Researchers investigate new targeted therapy for metastatic prostate cancer

prostatic_adenocarcinoma_with_perineural_invasion
Image by Nephron

Men with localized prostate cancer face good odds: Their relative five-year survival rate is nearly 100 percent. However, men with metastatic disease — prostate cancer that has spread to another organ like the lungs — have a relative five-year survival rate of only 29 percent.

Currently, the mainstay treatment for metastatic prostate cancer is hormone therapy, which uses drugs to lower the levels of male sex hormones like testosterone in the body to slow the growth of prostate cancer. Two of the latest hormonal agents, abiraterone acetate and enzalutamide, have shown some improvements in overall survival. Unfortunately, hormone therapy isn’t a cure and most patients become resistant to the drugs.

As an alternative, researchers are now investigating more targeted therapies, such as therapies that seek out prostate specific membrane antigen (PSMA). PSMA is present on the surface of nearly all prostate cancer cells as well as new blood vessels that supply nutrients to cancers, but PSMA is present on only a few healthy tissues in the body — making it an excellent potential target for drugs that selectively attack tumors while sparing healthy cells.

One such agent is PSMA-617 labeled with the radioactive element lutetium-177, which preferentially binds to PSMA on the surface of prostate cancer cells and delivers a toxic level of radiation to the disease sites.

A group of researchers recently investigated the safety and efficacy of lutetium-177-PSMA-617 for the treatment of metastatic prostate cancer. At 12 centers across Germany, a total of 145 patients, between 43 and 88 years in age, were treated with one to four cycles of the therapy. All the patients had metastatic drug-resistant prostate cancer that was continuing to progress. Receiving lutetium-177-PSMA-617 was their last therapeutic option.

As described in a paper appearing in the January issue of the Journal of Nuclear Medicine, the researchers found that 45 percent of the patients responded positively to lutetium-177-PSMA-617 following all therapy cycles, while 40 percent responded positively after a single cycle. Unfortunately, there were some adverse side effects, such as anemia and dry mouth, but these were considered to be manageable.

Other research groups are developing alternative PSMA targeted therapies, including researchers at Weill Cornell Cancer Center who are investigating a targeted radionuclide therapy called lutetium-177-J591.

So far the results have all been modest, but these PSMA targeted therapies may still have an important role in treating patients who are resistant to other drug therapies. Further studies are needed to determine the survival benefit of these treatments before they can be approved by the U.S. Food and Drug Administration for clinical use.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

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Genomic analysis allows researchers to identify three subtypes of prostate cancer

Photograph by Raul654
Photograph by Raul654

Many men with prostate cancer have slow-growing tumors that don’t require aggressive treatments such as surgery or radiation therapy, whereas others have rapidly-growing prostate tumors that are life threatening. Distinguishing between these patients with indolent versus aggressive disease is a major challenge, but researchers have just made a significant step towards identifying genetic risk factors for prostate cancer prognosis.

A multi-institutional research team has identified three distinct molecular subtypes of prostate cancer, which are correlated with survival rates and may guide future treatment planning. Their study results were presented at the annual meeting of the American Society of Radiation Oncology by Daniel Spratt, MD, an assistant professor in radiation oncology at the University of Michigan Heath System.

Spratt explained in a recent American Society of Radiation Oncology press release:

“Tumors that appear similar under a microscope can behave very differently, from a clinical standpoint. One promise of genomic analyses is to elucidate subtypes of cancer based on the genetics of the tumor rather than merely how they look or what size they are.”

The research team analyzed the RNA expression patterns of 4,236 primary prostate cancer samples taken from nine independent groups of men, who had their prostate surgically removed to treat primary prostate cancer. The investigators’ statistical clustering analysis identified three distinct patient groups based on 100 key genes, which they named the Prostate Cancer 100. These study results were then validated using samples from over 2100 patients.

The subtypes were found to be correlated with androgen receptor activity, ERG oncogene expression and other factors known to promote prostate tumor growth. They were also correlated with how long patients survived without metastasis. The distant metastasis-free survival rates varied among the three subgroups — 73.6 percent for group A, 64.4 percent for group B and 57.1 percent for group C — showing that subtype A patients had the most favorable prognosis.

Furthermore, the study found that subtype B and C patients responded significantly better to postoperative radiation therapy, which was used after the prostate was surgically removed in order to kill any remaining cancer cells. This is important because radiation therapy has many potential side effects, including impotence and incontinence.

Spratt summarized in the press release:

“We believe that these subtypes reflect truly distinctive underlying biology and that this work represents a significant advance in our understanding of prostate cancer biology. Moreover, our findings identify numerous genes and enriched biologically active pathways in prostate cancer that have been underappreciated to date but may be potential targets to improve cure rates in this disease by developing new targeted therapies.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

New Prostate Cancer Treatment Reduces Side Effects

Photograph of the University Hospital London
University College Hospital in London. Courtesy of Steve Parkinson via Creative Commons.

Standard prostate cancer treatments, such as prostatectomy surgery or radiotherapy, often lead to substantial side effects. These include erectile dysfunction (affecting 30-70%) and urinary incontinence (affecting 5-20%). However, these unwanted side effects could be reduced, if prostate cancer treatments could target just the cancer tumors while harming less of their surrounding healthy tissue.

A promising “proof of concept” research study has just demonstrated that a new technique to treat localized prostate cancer may significantly reduce side effects compared to standard treatments. This study was carried out by researchers from University College London and the results were just published in the peer-reviewed medical journal The Lancet Oncology.

This new treatment uses high-intensity focused ultrasound (HIFU) to target and destroy prostate tumors, while causing minimal damage to their surrounding nerves and muscles. A small ultrasound probe is placed close to the prostate through the patient’s rectum. This probe emits a narrow beam of intense sound waves that heat the targeted cells to 80 C for one second, killing a targeted area about the size of a grain of rice. The probe is then moved to focus and destroy additional cancerous areas.  The procedure is performed in the hospital under general anesthesia and most patients are back home within 24 hours.

Surgeon Hashim Ahmed from University College Hospital in London demonstrates in a BBC News short video how this probe heats only a small target area.

The “proof of concept” HIFU study was primarily focused on assessing the frequency and extent of side effects, rather than the success of the prostate cancer treatment. Forty-one men participated in the study, ranging in age from 45 to 80 years old. All participants had localized prostate cancer ranging from low to high risk, where 30 men (73%) had intermediate to high-risk disease. They also had a prostate volume of 40 mL or less in order to avoid an excessively long procedure. They had received no previous prostate treatment.

The prostate cancer tumor locations were identified using multiparametric MRI (magnetic resonance imaging) and a template-prostate-mapping biopsy. The identified tumors were then targeted by the HIFU treatment. The men were followed up at one, three, six, nine and twelve months after the HIFU procedure. Each follow-up included: (1) a PSA blood test to measure the levels of prostate specific antigen protein being produced by the prostate, since PSA is generally elevated for men with prostate cancer; and (2) questionnaires that evaluated side effects. In addition, the MRI and biopsy tests were repeated as part of the 6 months follow-up and an additional MRI was performed after a year.

Researchers found that a year after the HIFU treatment, 89% of the men still had erectile function and all were still continent. In addition, there was a significant decrease in PSA levels compared to baseline and 95% of the men showed no evidence of disease on the final MRI scan.

Clearly this HIFU pilot study has demonstrated a promising reduction in treatment side effects. However, it was a small observational study of 41 men and followed them for only a year. The results need to be confirmed by much larger clinical trials that assess both the effectiveness and safety of HIFU compared with standard therapies. As a result, the researchers at University College London have started recruiting patients for a larger phase 2 trial that will follow patients for 3 years.

FDA Approves Prostate Cancer Vaccine

How much is 4 months of your life worth? Some men with advanced prostate cancer will be able to find out, as a result of a new drug developed byDendreon Corporation. This drug, Provenge (sipuleucel-T), was recently approved by the FDA to treat advanced prostate cancer.

They are calling Provenge a “vaccine,” but it doesn’t work like vaccines against infections such as measles or mumps. This vaccine is used to treat advanced prostate cancer rather than prevent it. It works by using the patient’s own immune system. The vaccine is made by taking a sample of the patient’s blood, removing the white blood cells, and exposing them to the Dendreon PAP-GM-CSF protein. This specialized fused protein includesprostatic acid phosphatase (PAP), which is an enzyme produced by the prostate and found at increased levels in prostate cancer. Once the vaccine is made, the cells are then infused back into the patient’s vein. The patient receives three of these treatments, 2 weeks apart. Basically the treated cells help stimulate the patient’s immune system to attack his prostate cancer.

The FDA approval of this new vaccine was largely based on the results of Dendreon’s recently completed Provenge Phase III Trial. This was a randomized clinical trial involving 512 men between the ages of 40 and 91 years, of which 341 men received Provenge and 171 men received a placebo. All the men had advanced prostate cancer that was unresponsive to hormone therapy. The common side effects of the Provenge were reported to be minor — such as chills (54%), fevers (29%), and headaches (16%) — and only lasted a couple days after infusion. The men that received the Provenge on average lived 4.1 months longer than the men that took the placebo (25.8 months v.s. 21.7 months). This is a significant break through for men with advanced prostate cancer, who have few treatment options.

There was no evidence that Provenge slowed progression of the disease. How the drug can improve survival rate without slowing disease progression is not clear yet. The FDA approval of Provenge is also limited to only men with prostate cancer (that has progressed despite hormone treatments) with only minimal symptoms at the time of treatment. So this vaccine is not for everyone with prostate cancer. However, it is the first active immunotherapy to demonstrate improvement in overall survival for advanced prostate cancer. As a “proof of concept” drug, it is expected to spark new interest in the development of drugs based on similar principles.

Other prostate cancer vaccines are also in development, including PROSTVAC-VF that uses a genetically modified virus containing prostate-specific antigen. The patient’s immune system is expected to respond to the virus by recognizing and killing the cancer cells with prostate-specific antigen. A randomized phase II clinical study of Therion Biologic’s PROSTVAC-VF was published this January. It involved 122 patients with metastatic prostate cancer who did not respond to hormone therapy, of which 82 received the vaccine and 40 the placebo. This study also demonstrated an increase in survival rate for those taking the vaccine, in this case an average of 8.5 months. This study is small, but the researchers are planning a phase III trial with 600 patients to further evaluate the drug’s effectiveness.

So lets hope that these new drugs represent only the first step in finding effective new ways to treat cancers. In the future, hopefully we’ll be able to “turn on” the body’s own defense mechanisms to treat or prevent many types of cancer.

A Simple Blood Test Saved His Life

My brother-in-law was seemingly the healthiest person we knew. He hikes up and down steep hills as part of his daily work. He kayaks intense oceans as part of his weekend play. He never even gets a cold. So he rarely sees a doctor. Luckily he did finally go for a general checkup when he turned 50, and those simple blood tests saved his life. Turned out, he had aggressive prostate cancer. Standard screening, to find prostate cancer in people who do not have symptoms, allowed him to be treated in time.

Against a backdrop of uncertainty and controversy, the American Cancer Society recently updated their prostate screening guidelines for the first time in almost a decade. This was largely in response to the findings of a massive federal study that was published in the New England Journal of Medicine last year. This study evaluated the usefulness of a popular prostate screening test that measures the amount of prostate-specific antigen (PSA) in your blood. Basically, PSA is a protein produced by the prostate gland. PSA is present in small quantities for normal men, but it is generally elevated for men with prostate cancer or other prostate disorders.

Some recent news coverage sensationalized the results of this federal study, so here are the basics of the report. The research findings are based on 10 years of follow-up of nearly 77,000 men (ages 55-74). Half of the men received annual PSA tests for six years, and the other half received “usual care” from their own doctors (physicals that in some cases included PSA tests). After 10 years, the men that received annual screening were diagnosed with prostate cancer 17 percent more than those in the “usual care” group. However, the screening didn’t reduce the rate of death from the disease. (Various possible and plausible explanations are discussed in the report, but I’m not going to get into the gory details here.) This brings into question whether the PSA test should be used for general screening, because prostate cancer over-diagnosis leads to unnecessary treatment and potential lasting side effects such as impotence and incontinence.

So, what is a man to do? Since I work in the area of prostate cancer research, friends and family members have been asking my opinion on whether or not they should be regularly checked for prostate cancer.

To me, it seems like these new screening guidelines assume that ignorance is less stressful than having faith in your doctor. Namely, it is better to not even perform a simple PSA blood test, because patients with low PSA levels are often over-treated. I understand the issues that they are addressing, but I think the reasoning is somewhat flawed. Why not instead just change how you treat patients with low PSA levels? Such PSA test results would indicate that you probably have some non-aggressive cancer cells in your prostate but they are unlikely to harm you. Scary yes, but so are impotence and incontinence treatment side effects. So why not just repeat the blood test in 6 months or a year to see if PSA levels have risen? Is this common practice of “watchful waiting” by your doctor really more stressful than not having the blood test at all? Because, for some, that simple blood test could also indicate that you have aggressive prostate cancer that needs immediate treatment.

Based on my personal and professional experience, I recommend that men get at least one initial PSA test when they are in their early 40’s. Doctors can use this as an important baseline in the future. This agrees with the American Urological Association’s guidelines. However, I am not a medical physician and some men have higher risk for prostate cancer, so it is important to speak about your health and concerns with your physician