink either the primary tumor or metastases.
Steven Rosenberg of the National Cancer Institute, a leading tumor immunologist, says that raises doubts over whether Provenge helps patients live longer, as the IMPACT trial reported.
"We have a lot of data that supports the idea that the product works the way it was designed to," said Dr. Mark Frohlich, Dendreon's chief medical officer. "We're seeing evidence of immune-system activation. The only question is whether the T cells are killing the tumor."
The FDA acknowledges that data supporting Provenge's approval did not show the drug shrank tumors, but says the overall survival benefit was enough to bring it to market. Spokeswoman Rita Chapelle, citing data submitted by Dendreon, said there is a "lack of evidence of anti-tumor activity," the reason for which "is unclear."
SUSPICIONS OVER SURVIVAL BENEFIT
Huber's analysis comes from data showing that men who received the placebo had very different survival times based on their age. Men older than 65 lived 17.3 months on placebo and 23 months with Provenge. Men younger than 65 lived 28 months after receiving placebo and 29 months after Provenge.
Other studies have shown that age generally does not affect how long a man survives with this form of prostate cancer, says Peter Iversen, a urologist and prostate-cancer surgeon at the University of Copenhagen and co-author of the paper with Huber.
Combining these findings led to the new paper's conclusion: The four-month edge in median survival from Provenge for all patients was due to longer survival among older men who got the vaccine.
"There is no efficacy in the younger patients, the primary group where you would expect it," said Huber.
Since the immune system weakens with age, an immune-based therapy should work better in younger men.
Some experts agree.
"If it was really a vaccine, you'd think younger men would show more response, since they are more immunocompetent," said NCI's Rosenberg.
On that basis, Huber and her co-authors, including two prostate-cancer specialists, argue the placebo used in the trial may have harmed the older men, cutting months off their lives and inadvertently making Provenge seem beneficial.
One way that could have occurred was through leukapheresis. That process removed about 90 percent of certain kinds of circulating white blood cells, according to calculations by immunologist Laura Haynes of the Trudeau Institute, a co-author of the JNCI paper.
The Provenge men got back about 32 percent of those cells, which had been stored at body temperature. The placebo men got back 12 percent, which had been incubated at near-freezing temperatures. Cold storage has been reported to kill "most, if not all, of those cells," notes the JNCI paper. Moreover, said Haynes, "if you return dead and dying cells to older men you are likely to cause inflammation," which can stoke the growth of cancerous cells.
Younger men were better able to replace the lost white blood cells, argued Iversen. Older men could not, resulting in early death.
"These cells are very specialized and there is research suggesting that removing them can harm older men," he said.
Earlier this month, DynaMed, an online database used by physicians, added to its Provenge entry a note on the JNCI paper, but calls the concern "not substantiated." ACS's Lichtenfeld says the analysis "might inhibit some patients and doctors from going ahead with a very expensive drug."
Huber says she plans to approach European regulators as they consider Dendreon's application to approve Provenge.
Investor message boards have lit up in response to the new paper. In February, an anonymous commentator on InvestorVillage.com warned that Huber's work was about to be published "a few days before our earnings. Her agenda is obvious."
Critics of the new analysis argue the number of cells removed is too small to suppress the immune system. Charles Drake, an oncologist and immunologist at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, said there is no evidence the placebo men in IMPACT suffered more infections or other effects of a depleted immune system than the Provenge men.
The scientist who led IMPACT, oncologist Philip Kantoff of Dana Farber Cancer Center, said colleagues in immunology "dismissed as nonsense the idea that leukapheresis could hurt individuals."
He takes issue, too, with the statistics. Dividing the men by whether they are older or younger than 65, he said, is "arbitrary" and to pick apart data retrospectively is a statistical no-no.
Dendreon's Frohlich also criticizes the statistics: "If you do enough of these (post-hoc analyses) then by chance alone you'd expect to get one positive finding."
In other words, it is almost always possible to find a subset of patients who do better than others.
When Dendreon divided the men by whether they were older or younger than about 71, he added, they found no red flags.
The FDA agrees that such post-hoc statistical analyses "are exploratory" and their results "must be interpreted with caution, as acknowledged by the authors." Yet a paid consultant to Dendreon before the IMPACT trial agreed with many of Huber's concerns.
"The control vaccine used in IMPACT and in the predecessor trial had never been used anywhere for anything and may well have been detrimental to patients," said Donald Berry of MD Anderson Cancer Center, a leading biostatistician. "Here's a great way to get your drug approved: Kill the control patients."
Despite the heated rhetoric, Provenge may go out with a whimper more than a bang. Promising new agents for advanced prostate cancer include an oral drug from Medivation Inc called enzalutamide, in the final phase of clinical trials, and Zytiga from Johnson & Johnson, which won FDA approval in 2011. A vaccine that targets PSA, from Bavarian Nordic Immunotherapy, is in late-stage trials.
Dendreon does not disclose how many patients have been prescribed Provenge. CEO Johnson said that about 70 percent of its Provenge revenue comes from sales to community hospitals and doctors and 30 percent from academic medical centers. Some of the latter decline to use Provenge, deterred by lingering concerns over whether it provides a meaningful benefit.
Three such facilities in the Midwest, contacted at random by Reuters, confirmed they do not recommend Provenge. All asked not to be named for fear of receiving threats.
"It is my policy not to make public comments about this drug," said one oncologist. Patients who ask for it "are referred to another facility."
Source : Reuters
Link to Source
FDA: Include warnings on risk for class of prostate cancer drugs
The U.S. Food and Drug Administration today asked manufacturers to add new warnings to labeling of gonadotropin-releasing hormone (GnRH) agonists, a class of drugs primarily used to treat men with prostate cancer.
The warnings would alert patients and their health care professionals to the potential risk of heart disease and diabetes in men treated with these medications.
In May, the FDA said that a preliminary and ongoing analysis found that patients receiving GnRH agonists were at a small increased risk for diabetes, heart attack, stroke, and sudden death. The new labels will include updates in the Warnings and Precautions section about these potential risks.
Prostate cancer is the second most common type of cancer among men in the United States, behind skin cancer, and usually occurs in older men. This year an estimated 217,730 new cases of prostate cancer will be diagnosed and about 32,050 men will die from the disease, according to the Centers for Disease Control National Center for Health Statistics and the National Cancer Institute.
GnRH agonists are drugs that suppress the production of testosterone, a hormone involved in the growth of prostate cancer. This type of treatment is called androgen deprivation therapy, or ADT. Suppressing testosterone has been shown to shrink or slow the growth of prostate cancer.
GnRH agnoists are marketed under the brand names: Eligard, Lupron, Synarel, Trelstar, Vantas, Viadur, and Zoladex. Several generic products are available.
For more information:
Updated Drug Safety Communication: Ongoing Safety Review of GnRH Agonists and Possible Increased Risk of Diabetes and Certain Cardiovascular Diseases
May 3, 2010 News Release: FDA Conducting Safety Review of Commonly Used Prostate Cancer Drugs
Source FDA October 2010
LINK TO SOURCE
FDA Conducting Safety Review of Commonly Used Prostate Cancer Drugs
Preliminary review suggests an increase in the risk of diabetes and certain cardiovascular diseases in men treated with GnRH agonists
Gonadotropin-Releasing Hormone (GnRH) agonists, a class of medications primarily used to treat men with prostate cancer, have been associated with a small increased risk for diabetes, heart attack, stroke, and sudden death in men treated with one of the medications, according to a preliminary and ongoing analysis of several studies by the U.S. Food and Drug Administration.
Based on initial findings, FDA advises:
- Health care professionals should be aware of these potential risks and carefully weigh the benefits and risks of GnRH agonists when determining a treatment for patients with prostate cancer.
- Patients receiving a GnRH agonist should be monitored for the development of diabetes and cardiovascular disease.
- Cardiovascular risk factors such as smoking and increases in blood pressure, cholesterol, blood sugar and weight should be managed according to current clinical practice.
- Patients should not stop treatment with a GnRH agonist unless instructed to do so by a health care professional.
“While our review of these prostate cancer treatments is ongoing and there are some limitations to the data, FDA believes it is important to tell patients and health care professionals that there may be an increased risk of serious side effects,” said Robert Justice, M.D., director of the Division of Drug Oncology Products in FDA’s Center for Drug Evaluation and Research.
Medications in the GnRH class are marketed under the brand names Eligard, Lupron, Synarel, Trelstar, Vantas, Viadur, and Zoladex. There are also several generic products available.
The prostate gland is part of the male reproductive system. Prostate cancer is the second most common type of cancer among men in the United States, behind skin cancer, and usually occurs in older men. This year an estimated 203,415 new cases of prostate cancer will be diagnosed and about 28,372 men will die from the disease, according to the Centers for Disease Control and Prevention.
GnRH agonists are drugs that suppress the production of testosterone, a hormone that is involved in the growth of prostate cancer. This type of treatment is called androgen deprivation therapy, or ADT. Suppressing testosterone has been shown to shrink or slow the growth of prostate cancer.
Some GnRH agonists are also used in women to help manage the pain caused by endometriosis, to improve anemia associated with uterine fibroids prior to hysterectomy and in some cases for palliative treatment of advanced breast cancer. Use of these products should not exceed one year for women except in treating breast cancer. There are no known comparable studies that have evaluated the risk of diabetes and heart disease in women taking GnRH agonists.
Some GnRH agonists are also used in children to treat central precocious puberty. There are no known studies that have evaluated the risk of diabetes and heart disease in children taking GnRH agonists.
Eligard is marketed by Bridgewater, N.J.-based Sanofi-Aventis.
Lupron is marketed by Abbott Park, Ill.-based Abbott Laboratories.
Synarel is marketed by New York City-based Pfizer.
Trelstar is marketed by Corona, Calif.-based Watson Pharmaceuticals.
Vantas is marketed by Chadds Ford, Pa.-based Endo Pharmaceuticals.
Viadur is marketed by Wayne, N.J.-based Bayer Pharmaceuticals.
Zoladex is marketed by Wilmington, Del.-based AstraZeneca.
For more information:
- Drug Safety Communication: Ongoing Safety Review of GnRH Agonists and Possible Increased Risk of Diabetes and Certain Cardiovascular Diseases1
- FDA Office of Oncology Drug Products2
LINK TO SOURCE