Advanced Prostate Cancer, Sanofi Could See Expansion to First-Line Use
The Pink Sheet Daily. 2010 Jun 21, E Hayes
Sanofi-Aventis gained a fast approval for its chemotherapy Jevtana (cabazitaxel) - just 11 weeks after the final filing in a rolling submission for second-line treatment of advanced hormone-refractory prostate cancer. But the company is also positioned for a quick expansion to the first-line setting.
Cabazitaxel, the successor to the company's soon-to-lose exclusivity Taxotere , was cleared on June 17 for use in combination with the steroid prednisone to treat men with prostate cancer after treatment with Taxotere (docetaxel).
As part of its post-marketing commitments, Sanofi is required to conduct another Phase III study in second-line treatment and a Phase III study in the first-line setting.
However, Jevtana's potential in earlier-stage disease could be limited by its toxicity profile, Leerink Swann analyst Seamus Fernandez noted. Cabazitaxel is linked to severe, potentially fatal side effects that are given a very high profile in FDA labeling, including a boxed warning for neutropenia and severe hypersensitivity.
The side effect profile could be a determining factor, especially given the availability of Dendreon's just approved first-line treatment Provenge , as well as less toxic agents in late-stage development, particularly Cougar/Johnson & Johnson's abiraterone, Fernandez added. On the other hand, Provenge's penetration is likely to be limited by supply constraints, the analyst noted.
Sanofi said it is confident in Jevtana's potential, and has trials getting under way in lung, ovarian and breast cancer.
Taxotere is Sanofi's fourth best-selling product with sales of €2.1 billion ($2.5 billion) in 2009. But the product faces patent expiry at the end of 2010. While sales breakdowns are not available, Taxotere's success clearly has been driven by its application in multiple indications. In addition to prostate cancer, the drug is approved in non-small cell lung cancer, breast cancer, gastric cancer and head and neck cancer.
Targeting Area Of High Unmet Need
Approval of Jevtana was supported by the open-label Phase III TROPIC study of 755 patients, in which Jevtana was shown to improve survival in a very tough-to-treat population. Median overall survival for patients receiving Jevtana plus prednisone was 15.1 months compared with 12.7 months for patients receiving the chemotherapy drug mitoxantrone.
Jevtana marks an important achievement for an area in need of clinical advances. Metastatic prostate cancer ultimately becomes resistant to hormone treatment, and no drugs had been cleared for those who progress on Taxotere. Results were presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium in March and were considered game-changing.
Room To Maneuver On Pricing
After the glowing reception of the TROPIC results at the ASCO symposium, Leerink doubled its pricing assumption for Jevtana to $5,000 per cycle, with each patient receiving four cycles. Taxotere has a "surprisingly low" price of about $3,000 per cycle, with patients typically receiving six cycles, Fernandez noted.
Leerink estimates that of the 2 million men with prostate cancer in the U.S., about 17,000 could be eligible to take Jevtana. Assuming a $5,000 price, Leerink conservatively projected in a March 9 note Jevtana sales of €270 million ($333 million) in 2016. This estimate is for the second-line prostate cancer indication alone.
Fernandez also noted that Sanofi has a "wide berth to operate in, given pricing that we have seen with Provenge." Provenge came with a whopping sticker price of $93,000 per year, surpassing analyst expectations.
In an interview, Paul Chew, Sanofi's chief science officer and chief medical officer for the U.S., declined to comment on the price, beyond saying it would reflect the 14 years of development time and the value the product brings to patients.
Dendreon had argued that the price was on par with other oncology treatments when the four months of survival made possible by the vaccine were taken into account. If Sanofi applied the same logic, 2.4 months of benefit could equate to a $50,000-plus price, Fernandez observed.
Label Includes Extensive Safety Warnings
While extensive side effects are to be expected with cytotoxic drugs, Jevtana's labeling indicates a high range of potentially fatal outcomes and significant requirements for management that could present a barrier to wider use.
There is potential for severe hypersensitivity, including generalized rash/erythema, hypotension and bronchospasm - as detailed in a boxed warning. Consequently, every time cabazitaxel is administered patients must be premedicated 30 minutes prior to treatment with a corticosteroid, an antihistamine and an H2 agonist. Antiemetic prophylaxis also is advised, and labeling calls for monitoring of complete blood counts on a weekly basis; Jevtana should not be administered to patients with low neutrophil counts.
Many of the side effects associated with Jevtana are familiar with chemotherapy, but labeling spells out the degree of severity (including deaths) of neutropenia and diarrhea.
"Five patients experienced fatal infectious adverse events (sepsis or septic shock)," labeling states. The label advises G-CSF may be administered to reduce the risks of neutropenia complications, recommending prophylactic use in high-risk patients.
In a clinical trial, deaths related to diarrhea and electrolyte imbalance also occurred, and labeling states "intensive measures may be required." Renal failure is another risk that can have a fatal outcome.
Safety data were collected from a randomized controlled trial comparing Jevtana with prednisone to mitoxantrone and prednisone in 371 patients with hormone-refractory metastatic prostate cancer. Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5 percent) Jevtana-treated patients compared to 3 (<1 percent) of mitoxantrone-treated patients. The most common fatal adverse reactions in Jevtana-treated patients were infections (5 patients) and renal failure (4 patients). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of Jevtana.
Patients older than 65 were more likely to experience fatal outcomes not related to disease progression and certain adverse reactions, including neutropenia and febrile neutropenia. Older patients need to be monitored closely, the label advises.
Though the risks associated with cabazitaxel are heavy, they are countered by the significance of the efficacy findings: a survival advantage in a population without treatment options.
Approved With Gleevec-like Speed
FDA approval came well before the Sept. 30, 2010, user fee goal date, and the press statement on the approval included a big endorsement from Richard Pazdur, director of the Office of Oncology Drug Products.
"Patients have few therapeutic options in this disease setting. ... FDA was able to review and approve the application for Jevtana in 11 weeks, expediting the availability of this drug to men with prostate cancer," the statement said.
Sanofi's Chew stressed the value his company places on showing a survival benefit for oncology drugs: "The Holy Grail in drug development is increased survival over standard of care. I believe FDA saw this as a significant advance, the first and only drug to provide significant benefit in second-line treatment of hormone resistant prostate cancer."
The swift approval is certainly outstanding - though it has a few precedents in the oncology sphere, such as Novartis' Gleevec , approved in nine weeks.
FDA noted that Sanofi's own Eloxatin (oxaliplatin) for second-line colorectal cancer was approved in only six weeks (6 'The Pink Sheet,' Aug. 13, 2002). Other examples of oncology drugs that had extremely fast reviews include Millennium's Velcade (bortezomib) and Genenetch's Herceptin (trasztuzumab).
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Wednesday, June 30, 2010
New 2008 Study Strengthens Agent Orange PCa Assn
http://www.sciencedaily.com/releases/2008/05/080515072810.htm
New Study Strengthens Association Of Prostate Cancer With Exposure To Agent Orange
ScienceDaily (May 16, 2008) — As men age, their risk of developing prostate cancer increases. Aging Vietnam veterans are giving researchers new opportunities to solidify the connection between in-country exposure to Agent Orange and subsequent prostate cancer development. In a study presented during the Annual Scientific Meeting of the American Urological Association (AUA) in Orlando, researchers presented data from a large study of veterans enrolled in the Northern California VA System, examining prostate cancer incidence and disease characteristics in those exposed to Agent Orange compared to those who were not exposed.
More than 13,000 Vietnam Veterans were divided into two groups based on their exposure to Agent Orange. Twice as many men exposed to Agent Orange were identified with prostate cancer. Agent Orange-exposed men were also diagnosed younger and were more likely to present with aggressive or metastatic disease. Other prostate cancer risk factors – race, body-mass index (BMI) and smoking – were not statistically different between the two groups.
This increased evidence suggests that exposure to Agent Orange should be considered a risk factor for developing prostate cancer, similar to African-American heritage or a family history of the disease.
About Agent Orange
Agent Orange is a combination of two synthetic compounds known to be contaminated with the dioxin tetrachlorodibenzo-para-dioxin (TCDD) during the manufacturing process. Named for the color of the barrel in which it was stored, Agent Orange was one of many broad-leaf defoliants used in Vietnam to destroy enemy ground cover. It is estimated that more than 20 million gallons of the chemicals, also known as “rainbow herbicides,” were used between 1962 and 1971; approximately half of the herbicides were Agent Orange. In 1997, the International Agency for Research on Cancer re-classified TCDD as a Group 1 carcinogen, a classification that includes arsenic, asbestos and gamma radiation.
Email or share this story:
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by American Urological Association.
Journal Reference:
0. Chamie K, deVere White RW, Ellison LM: Agent Orange exposure, Vietnam War veterans and the risk of prostate cancer. J Urol, suppl., 2008; 179: 149, abstract 421. [link]
Need to cite this story in your essay, paper, or report? Use one of the following formats:
APA
MLA
American Urological Association (2008, May 16). New Study Strengthens Association Of Prostate Cancer With Exposure To Agent Orange. ScienceDaily. Retrieved June 29, 2010, from http://www.sciencedaily.com /releases/2008/05/080515072810.htm
Note: If no author is given, the source is cited instead.
http://www.sciencedaily.com/releases/2007/05/070520091858.htm
Veterans Exposed To Agent Orange Have Higher Rates Of Prostate Cancer Recurrence
ScienceDaily (May 21, 2007) — Veterans exposed to Agent Orange have a 48 percent increased risk of prostate cancer recurrence following surgery than their unexposed peers, and when the disease comes back, it seems more aggressive, researchers say.
"We need to be screening these patients earlier, treating their cancer aggressively and following them closely afterward because they are at higher risk for recurrence," says Dr. Martha Terris, chief of the Urology Department at the Augusta Veterans Affairs Medical Center and professor of urology at the Medical College of Georgia.
"We looked at all patients, whether they were exposed or not, to see which were more likely to develop a recurrence and patients with a history of Agent Orange exposure were more likely," says Dr. Sagar R. Shah, MCG urology resident who is presenting the data May 20 during the American Urological Association Annual Meeting in Anaheim, Calif.
The study looked at 1,653 veterans who had prostate cancer surgery at Department of Veterans Affairs Medical Centers in five cities between 1990 and 2006; 199 had been exposed to Agent Orange, a herbicide and defoliant sprayed on the dense forests of Vietnam during the war.
Agent Orange contains the carcinogen, dioxin, which can be stored in body fat and is believed to make its way into the cell nucleus and work as a tumor promoter. In the past, relatively higher mortality rates have been found in chemical plant workers and farmers with prostate cancer who were exposed to dioxin, the researchers write in their abstract.
Dioxin's impact is dose-related, and while the researchers did not measure levels of dioxin or Agent Orange, they suspect that blacks, who were more likely to be ground troops, also were more likely to have had more Agent Orange exposure.
Researchers found veterans with Agent Orange exposure more likely to be black and younger at the time of surgery to remove their prostate gland. The disease appeared to be caught earlier in exposed veterans. Most had their disease staged as T1 by pathologists, which means it appeared confined to the prostate gland, and had lower pre-operative prostate specific antigen scores, an indicator of disease aggressiveness.
However, when the disease recurred, exposed veterans experienced a more rapid biochemical progression of their disease, which PSA measures. In blacks, the PSA doubled in almost half the time of their unexposed peers.
A blood PSA level screens for prostate cancer for most men beginning at age 50 and at age 40 for blacks and men with a family history. Black men have been shown by Dr. Terris and others to have more aggressive disease earlier in life.
To account for known racial differences, researchers also compared recurrence rates in exposed and non-exposed blacks and whites and the results held up. "As a population in general, if you were exposed to Agent Orange, you're more likely to have a recurrence," says Dr. Shah. "If you were black and exposed, you were more likely to recur than if you were black and unexposed."
If it sounds odd that men who had their prostate removed could have disease recurrence, Dr. Terris points out that microscopic cancer cells can migrate out of the area before surgery, becoming detectable later when they start pushing PSA levels back up.
In fact, following any type of prostate cancer treatment, men routinely get PSA levels checked for the rest of their lives. Without cancer recurrence, they should stay at zero.
The study was funded by the Georgia Cancer Coalition and the Department of Veterans Affairs.
Email or share this story:
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Medical College of Georgia.
Need to cite this story in your essay, paper, or report? Use one of the following formats:
APA
MLA
Medical College of Georgia (2007, May 21). Veterans Exposed To Agent Orange Have Higher Rates Of Prostate Cancer Recurrence. ScienceDaily. Retrieved June 29, 2010, from http://www.sciencedaily.com /releases/2007/05/070520091858.htm
Note
New Study Strengthens Association Of Prostate Cancer With Exposure To Agent Orange
ScienceDaily (May 16, 2008) — As men age, their risk of developing prostate cancer increases. Aging Vietnam veterans are giving researchers new opportunities to solidify the connection between in-country exposure to Agent Orange and subsequent prostate cancer development. In a study presented during the Annual Scientific Meeting of the American Urological Association (AUA) in Orlando, researchers presented data from a large study of veterans enrolled in the Northern California VA System, examining prostate cancer incidence and disease characteristics in those exposed to Agent Orange compared to those who were not exposed.
More than 13,000 Vietnam Veterans were divided into two groups based on their exposure to Agent Orange. Twice as many men exposed to Agent Orange were identified with prostate cancer. Agent Orange-exposed men were also diagnosed younger and were more likely to present with aggressive or metastatic disease. Other prostate cancer risk factors – race, body-mass index (BMI) and smoking – were not statistically different between the two groups.
This increased evidence suggests that exposure to Agent Orange should be considered a risk factor for developing prostate cancer, similar to African-American heritage or a family history of the disease.
About Agent Orange
Agent Orange is a combination of two synthetic compounds known to be contaminated with the dioxin tetrachlorodibenzo-para-dioxin (TCDD) during the manufacturing process. Named for the color of the barrel in which it was stored, Agent Orange was one of many broad-leaf defoliants used in Vietnam to destroy enemy ground cover. It is estimated that more than 20 million gallons of the chemicals, also known as “rainbow herbicides,” were used between 1962 and 1971; approximately half of the herbicides were Agent Orange. In 1997, the International Agency for Research on Cancer re-classified TCDD as a Group 1 carcinogen, a classification that includes arsenic, asbestos and gamma radiation.
Email or share this story:
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by American Urological Association.
Journal Reference:
0. Chamie K, deVere White RW, Ellison LM: Agent Orange exposure, Vietnam War veterans and the risk of prostate cancer. J Urol, suppl., 2008; 179: 149, abstract 421. [link]
Need to cite this story in your essay, paper, or report? Use one of the following formats:
APA
MLA
American Urological Association (2008, May 16). New Study Strengthens Association Of Prostate Cancer With Exposure To Agent Orange. ScienceDaily. Retrieved June 29, 2010, from http://www.sciencedaily.com /releases/2008/05/080515072810.htm
Note: If no author is given, the source is cited instead.
http://www.sciencedaily.com/releases/2007/05/070520091858.htm
Veterans Exposed To Agent Orange Have Higher Rates Of Prostate Cancer Recurrence
ScienceDaily (May 21, 2007) — Veterans exposed to Agent Orange have a 48 percent increased risk of prostate cancer recurrence following surgery than their unexposed peers, and when the disease comes back, it seems more aggressive, researchers say.
"We need to be screening these patients earlier, treating their cancer aggressively and following them closely afterward because they are at higher risk for recurrence," says Dr. Martha Terris, chief of the Urology Department at the Augusta Veterans Affairs Medical Center and professor of urology at the Medical College of Georgia.
"We looked at all patients, whether they were exposed or not, to see which were more likely to develop a recurrence and patients with a history of Agent Orange exposure were more likely," says Dr. Sagar R. Shah, MCG urology resident who is presenting the data May 20 during the American Urological Association Annual Meeting in Anaheim, Calif.
The study looked at 1,653 veterans who had prostate cancer surgery at Department of Veterans Affairs Medical Centers in five cities between 1990 and 2006; 199 had been exposed to Agent Orange, a herbicide and defoliant sprayed on the dense forests of Vietnam during the war.
Agent Orange contains the carcinogen, dioxin, which can be stored in body fat and is believed to make its way into the cell nucleus and work as a tumor promoter. In the past, relatively higher mortality rates have been found in chemical plant workers and farmers with prostate cancer who were exposed to dioxin, the researchers write in their abstract.
Dioxin's impact is dose-related, and while the researchers did not measure levels of dioxin or Agent Orange, they suspect that blacks, who were more likely to be ground troops, also were more likely to have had more Agent Orange exposure.
Researchers found veterans with Agent Orange exposure more likely to be black and younger at the time of surgery to remove their prostate gland. The disease appeared to be caught earlier in exposed veterans. Most had their disease staged as T1 by pathologists, which means it appeared confined to the prostate gland, and had lower pre-operative prostate specific antigen scores, an indicator of disease aggressiveness.
However, when the disease recurred, exposed veterans experienced a more rapid biochemical progression of their disease, which PSA measures. In blacks, the PSA doubled in almost half the time of their unexposed peers.
A blood PSA level screens for prostate cancer for most men beginning at age 50 and at age 40 for blacks and men with a family history. Black men have been shown by Dr. Terris and others to have more aggressive disease earlier in life.
To account for known racial differences, researchers also compared recurrence rates in exposed and non-exposed blacks and whites and the results held up. "As a population in general, if you were exposed to Agent Orange, you're more likely to have a recurrence," says Dr. Shah. "If you were black and exposed, you were more likely to recur than if you were black and unexposed."
If it sounds odd that men who had their prostate removed could have disease recurrence, Dr. Terris points out that microscopic cancer cells can migrate out of the area before surgery, becoming detectable later when they start pushing PSA levels back up.
In fact, following any type of prostate cancer treatment, men routinely get PSA levels checked for the rest of their lives. Without cancer recurrence, they should stay at zero.
The study was funded by the Georgia Cancer Coalition and the Department of Veterans Affairs.
Email or share this story:
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Medical College of Georgia.
Need to cite this story in your essay, paper, or report? Use one of the following formats:
APA
MLA
Medical College of Georgia (2007, May 21). Veterans Exposed To Agent Orange Have Higher Rates Of Prostate Cancer Recurrence. ScienceDaily. Retrieved June 29, 2010, from http://www.sciencedaily.com /releases/2007/05/070520091858.htm
Note
Tuesday, June 29, 2010
WSJ Article,At Least 24 Different Forms of PCa
Scientists may soon be able to answer the agonizing question facing men with prostate cancer: Does their cancer
need immediate treatment or can it be left alone?
Some 218,000 American men will be diagnosed with prostate cancer this year. An estimated 85% of those
tumors will grow so slowly that they will never cause problems. But the rest are aggressive and lethal. As of now,
there's no way to tell early on which cancers are which, so tens of thousands of men undergo surgery or radiation
each year for cancers that never needed treatment, risking impotence or incontinence in the process.
Several recent genetic discoveries could help doctors evaluate how aggressive a man's prostate cancer is much
earlier. Scientists at the University of Michigan have identified at least 24 different kinds of prostate cancer of
varying virulence whose DNA signatures can be read like a bar code. Memorial Sloan-Kettering Cancer Center
researchers have identified other genetic subtypes of prostate cancer that seem to predict whether the tumor will
be low or high risk. And Harvard Medical School scientists have found a specific gene that causes prostate
cancers to spread. Some of the discoveries also could lead to new treatments, tailored specifically for the kind of
prostate tumor a man has.
Such genetic tests for prostate cancers would go well beyond the current PSA test (for prostate-specific antigen)
used for screening men in general. PSA tests have helped find prostate cancers at much earlier stages, saving
thousands of lives in recent years. But PSA levels also rise for reasons that have nothing to do with cancer,
prompting many men to have prostate biopsies each year that don't find cancer or that find tumors of the
slow-growing variety.
Scientists say new prostate-cancer tests could be available in the
not-too-distant future. "It won't be tomorrow, but if you go by
the pace at which such technology entered the field of breast
cancer, it will be several years [for new prostate tests], not a
decade," says Charles Sawyers, chairman of human oncology and pathogenesis at Memorial Sloan-Kettering.
At the University of Michigan, researchers have focused mainly on what are known as gene fusions, in which
DNA from some genes gets stuck to other genes, altering what they do. Two of the 24 types they have identified
involve the same gene, known as RAF, that drives malignant melanoma, according to a report in the journal
Nature Medicine this month. Although those two types make up only about 2% of the tumors studied so far, they
are highly aggressive, killing an estimated 3,600 men each year.
Treatment for those prostate cancers is on the horizon. Several anti-RAF drugs to treat melanoma have
regulatory approval or are in late-stage clinical trials. Early lab tests show that some of those drugs are effective
What the Genes Tell
Researchers are closing in on ways to determine
whether a prostate tumor is likely to metastasize,
based on gene analyses. Click to enlarge image.
against RAF prostate-cancer cells.
Most of the remaining prostate-cancer types involve fusions of a
gene called ETS, and they are more or less virulent depending
on which fragments of other genes are fused to them. Jonathan
Simons, chief executive officer of the Prostate Cancer
Foundation, which funds much of the Michigan research, likens
the process to rebuilding car engines out of random automotive
parts.
"If you have a tumor with a lawn-mower engine, it may look like
a cancer, we may call it a cancer, but it may never be a problem
in the life of a 72-year old man," he says. "But if you have a
cancer with a bulky Dodge Hemi stuck to a BMW 850csi V-12
engine, that needs treatment."
Four of the 24 cancer types discovered, which together make up
over 50% of the prostate cancers classified so far, have the
equivalent of lawn-mower engines and probably don't have enough power to grow past the prostate gland, Dr.
Simons says. Another 20% are more highly powered and could pose problems in the presence of other gene
fusions.
Getting Aggressive
And one of the most aggressive types, representing 10% to 15% of prostate cancers, appears to follow a different
mechanism: It results when there are excess amounts of a protein known as SPINK1. Since the protein shows up
in urine, the researchers say a urine test could be designed to measure its presence.
There could be more types, represented by different genetic bar codes. "We are finding more every month or so,
filling in the gaps," says the lead investigator Arul Chinnaiyan, director of the Michigan Center for Translational
Pathology. To validate the findings, researchers, who so far have studied some 300 tumor samples, plan to
analyze at least 1,000 samples and to follow how the patients progress.
"We are not there yet, but within the next year, we hope to have a clinical lab test where we can predict what kind
of cancer a man has," says Dr. Chinnaiyan.
Researchers at Memorial Sloan-Kettering are studying a different kind of genetic error involved in prostate
cancer. Instead of two copies of a gene, some cancer cells have too many or too few, known as copy-number
alterations.
In a study in the journal Cancer Cell last week, the researchers analyzed the copy-number alterations in 218
cancerous prostates surgically removed at Sloan-Kettering and found that they fell into six clusters. Those
clusters corresponded closely with how quickly the patients' cancer returned, judging by their PSA.
"It was a surprise to us that so much prognostic information was there in the original samples after surgery," Dr.
Sawyers says. Ideally, "we'd be able to tell a man, 'Your tumor looks like it's in cluster five, so you should get
surgery and radiation and perhaps even more aggressive therapy. Or, you are in cluster two, so you can relax and
maybe just get another biopsy in another year and see if your cluster has changed," he says.
Tracking Patients
Further testing at Sloan Kettering is continuing. The researchers have 1,000 additional samples from prostates
removed more than 10 years ago and can correlate their findings with how the patients fared in that time.
In still another recent breakthrough, researchers at Harvard Medical School identified a gene pathway directly
involved in prostate-cancer metastasis. They isolated a gene, DAB2IP, that acts as a brake for cancer. When too
Previously
The Man, the Gland, the Dilemmas (3/31/2009)
Prostate Cancer: Weighing Options (4/7/2009)
Health Matters: Weighing the Benefits of
'Watchful Waiting' for Prostate Cancer
(4/17/2009)
much of an enzyme, EZH2, is present, the DAB2IP gene is suppressed, removing the brake and allowing the
cancer to spread.
"It's more than just correlation; it's cause and effect," says lead researcher Karen Cichowski, a cancer biologist,
who demonstrated the process in mice in a study in Nature Medicine this year. The Harvard researchers also
studied data from human prostate cancers and found that the patients with the most aggressive tumors had
either excess EZH2 or too little DAB2IP or both.
These findings, too, could yield tests to predict how aggressive a patient's prostate cancer could be. Several
biotech companies have drugs in the works to inhibit EZH2.
The various research findings complement each other by describing different ways that genes mutate as cancers
evolve, says Dr. Chinnaiyan. He expects that diagnostic tests in the future will look at a variety of genes, as well as
proteins, molecules and other "biomarkers" to predict how aggressive a cancer might be.
Another technique being applied to prostate cancer involves
magnetic resonance spectroscopy, a form of imaging that tracks
chemical changes in tissues. In a small study in the journal
Science Translational Medicine this year, researchers at
Harvard showed that the scanning technology can not only
locate cancers within the prostate, but also has the potential to
distinguish fast and slow-moving cancers.
Progress is also being made on ways to measure prostate cancers through simple blood and urine tests, or what
scientists call "liquid biopsies." The biotech firm Gen-Probe Inc., working with the University of Michigan
researchers, has developed a test for a gene called PCA3 that shows up in urine only when a man has prostate
cancer.
For now, the PCA3 test is mainly useful to tell men who have a rising PSA level that they should have a biopsy as
well, or for men who have a negative biopsy that might have missed cancer. Dr. Chinnaiyan hopes the PCA3 test
can also check for gene fusions that can identify which type of prostate cancer a man has.
'Liquid Biopsies'
The PCA3 test is not yet approved by the Food and Drug Administration, but it is approved for use in Europe and
is available in several U.S. labs on an investigational basis.
In other prostate-cancer news, there's more evidence that cholesterol-lowering statin drugs may play a role in
controlling the spread of prostate cancer. In a study in the journal Cancer, researchers at Duke University
Medical Center and elsewhere analyzed the records of 1,319 men who had their prostates removed between 1988
and 2008 and found that 304 of them had a rising PSA level after surgery, which generally indicates that the
cancer has reoccurred and spread. Men who were taking the equivalent of 20 mg of simvastatin a day were 43%
less likely to see a recurrence. In men taking a higher dose, the risk of recurrence was reduced by 50%.
The researchers cautioned that the reduced risk could be due to factors other than statins, such as diet, exercise
or smoking habits; only a randomized clinical trial could tell for sure. Five other recent studies also have found
that statins appear to lower the risk for advanced prostate cancer.
Write to Melinda Beck at HealthJournal@wsj.com
Copyright 2009
need immediate treatment or can it be left alone?
Some 218,000 American men will be diagnosed with prostate cancer this year. An estimated 85% of those
tumors will grow so slowly that they will never cause problems. But the rest are aggressive and lethal. As of now,
there's no way to tell early on which cancers are which, so tens of thousands of men undergo surgery or radiation
each year for cancers that never needed treatment, risking impotence or incontinence in the process.
Several recent genetic discoveries could help doctors evaluate how aggressive a man's prostate cancer is much
earlier. Scientists at the University of Michigan have identified at least 24 different kinds of prostate cancer of
varying virulence whose DNA signatures can be read like a bar code. Memorial Sloan-Kettering Cancer Center
researchers have identified other genetic subtypes of prostate cancer that seem to predict whether the tumor will
be low or high risk. And Harvard Medical School scientists have found a specific gene that causes prostate
cancers to spread. Some of the discoveries also could lead to new treatments, tailored specifically for the kind of
prostate tumor a man has.
Such genetic tests for prostate cancers would go well beyond the current PSA test (for prostate-specific antigen)
used for screening men in general. PSA tests have helped find prostate cancers at much earlier stages, saving
thousands of lives in recent years. But PSA levels also rise for reasons that have nothing to do with cancer,
prompting many men to have prostate biopsies each year that don't find cancer or that find tumors of the
slow-growing variety.
Scientists say new prostate-cancer tests could be available in the
not-too-distant future. "It won't be tomorrow, but if you go by
the pace at which such technology entered the field of breast
cancer, it will be several years [for new prostate tests], not a
decade," says Charles Sawyers, chairman of human oncology and pathogenesis at Memorial Sloan-Kettering.
At the University of Michigan, researchers have focused mainly on what are known as gene fusions, in which
DNA from some genes gets stuck to other genes, altering what they do. Two of the 24 types they have identified
involve the same gene, known as RAF, that drives malignant melanoma, according to a report in the journal
Nature Medicine this month. Although those two types make up only about 2% of the tumors studied so far, they
are highly aggressive, killing an estimated 3,600 men each year.
Treatment for those prostate cancers is on the horizon. Several anti-RAF drugs to treat melanoma have
regulatory approval or are in late-stage clinical trials. Early lab tests show that some of those drugs are effective
What the Genes Tell
Researchers are closing in on ways to determine
whether a prostate tumor is likely to metastasize,
based on gene analyses. Click to enlarge image.
against RAF prostate-cancer cells.
Most of the remaining prostate-cancer types involve fusions of a
gene called ETS, and they are more or less virulent depending
on which fragments of other genes are fused to them. Jonathan
Simons, chief executive officer of the Prostate Cancer
Foundation, which funds much of the Michigan research, likens
the process to rebuilding car engines out of random automotive
parts.
"If you have a tumor with a lawn-mower engine, it may look like
a cancer, we may call it a cancer, but it may never be a problem
in the life of a 72-year old man," he says. "But if you have a
cancer with a bulky Dodge Hemi stuck to a BMW 850csi V-12
engine, that needs treatment."
Four of the 24 cancer types discovered, which together make up
over 50% of the prostate cancers classified so far, have the
equivalent of lawn-mower engines and probably don't have enough power to grow past the prostate gland, Dr.
Simons says. Another 20% are more highly powered and could pose problems in the presence of other gene
fusions.
Getting Aggressive
And one of the most aggressive types, representing 10% to 15% of prostate cancers, appears to follow a different
mechanism: It results when there are excess amounts of a protein known as SPINK1. Since the protein shows up
in urine, the researchers say a urine test could be designed to measure its presence.
There could be more types, represented by different genetic bar codes. "We are finding more every month or so,
filling in the gaps," says the lead investigator Arul Chinnaiyan, director of the Michigan Center for Translational
Pathology. To validate the findings, researchers, who so far have studied some 300 tumor samples, plan to
analyze at least 1,000 samples and to follow how the patients progress.
"We are not there yet, but within the next year, we hope to have a clinical lab test where we can predict what kind
of cancer a man has," says Dr. Chinnaiyan.
Researchers at Memorial Sloan-Kettering are studying a different kind of genetic error involved in prostate
cancer. Instead of two copies of a gene, some cancer cells have too many or too few, known as copy-number
alterations.
In a study in the journal Cancer Cell last week, the researchers analyzed the copy-number alterations in 218
cancerous prostates surgically removed at Sloan-Kettering and found that they fell into six clusters. Those
clusters corresponded closely with how quickly the patients' cancer returned, judging by their PSA.
"It was a surprise to us that so much prognostic information was there in the original samples after surgery," Dr.
Sawyers says. Ideally, "we'd be able to tell a man, 'Your tumor looks like it's in cluster five, so you should get
surgery and radiation and perhaps even more aggressive therapy. Or, you are in cluster two, so you can relax and
maybe just get another biopsy in another year and see if your cluster has changed," he says.
Tracking Patients
Further testing at Sloan Kettering is continuing. The researchers have 1,000 additional samples from prostates
removed more than 10 years ago and can correlate their findings with how the patients fared in that time.
In still another recent breakthrough, researchers at Harvard Medical School identified a gene pathway directly
involved in prostate-cancer metastasis. They isolated a gene, DAB2IP, that acts as a brake for cancer. When too
Previously
The Man, the Gland, the Dilemmas (3/31/2009)
Prostate Cancer: Weighing Options (4/7/2009)
Health Matters: Weighing the Benefits of
'Watchful Waiting' for Prostate Cancer
(4/17/2009)
much of an enzyme, EZH2, is present, the DAB2IP gene is suppressed, removing the brake and allowing the
cancer to spread.
"It's more than just correlation; it's cause and effect," says lead researcher Karen Cichowski, a cancer biologist,
who demonstrated the process in mice in a study in Nature Medicine this year. The Harvard researchers also
studied data from human prostate cancers and found that the patients with the most aggressive tumors had
either excess EZH2 or too little DAB2IP or both.
These findings, too, could yield tests to predict how aggressive a patient's prostate cancer could be. Several
biotech companies have drugs in the works to inhibit EZH2.
The various research findings complement each other by describing different ways that genes mutate as cancers
evolve, says Dr. Chinnaiyan. He expects that diagnostic tests in the future will look at a variety of genes, as well as
proteins, molecules and other "biomarkers" to predict how aggressive a cancer might be.
Another technique being applied to prostate cancer involves
magnetic resonance spectroscopy, a form of imaging that tracks
chemical changes in tissues. In a small study in the journal
Science Translational Medicine this year, researchers at
Harvard showed that the scanning technology can not only
locate cancers within the prostate, but also has the potential to
distinguish fast and slow-moving cancers.
Progress is also being made on ways to measure prostate cancers through simple blood and urine tests, or what
scientists call "liquid biopsies." The biotech firm Gen-Probe Inc., working with the University of Michigan
researchers, has developed a test for a gene called PCA3 that shows up in urine only when a man has prostate
cancer.
For now, the PCA3 test is mainly useful to tell men who have a rising PSA level that they should have a biopsy as
well, or for men who have a negative biopsy that might have missed cancer. Dr. Chinnaiyan hopes the PCA3 test
can also check for gene fusions that can identify which type of prostate cancer a man has.
'Liquid Biopsies'
The PCA3 test is not yet approved by the Food and Drug Administration, but it is approved for use in Europe and
is available in several U.S. labs on an investigational basis.
In other prostate-cancer news, there's more evidence that cholesterol-lowering statin drugs may play a role in
controlling the spread of prostate cancer. In a study in the journal Cancer, researchers at Duke University
Medical Center and elsewhere analyzed the records of 1,319 men who had their prostates removed between 1988
and 2008 and found that 304 of them had a rising PSA level after surgery, which generally indicates that the
cancer has reoccurred and spread. Men who were taking the equivalent of 20 mg of simvastatin a day were 43%
less likely to see a recurrence. In men taking a higher dose, the risk of recurrence was reduced by 50%.
The researchers cautioned that the reduced risk could be due to factors other than statins, such as diet, exercise
or smoking habits; only a randomized clinical trial could tell for sure. Five other recent studies also have found
that statins appear to lower the risk for advanced prostate cancer.
Write to Melinda Beck at HealthJournal@wsj.com
Copyright 2009
Monday, June 28, 2010
Scholz Cmment on PCa Screening
Dr. Mark Scholz Comments on Recently Published Studies of the Effectiveness of PSA Screening. Re: Letter to the Editor Regarding a Wall Street Journal Article titled:
Two Big Studies Tackle Debate on Prostate Test published on Thursday March 19, 2009
The Wall Street Journal recently published a letter to the editor under the heading, “Lifestyle Is Fine, but Cancer Needs Effective Treatment.” The physician writing the letter vilified the idea of using anything but surgery to treat his prostate cancer. Unfortunately, his uninformed convictions are prevalent throughout the medical community. Now definitive, well-performed studies unequivocally prove that overtreatment is the norm (New England Journal of Medicine 2009;360:1310-9 and 1320-8) .
As has been the case for years, the a priori assumption that “all cancer needs treatment” has confused the expert commentators who are interpreting these crystal-clear study results as being part of an ongoing unresolved controversy about PSA testing. The reality is that huge amounts of precious research dollars are being spent to answer a foolish question. Whether or not to do PSA testing is not the issue. The issue is deciding what to do with the information the PSA provides.
Right now the nation is in the grip of 8-billion dollar industry hell-bent on administering treatment to every kind of prostate cancer whether it is life-threatening or not. The solution to the problem of over-treating prostate cancer is not less PSA testing. The solution is educating physicians to forgo recommending immediate surgery or radiation to every last man who gets a diagnosis of prostate cancer.
Newly-diagnosed patients need to research all their options before agreeing to irreversible radical treatment. PSA testing (in conjunction with other means) has a useful role in determining which men harbor the more aggressive types of prostate cancer. Only with a “go slow” approach, ongoing monitoring known as Active Surveillance, can we distinguish men with aggressive disease who need treatment from men with indolent disease who don’t need treatment.
Mark Scholz, M.D.
Prostate Cancer Research Institute
Los Angeles, California
MATERIAL PROVIDED BY PCRI IS INTENDED FOR EDUCATIONAL PURPOSES AND SHOULD NOT BE CONSIDERED AS MEDICAL ADVICE
|
Administration 310-743-2116 • Fax 310-743-2113 • info@pcri.org ••• Helpline 800-641-PCRI • help@pcri.org
Two Big Studies Tackle Debate on Prostate Test published on Thursday March 19, 2009
The Wall Street Journal recently published a letter to the editor under the heading, “Lifestyle Is Fine, but Cancer Needs Effective Treatment.” The physician writing the letter vilified the idea of using anything but surgery to treat his prostate cancer. Unfortunately, his uninformed convictions are prevalent throughout the medical community. Now definitive, well-performed studies unequivocally prove that overtreatment is the norm (New England Journal of Medicine 2009;360:1310-9 and 1320-8) .
As has been the case for years, the a priori assumption that “all cancer needs treatment” has confused the expert commentators who are interpreting these crystal-clear study results as being part of an ongoing unresolved controversy about PSA testing. The reality is that huge amounts of precious research dollars are being spent to answer a foolish question. Whether or not to do PSA testing is not the issue. The issue is deciding what to do with the information the PSA provides.
Right now the nation is in the grip of 8-billion dollar industry hell-bent on administering treatment to every kind of prostate cancer whether it is life-threatening or not. The solution to the problem of over-treating prostate cancer is not less PSA testing. The solution is educating physicians to forgo recommending immediate surgery or radiation to every last man who gets a diagnosis of prostate cancer.
Newly-diagnosed patients need to research all their options before agreeing to irreversible radical treatment. PSA testing (in conjunction with other means) has a useful role in determining which men harbor the more aggressive types of prostate cancer. Only with a “go slow” approach, ongoing monitoring known as Active Surveillance, can we distinguish men with aggressive disease who need treatment from men with indolent disease who don’t need treatment.
Mark Scholz, M.D.
Prostate Cancer Research Institute
Los Angeles, California
MATERIAL PROVIDED BY PCRI IS INTENDED FOR EDUCATIONAL PURPOSES AND SHOULD NOT BE CONSIDERED AS MEDICAL ADVICE
|
Administration 310-743-2116 • Fax 310-743-2113 • info@pcri.org ••• Helpline 800-641-PCRI • help@pcri.org
Friday, June 18, 2010
Chemo Drug Jevtana Wins FDA Approval
Today's Wall St Journal reports that the new chemo drug Jevtana, manufactured by the French drug company Sanofi-Aventis has received FDA approval under its priority review program, 3 months ahead of schedule. Its safety & effectiveness were established in a single 755-patient study. The goal of the study was human survival time. Jevtana along with a steroid achieved a survival time of 15.1 months, compared with only 12.7 months achieved with chemo drug mitroxantrone plus the same steroid
Friday, June 4, 2010
NIH Supporters Also Support FDA
ANALYSIS AND COMMENTARY
NIH-oriented patient and research advocacy groups were key to the founding of the Alliance for a Stronger FDA and make up a third of the Alliance’s board. Our membership from this stakeholder group has grown over the last couple of years as more organizations recognize that “the very best NIH, even well-funded” is still limited in its impact unless new therapies are approved by FDA. An Alliance member asked us this week if we could send over a few talking points on the theme: NIH advocates need to be FDA advocates. Here is an edited version of what we provided.
Billions of dollars are spent on biomedical research at NIH and academic health centers and by biopharmaceutical and medical device companies. While much remains to be done, there have been some great successes and a lot of progress. Patients, clinicians and researchers need to be leaders in advocating for increased funding of NIH.
Through public and private funding, patient care has also come a long way as a result of advances in medical knowledge derived from research. The combination of centers of excellence and networks of community providers has advanced treatment to the point that most patients can expect to receive treatment based on the latest research and up-to-date protocols. Patients, clinicians and researchers have also been strong supporters of efforts to translate new knowledge into better care.
In between the promise of research and the benefits of improved care … lies the US Food and Drug Administration, which must consider and approve all new medical therapies that involve drugs, biologics and devices.
The patient and research advocacy community have a large stake in a strong, well-funded and effective FDA. Patients and family members want breakthroughs to move quickly to the clinic, so improved care is available sooner. They also want thorough reviews to assure that patients are not exposed needlessly to treatments that don’t work or are unsafe.
To accomplish this, FDA needs to be strengthened as an institution to assure that there are more scientists, statisticians and clinicians at the agency to review applications for new treatments. Otherwise the fruits of research may never make their way to patient bedsides.
Leading the charge for better FDA funding is the Alliance for a Stronger FDA, a broad coalition of consumers, patients and industry that has come together to advocate for more appropriated funds for the Agency. Increases in FDA’s budget would:
allow the FDA to provide faster and safer approval of products that are saving lives and transforming health care;
promote new drug technologies that will revolutionize pharmaceutical therapies
ensure continued U.S. leadership in drug innovation;
enhance the surveillance capability over new drugs once they reach the market; and
further integrate emerging science into the regulatory process.
All patients benefit when FDA has more resources.
Note: This analysis and commentary is written by Steven Grossman, Deputy Executive Director of the Alliance.
NIH-oriented patient and research advocacy groups were key to the founding of the Alliance for a Stronger FDA and make up a third of the Alliance’s board. Our membership from this stakeholder group has grown over the last couple of years as more organizations recognize that “the very best NIH, even well-funded” is still limited in its impact unless new therapies are approved by FDA. An Alliance member asked us this week if we could send over a few talking points on the theme: NIH advocates need to be FDA advocates. Here is an edited version of what we provided.
Billions of dollars are spent on biomedical research at NIH and academic health centers and by biopharmaceutical and medical device companies. While much remains to be done, there have been some great successes and a lot of progress. Patients, clinicians and researchers need to be leaders in advocating for increased funding of NIH.
Through public and private funding, patient care has also come a long way as a result of advances in medical knowledge derived from research. The combination of centers of excellence and networks of community providers has advanced treatment to the point that most patients can expect to receive treatment based on the latest research and up-to-date protocols. Patients, clinicians and researchers have also been strong supporters of efforts to translate new knowledge into better care.
In between the promise of research and the benefits of improved care … lies the US Food and Drug Administration, which must consider and approve all new medical therapies that involve drugs, biologics and devices.
The patient and research advocacy community have a large stake in a strong, well-funded and effective FDA. Patients and family members want breakthroughs to move quickly to the clinic, so improved care is available sooner. They also want thorough reviews to assure that patients are not exposed needlessly to treatments that don’t work or are unsafe.
To accomplish this, FDA needs to be strengthened as an institution to assure that there are more scientists, statisticians and clinicians at the agency to review applications for new treatments. Otherwise the fruits of research may never make their way to patient bedsides.
Leading the charge for better FDA funding is the Alliance for a Stronger FDA, a broad coalition of consumers, patients and industry that has come together to advocate for more appropriated funds for the Agency. Increases in FDA’s budget would:
allow the FDA to provide faster and safer approval of products that are saving lives and transforming health care;
promote new drug technologies that will revolutionize pharmaceutical therapies
ensure continued U.S. leadership in drug innovation;
enhance the surveillance capability over new drugs once they reach the market; and
further integrate emerging science into the regulatory process.
All patients benefit when FDA has more resources.
Note: This analysis and commentary is written by Steven Grossman, Deputy Executive Director of the Alliance.
Tuesday, June 1, 2010
Low Dose Nitroglycerin for Prostate Cacer
KINGSTON, ONTARIO -- (Marketwire) -- 02/04/10 -- Treatment of prostate cancer using a very low dose of nitroglycerin may slow and even halt the progression of the disease without the severe side effects of current treatments, Queen's University researchers have discovered.
The findings are the result of the first-ever clinical trial using nitroglycerin to treat prostate cancer.
The 24-month, Phase II study targeted 29 men with increasing levels of prostate-specific antigen (PSA) following prostate surgery or radiation. PSA levels are a key predictor of cancer progression.
"We were very excited to see a significant slowing in the progression of the disease as evidenced by the men's PSA levels, and to see this result in many of the men who completed the study," says Dr. Robert Siemens of Queen's Department of Urology, who led the study.
The researchers are encouraged by the results, particularly because safe and effective treatments for men with rising PSA levels following surgery or radiation are limited. They note that further testing needs to be done to confirm the results of this very small study.
The men were treated with a low-dose, slow-release nitroglycerin skin patch and their PSA levels monitored. Of the 17 patients who completed the study, all but one showed a stabilization or decrease in the rate of cancer progression, as measured by their PSA Doubling Time.
Nitroglycerin has been used at significantly higher doses for more than a century to treat angina. This trial was based on a key finding from pre-clinical research carried out at Queen's, which showed that decreases in nitric oxide play an important role in tumor progression and that this progression can be stopped by low-dose nitroglycerin.
Prostate cancer is diagnosed in approximately 235,000 men per year in the United States and 20,700 in Canada. Of patients who have undergone radical prostatectomy and/or radiation treatment, it is estimated that 30 to 50 percent will experience a recurrence of cancer.
Results of the study, conducted by Queen's University researchers Robert Siemens, Jeremy Heaton, Michael Adams, Jun Kawakami and Charles Graham, appeared in a recent issue of the journal Urology.
Research into the use of nitroglycerin and similar compounds for the treatment of cancer by Drs. Adams, Graham and Heaton has resulted in the issue of 10 patents worldwide. PARTEQ Innovations, the technology transfer office of Queen's, has licensed some of this intellectual property to Nometics Inc., a Queen's spinoff company, which is developing products and therapies based on this and related research.
"This peer-reviewed research is our first clear clinical evidence that low-dose nitric oxide therapy offers prostate cancer patients a new non-invasive treatment option," says Robert Bender, CEO of Nometics. "It is our intention to start broader clinical trials in 2010 to confirm and expand these results."
Contacts:
PARTEQ Innovations
John Molloy
The findings are the result of the first-ever clinical trial using nitroglycerin to treat prostate cancer.
The 24-month, Phase II study targeted 29 men with increasing levels of prostate-specific antigen (PSA) following prostate surgery or radiation. PSA levels are a key predictor of cancer progression.
"We were very excited to see a significant slowing in the progression of the disease as evidenced by the men's PSA levels, and to see this result in many of the men who completed the study," says Dr. Robert Siemens of Queen's Department of Urology, who led the study.
The researchers are encouraged by the results, particularly because safe and effective treatments for men with rising PSA levels following surgery or radiation are limited. They note that further testing needs to be done to confirm the results of this very small study.
The men were treated with a low-dose, slow-release nitroglycerin skin patch and their PSA levels monitored. Of the 17 patients who completed the study, all but one showed a stabilization or decrease in the rate of cancer progression, as measured by their PSA Doubling Time.
Nitroglycerin has been used at significantly higher doses for more than a century to treat angina. This trial was based on a key finding from pre-clinical research carried out at Queen's, which showed that decreases in nitric oxide play an important role in tumor progression and that this progression can be stopped by low-dose nitroglycerin.
Prostate cancer is diagnosed in approximately 235,000 men per year in the United States and 20,700 in Canada. Of patients who have undergone radical prostatectomy and/or radiation treatment, it is estimated that 30 to 50 percent will experience a recurrence of cancer.
Results of the study, conducted by Queen's University researchers Robert Siemens, Jeremy Heaton, Michael Adams, Jun Kawakami and Charles Graham, appeared in a recent issue of the journal Urology.
Research into the use of nitroglycerin and similar compounds for the treatment of cancer by Drs. Adams, Graham and Heaton has resulted in the issue of 10 patents worldwide. PARTEQ Innovations, the technology transfer office of Queen's, has licensed some of this intellectual property to Nometics Inc., a Queen's spinoff company, which is developing products and therapies based on this and related research.
"This peer-reviewed research is our first clear clinical evidence that low-dose nitric oxide therapy offers prostate cancer patients a new non-invasive treatment option," says Robert Bender, CEO of Nometics. "It is our intention to start broader clinical trials in 2010 to confirm and expand these results."
Contacts:
PARTEQ Innovations
John Molloy