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Understanding Prostate Cancer

July 2011 Advances

2011 American Society of Clinical Oncology (ASCO)
Annual Meeting Highlights

June 3 – June 7, 2011

Introduction

3D structure of the signaling domain of the murine sonic hedgehog from PDB 1vhhThe 2011 American Society of Clinical Oncology Annual (ASCO) meeting witnessed compelling data on 3 new drugs heading rapidly towards FDA review and approval for metastatic prostate cancer: cabozantinib, Alpharadin and MDV3100. We also saw the first data from hundreds of patients showing that counting circulating tumor cells (CTCs) in blood outperform the prostate specific antigen (PSA) test in predicting whether an experimental treatment is working. More innovation was also reported. For example, a 1992 FDA-approved drug called itraconazole, a toenail fungus antibiotic, emerged as an important antagonist in micro-metastatic prostate cancer. It blocks the “Sonic Hedgehog pathway,” a biochemical growth signal in cancer stem cells.

ASCO annually convenes the largest oncology meeting in the world. The meeting provides an optimal opportunity for oncology practitioners to learn the latest scientific advances in a collective setting. ASCO has 30,000 members. Add drug and pharmaceutical attendees, and McCormick Place bustled with approximately 40,000 attendees from more than 130 different countries. 

The theme of the 2011 ASCO Annual Meeting, “Patients, Pathways, Progress” was reflected in many different aspects of the ASCO program, especially in the area of prostate cancer research. Achievements of PCF-supported cancer researchers were represented in the 30 out of 218 total prostate cancer papers presented at ASCO. Of these 30 papers, 16 were the work of PCF Young Investigators mentored by PCF senior investigators.

ASCO meetings are designed to update oncology practitioners on new clinical trial findings and trends and how to better care for problems that patients experience. While it is impossible to summarize all of the new science presented at the meeting, what follows below are the most relevant highlights which concern 10 new drugs as well as three new trends in biomarker research. These are promising developments that patients with advanced disease will want to track and stay informed of with their physicians.

New Agents in the Pipeline and Entering Practice

1. Cabozantinib (XL184) – Exelixis, Inc.

Andrew Pollack recently reported from ASCO in The New York Times, that cabozantinib, formerly XL184, “seems to be able to virtually eradicate bone metastases in some patients, at least as measured by bone scans, something no other drug has done.” Below is a prostate cancer patient bone scan before and after treatment with cabozantinib:

Bone-scan images before and after treatment with cabozantinib

PCF-funded investigator Maha Hussain from the University of Michigan, Ann Arbor presented interim data from a phase II study showing that cabozantinib (XL184) reduced bone metastases in 76% of prostate cancer patients with advanced castration-resistant disease. No other drug has done this to abnormal bone scans before in prostate oncology. The current standard of care for metastatic castration-resistant prostate cancer (mCRPC) is a combination of the chemotherapy drug docetaxel and the steroid prednisone. Docetaxel regimens have a limited impact on bone metastases and what they look like on bone scans.

While most chemotherapy is administered intravenously, cabozantinib, by contrast, is a small molecule tyrosine kinase inhibitor (TKI) that can be taken orally. Tyrosine kinases are part of the complex network of proteins involved in many different kinds of cancer cell functions, including several that drive prostate cancer cells to replicate. There are over 518 kinases found in the human genome. All 518 of them are potentially drug targets for diseases as often a disease state is “signaled” by an abnormal kinase. Specifically, cabozantinib is a “multi-kinase inhibitor” of specific kinds of tyrosine kinases: c-Met (MET) and the vascular endothelial growth factor receptor (VEGFR-2) and, at least in a test tube, kinases called RET, KIT and TEK.

Exelixis chemists designed cabozantinib, originally called XL184, to block the promotion of angiogenesis, the process by which tumors actually induce new blood vessels to form within them so that they can receive nutrients. Unexpectedly, as described below in the abstract, the drug can also affect the bone cells (osteoclasts and osteoblasts) that support the survival of prostate cancer cell clones within a bone metastasis.

In the University of Michigan study, 168 patients with metastatic PCa were treated with a 100mg dosage of cabozantinib daily. Overall, 71% of patients benefited and 86% of patients showed bone effects indicative of improvement. Of the patients treated, 51% required a dose reduction due to severe fatigue, high blood pressure, and “hand and foot syndrome” (burning sensation). Ten percent of patients had side effects at a 100mg per day dose that were so difficult they could not cope with the treatment. None of the side effects, as reported by careful grading, appeared life-threatening for the men on this trial. Sixty-four percent had marked improvement in pain at the site of bone metastases. Forty-six percent of patients were able to cease taking pain killers for bone metastases. Another striking observation was that anemic patients had improvements in their red blood cell counts. Many experts believe 100mg may be too high a dose, and further research is underway to find the optimal dose as well as whether or not patients should come on and off the drug periodically, rather than have it administered continuously.

2. Alpharadin® (radium-223 chloride) – AlgetaRL

A lesser known area of radiation oncology is radiopharmaceutical therapy. This approach involves the injection of a radioactive substance, such as strontium-89 or samarium-153, intravenously for systemic distribution to cancer cells. These two radiopharmaceuticals are atomically like calcium in the periodic table of the elements. As minerals, they are actively deposited by the body into areas of bone that contain cancer metastases where damaged bone matrix is exposed to blood flow. Providing radiation from a deposit of radiopharmaceuticals in this way can irradiate and destroy cancer cells in the bone, and subsequently relieve pain from bone metastases.   Common side effects of strontium-89 and samarium-153 include dangerously lowered levels of normal platelets, and white and red blood cells, as they are radiated and killed.

Radium-223 is different. Radium-223 is a new type of radiopharmaceutical therapy that may produce fewer side effects. It does so by delivering its cell killing action over a very “short range” via an alpha particle (2 protons and 2 neutrons) of radiation in its nuclear decay—rather than through a beta particle (an electron). Alpha particles for prostate cancer cell killing in the bone are “first in field” and distinctive. In contrast, gamma rays from external beam radiation are so energetic they pass through the body if they do not hit molecules. Beta particles can penetrate many cell diameters away from the cancer deposit and kill radiation ultra-sensitive normal red blood cell and platelet-forming cells in the bone marrow.
        
From 1997-2000, PCF funded Dr. Logothetis, at the University of Texas MD Anderson Cancer Center, to test the concept of radiopharmaceutical targeting of bone metastatic prostate cancer with beta particles from strontium-89. Two important, PCF-funded papers were published from Dr. Logothetis’ group in 2001 and 2003 confirming that a) prostate cancer bone metastases can be controlled and, in some cases, eradicated in the bone with radiopharmaceuticals and b) side effects on bone marrow in many patients make it impossible to safely use Sr89 routinely in combination with existing cell-killing drugs. Building on this clinical scholarship, a Norwegian cancer therapeutics company, Algeta, presented data in 2007 from a phase II study that showed a remarkable two-year survival advantage with bone-targeting alpha particles from radium-223 when used as a treatment for castrate-resistant prostate cancer. What then followed was a phase III trial with the significant U.S. leadership of Dr. Oliver Sartor at Tulane University.

On Monday, June 6, 2011 at ASCO, Algeta’s partner, Bayer Healthcare, announced promising results for Alpharadin (radium-223 chloride). In that phase III clinical trial, four intravenous doses of radium-223 alone improved overall survival by 3 months for patients with extensive bone metastatic castration-resistant prostate cancer. The radiopharmaceutical treatment period was 12 weeks. The clinical trial was a randomized, double-blind, multi-dose, placebo-controlled international study that included 922 patients. The primary endpoint of the study was overall survival.

Side effects were very similar to those seen in the Algeta phase II trial where platelet counts, white cell counts and red cell counts were not significantly lowered and patients remained as outpatients. Based on a recommendation by the Independent Data Monitoring Committee (IDMC) for the FDA, the clinical radium-223 trial was stopped and patients on the placebo arm were proposed to be given the drug. Based on these data, Bayer-Algeta is re-evaluating its timeline for gaining FDA approval and looking at supply chain issues for distribution globally.

Among public and private biomedical research funding entities, PCF was the only Foundation to fund the “proof of concept” of radiopharmaceuticals at the University of Texas MD Anderson Cancer Center.

3. Zytiga® (abiraterone) – Johnson & Johnson

In early May, the Food and Drug Administration approved abiraterone, a new targeted therapy in the class of androgen production blockers. The drug improves overall survival by nearly four months for men with metastatic, castration-resistant prostate cancer after being treated with docetaxel chemotherapy.

Radiologic responses to abiraterone acetateIn total, PCF invested $8.2 million in research (PCF Creativity and Challenge Awards 2007-2010) for fast forwarding treatment science research around abiraterone. The PCF research support was global, and it was funded in independent, university research laboratories. Most of that research focused on abiraterone’s mechanism of action, discovery of  biomarkers to predict patient response, e.g. circulating tumor cells, and identification of mechanisms of resistance. All this research occurred prior to Johnson & Johnson’s acquisition of the drug. Pivotal clinical trials led by Dr. Johann de Bono at The Royal Marsden Hospital in London were enabled by critical contributions of a “star” cast of PCF Prostate Cancer Clinical Trials Consortium (PCCTC) collaborators including: Howard Scher, MD, at Memorial Sloan-Kettering Cancer Center;  Gerhardt Attard, MD, PhD, The Susan and James Blair PCF Young Investigator 2008-2011 at The Royal Marsden Hospital; Peter Nelson, MD, at the Fred Hutchinson Cancer Research Center; Eric Small, MD, and Charles Ryan, MD, at the University of California, San Francisco and Christopher Logothetis, MD, and Eleni Efstathiou, MD, PhD, GenProbe PCF Young Investigator 2008-2011 at MD Anderson. When the pivotal clinical trial (comprised of 1,195 patients) was published, over 34 clinical investigators were listed on the New England Journal of Medicine paper which Dr. de Bono published. That paper gives the results and provides the details on how clinicians should use abiraterone in the clinic.

Abiraterone works in about 60% of men with metastatic prostate cancer following docetaxel chemotherapy, but studies are ongoing about its use earlier in the disease and in combination with new agents. Dr. Logothetis presented additional findings on abiraterone. In a study of 797 patients randomized to abiraterone with prednisone (5mg twice a day) and 398 to placebo, abiraterone markedly delayed “SREs” (skeletal related events) and delayed the time or need for palliative radiation therapy of painful bone metastases. Pain relief from bone metastases and delay of painful recurrence were striking with abiraterone. These findings of increased symptom-free survival were observed in men with the most advanced, docetaxel-treated, and then refractory, metastatic hormone refractory disease. Dr. Logothetis educated the ASCO audience on the concept of “intracrine” androgens, production of testosterone within the tumor cell and around the metastatic site. He also suggested to drug developers in the industry that with this data, abiraterone—in addition to being used earlier in the disease course—should be integrated in co-targeting strategies with other bone targeting therapies.

Dr. Charles Ryan of the University of California, San Francisco (UCSF) also presented a paper on the use of abiraterone in men who had been treated with ketoconazole for at least 28 days in the “pre-abiraterone FDA-approved era.”  Ryan reported 63% of those UCSF patients responded to abiraterone after ketoconazole treatment. This important single-institution study, supported by PCF’s PCCTC, suggests that some tumors stay “Cyp17 pathway dependent” (which abiraterone inhibits better than ketoconazole). Pathways where continued “dependency” or “addiction” are demonstrated in the clinic, have been places for the research and development of better “second generations” of drugs than the “first generation.” The work of PCF-funded scientists in San Francisco, Seattle, London, Boston and Houston has collectively supported the thinking that intracrine androgen signaling must be completely blocked in patients whose tumors are “addicted” to androgen for survival.

4. TAK-700 – Takeda Pharmaceuticals

Takeda Pharmaceuticals has introduced another molecule into clinical trials to disrupt intracrine testosterone synthesis in metastatic prostate cancer. TAK-700 is a pill like abiraterone that has a unique chemical structure enabling it to inhibit a key enzyme called the 17,20 lyase enzyme. The 17,20 lyase is a key enzyme in the production of the common precursor molecules derived from cholesterol for male and female sex steroid hormones which normally are synthesized in both the testes and the adrenal glands. 

TAK-700 showed significant activity in 96 patients in a phase I/II trial. Patients had metastatic, castration-resistant prostate cancer with a median age of 70 years and median PSA at treatment of 22 ng/ml. At every TAK-700 dose tested, at least 50% of patients treated had PSA declines over 50% by 12 weeks of treatment. In those patients who had not received ketoconazole, 62% of patients had a PSA decline of >50% by 12 weeks on the drug. Patients experienced the predicted significant reduction of testosterone and DHEA-S in their blood; those findings should occur if the 17,20 lyase enzyme was being blocked adequately. Circulating tumor cell data from CellSearch systems was also illustrative of antitumor activity.

At 12 weeks after the start of treatment, 48 of 61 evaluable patients either had shifts from >5 cells/7.5mls (unfavorable) to <5 cells/7.5mls (favorable or retained favorable CTC counts). The drug also has toxicities. Seventy-one percent of patients reported fatigue, and nausea as an issue. Management of severe blood potassium levels was required in 6% of patients. TAK-700 is now in global phase III trials in docetaxel untreated, and docetaxel pre-treated patients on LHRH treatment.
 
5. MDV3100 – Medivation

In the laboratory, MDV3100 is a superior molecule to Casodex for inhibiting the androgen receptor. MDV3100 binds to the androgen receptor with 5x the affinity of Casodex. PCF supported significant molecular pharmacology around MDV3100 in Dr. Charles Sawyer’s laboratory at UCLA. MDV3100 is currently in phase III clinical trials, and there was no new clinical data presented at this ASCO. However, Dr. Eleni Efstathiou presented a provocative treatment sciences paper in CT-guided, serial biopsies of bone metastases in 47 MD Anderson patients who were treated with MDV3100 in earlier clinical trials. With drug treatment, nuclear androgen receptor levels were reduced by MDV3100 in the bone metastasis clones—but with this was evidence of increased intracrine androgen production in the bone (observed by tandem mass spectroscopy). Increased phosphorylated-src oncogene as a research biomarker appeared to be correlated with MDV3100 treatment resistance. By studying patient volunteers in “real time,” and by interrogating their bone metastases directly after biopsy in a protocol, Dr. Efstathiou has elevated a molecular rationale into an imperative: co-targeting of increased intracrine androgen production, which can be blocked by abiraterone, with MDV3100 treatment. It is possible that the two international phase III trials for MDV3100 called AFFIRM and PREVAIL, respectively, will have available data for presentation at the 2012 ASCO meeting in Orlando.

6. Jevtana® (cabazitaxel) – Sanofi-Aventis

For practitioners caring for advanced prostate cancer patients, additional data was presented on the newly FDA-approved chemotherapy drug Jevtana from Sanofi-Aventis. Patient data from the 755 patient phase III trial suggests that even in men treated with docetaxel—who responded and then had tumor progression—25 mg/m2 of Jevtana treatment every 3 weeks confers additional survival. Both Jevtana and docetaxel are in the taxane class of chemotherapeutic drugs. The data from the Sanofi-Aventis clinical trial suggests that even though castration-resistant prostate cancer (CRPCA) may become docetaxel resistant, it is not necessarily taxane resistant. These data open up new questions about the pathway mechanism of action of taxanes in hormone resistant prostate cancer. Using the same logic that MDV3100 is a superior molecule than Casodex, researchers are now studying Jevtana as a molecule superior to docetaxel for disrupting microtubule dynamics in prostate cancer cells. Microtubules in prostate cancer cells seem to be integral in prostate cancer cell survival. Dr. Johann de Bono from The Royal Marsden Hospital presented new data on Jevtana that suggested a survival advantage for patients who were treated with Jevtana regardless of when docetaxel treatment was stopped. The New York Times captured the theme of that data: specifically that there is still evidence that research on more efficient (and likely more costly) chemotherapy may confer greater survival with acceptable side effects for certain sets of patients.

7. Xgeva (denosumab) – Amgen

Xgeva (denosumab) was FDA approved for prostate cancer in November 2010. The drug is superior to Zometa in delaying or preventing skeletal related events in patients with known bone metastases. PCF-funded researcher and professor, Matthew R. Smith, MD, PhD, director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center championed the clinical research. PCF invested more than $1.8 million in Dr. Smith and his team’s critical research projects on denosumab and treatment sciences on improving survivorship. The more than $1.8 million in funding support for Dr. Smith and denosumab from the Prostate Cancer Foundation came from peer-reviewed, non-corporate academic grants starting in 1997. Denosumab prevents cancerous cells from recruiting normal cells to assist in adhering to bone and forming metastatic tumors. The treatment does this through the inhibition of RANK Ligand, a protein that activates signals that lead to the breakdown of bones in a bone metastasis of prostate cancer.

Rank Ligand - Key Mediator in Vicious Cycle of Bone Destruction 

Denosumab treatment also increased the time it takes to first bone metastasis and the time it takes to develop asymptomatic bone metastases. “Denosumab provides a new therapeutic strategy that is complimentary to other forms of treatment for men with prostate cancer,” said Dr. Smith at ASCO. “In addition to providing a potential new treatment option, the study results widen the perception of metastasis prevention as a much more attractive area for research and an effective path for new drug development.”

Despite the FDA approval and significant implications of the drug in the field of research on RANK Ligand in the cancer microenvironment and metastasis prevention or delay, denosumab was controversial at ASCO 2011 with respect to both cost of treatment and degree of patient survival benefit.

8. Provenge (sipuleucel–T) – Dendreon

It was a quiet ASCO for any new data following FDA approval of Provenge, especially for those looking for data on how the treatment works at the cellular level of apoptosis; destruction of cancer.

Knowing more specifically how Provenge extends survival without causing remissions is one of the privotal new questions in prostate cancer oncology. Research is ongoing on how to vaccinate a patient and then sculpt and redirect the key cancer-killing immune cells to the metastatic site. However, Dr. Gomella from Thomas Jefferson University presented a provocative follow up of data on what happened to patients on the placebo arm of the positive phase III FDA approval trial. These “placebo arm” patients were treated with their own, autologous, cellular immunotherapy at the time of disease progression. Those patients who “crossed over,” and then were treated with Provenge, had a median survival of 23.6 months compared with 12.7 months median survival in men on the placebo arm who, for various reasons, were not treated.

9. Novel Agent [except it is an “old drug for something else”]:  Itraconazole

At ASCO, novel data was presented on the FDA-approved oral antifungal drug itraconazole in an exploratory clinical trial in men with advanced prostate cancer. Itraconazole is an “old drug” most commonly used to treat nail fungus and approved by the FDA in 1992.

Supported by PCF-funding, itraconazole was identified as a potential anti-prostate cancer drug after Hopkins scientists led by Drs. Michael Carducci and Emmanuel Antonarakis tested a library of more than 3,000 FDA-approved drugs for diseases other than prostate cancer for potential anti-prostate cancer use. Itraconazole scored an unequivocal “hit” as an unexpected anti-prostate cancer drug in a dish. Laboratory testing by Johns Hopkins University investigator Jun Liu, PhD, demonstrated that human prostate tumors implanted in mice regress impressively when treated with itraconazole at doses that can be achieved in humans. In that research, itraconazole appeared to inhibit angiogenesis (the development of blood supply) around the tumors—the only drug in its chemical and antifungal class to act that way. Even more intriguingly, the Hopkins group discovered that the antifungal inhibits a key cancer stem cell activating-pathway called Hedgehog. PubMed has at least 105 research papers on Hedgehog signaling pathway in prostate cancer biology, but itraconazole is the first agent to enter the clinic in Baltimore as a “first-in-field” anti-Hedgehog molecule to target this pathway.

Dr. Antonarakis and colleagues tracked prostate cancer progression-free survival over 24 weeks of daily treatment with oral itraconazole in patients with CRPCA. Evidence of worsening disease was measured by a 25% increase in their blood level of prostate specific antigen (PSA). Early in the trial, preliminary analysis of 17 men with CRPCA received lower doses of itraconazole and 2/17 had stable or declining PSA. However, 11 of 24 (48.4%) men taking high doses of itraconazole, 600mg/day, had stable or declining PSA levels lasting at least 24 weeks. In addition, nearly a third of men taking the high dose had PSA reductions of 30% or more. Itraconazole did not affect blood testosterone levels or DHEA (a testosterone precursor). Interestingly, 12/14 men taking high doses of itraconazole had lower levels of CTCs in their blood after therapy, compared with their baseline levels. Side effects included lowered potassium, hypertension and fluid retention, but were manageable in the outpatient setting.

Translational research will now continue to interrogate blood and skin samples taken from patients on the trial to assess levels of proteins linked to both tumor blood vessel formation and inhibition of the Hedgehog pathway. In addition to Dr. Antonarakis, other investigators within PCF’s PCCTC participated in the study. High-dose itraconazole is now slated for clinical research in larger studies of men with CRPCA.

10. Novel Agent [First Lead to Treat ETS fusion+Castration-Resistant Prostate Cancer]:  Oliparb

More than 50% of prostate cancers have ETS gene chromosomal fusions according to the University of Michigan “Rosetta Stone” of human prostate cancer clonotypes. ETS fusions are now viewed as “driving mutations.” Such driving mutations have generated game-changing drugs in other cancers such as Gleevec for the BCR-ABL protein in chronic myelogenous leukemia, Herceptin for breast cancer, and most recently crizonitib for ALK fusion lung cancer. The Stewart Rahr-PCF Young Investigator, Dr. Felix Feng, and his mentor Dr. Arul Chinnaiyan, reported that ETS fusions in prostate cancer confer sensitivity of cancer cells to an experimental drug class being investigated in ovarian cancer and breast cancer therapeutics called PARP inhibitors. According to the NCI, six different PARP inhibitors are being developed in biotech and pharma. Thus, an extensive body of work in breast and ovarian therapeutics research now has implications for research on ETS-fusion positive prostate cancer patients therapeutics.

Conversely, research in ETS-fusion prostate cancer is likely to have applications to “DNA damage-repair therapeutics” for breast cancer and ovarian cancer. These are direct consequences of research on DNA fusions in prostate cancer at the University of Michigan. Dr. Feng and colleagues’ findings also motivate the use of PARP1 inhibitors as radiosensitizers in clinical trials of patients with localized ETS fusion-positive prostate cancers getting radiation therapy. Furthermore, for patients with bone metastatic disease facing the near-term possibility of FDA approval of radium-223, the co-targeting of PARP, with PARP inhibitors combined with radium-223 therapeutics, has a very strong rationale

Three Important New Trends

1. Intermittent Androgen Deprivation Therapy for Prostate Cancer           

The results of intermittent androgen treatment in a large phase III randomized, controlled trial were presented at ASCO in a way that can be thought to be “practice changing.” The trial was run by the National Cancer Institute of Canada and Dr. Juanita Crook presented the data. The patient group tested were those men whose PSA recurs with no evidence of metastatic disease on scans—and after primary tumor treatment, either radiation therapy or radical prostatectomy. Eligible patients had a PSA of >3.0 ng/ml at more than 12 months following either surgery, radiation following surgery, or primary radiation therapy. The two arms of the randomized trial were equally balanced for multiple variables and 1,386 men participated. The median follow up for all patients was 6.9 years and the intermittent androgen treated patients received between 1-9 cycles of treatment with the median number being 2 cycles of hormonal therapy between periods of discontinuation. Median survival was 8.8 years for the intermittent patients and 9.1 years for the patients treated continuously. The median age of the treated men was 74.2 years. In quality of life measures, intermittent antiandrogen treated patients complained of fewer hot flashes and 35% of them had full recovery of serum testosterone; myocardial events and osteoporotic fracture events were equal basically in both arms.

Here are the five key take away points for patients and clinicians:

  1. Intermittent androgen suppression was given for eight months then stopped and restarted only when PSA reached >3 ng/ml when off the treatment, compared to men treated with continuous androgen deprivation (called CAD).
  2. Intermittent antiandrogen treatment was equivalent to continuous antiandrogen treatment with similar overall survival and quality of life measures.
  3. Biostatiscally, intermittent therapy was called “a non-inferior” arm of the trial [non-inferiority is admittedly a double negative but is the language of the ASCO clinical trialist realm].
  4. Intermittent androgen suppression offers “cost-saving” to health systems as both patients and the systems pay only 27% of the cost of CAD.
  5. ASCO 2011 endorsed the concept that IAD now be presented to patients at the time of “biochemical PSA recurrence” in the absence of metastatic disease on scans.


2. Use of PSA and Prostate Cancer Screening “Rationally” in a Health System

While the PSA test cannot be made “prostate cancer specific,” and over diagnosis and cost of treating indolent, non-life-threatening prostate cancer is the dominant discussion in the press, interesting data from Sweden was presented by a Swedish-American research group led by Drs. Hans Lilja and Peter Scardino. The paper is comprehensive and provided below. The major question raised in the discussion at ASCO 2011 was: since the U.S. is not Sweden, are the results applicable here?


3. Circulating Tumor Cells “Version 1.0” Outperforms PSA for Predicting Treatment Benefit

PCF has funded research on several different biotechnologies and university teams to capture, measure and analyze Circulating Tumor Cells (CTCs) as progression biomarkers. The purpose of this emphasis in the PCF Research Enterprise is to provide to patients new “surrogacy measures” that are specific to prostate cancer disease activity. See “Evans Test for Prostate Cancer CTCs” at www.pcf.org. With “survival surrogacy” markers new experimental therapies can be evaluated for efficacy quickly and earlier in the disease course—when measuring overall patient survival alone might require years to a decade to get a convincing answer. For example, it took nearly a decade to get a rigorous answer of “non-inferiority” of treatment, with intermittent androgen suppression, versus continuous treatment.

As of ASCO 2011, CTCs are now the best platform so far ever seen for surrogacy of treatment and survival benefit. There are several “versions” of the CTC technology, and more being “pitched” to PCF by bioengineers. At ASCO 2011, the Veridex CellSearch system was used in the abiraterone phase III trial to show CTCs could be a predictive surrogate for patient benefit and survival with abiraterone. The Veridex CellSearch test is approved by the FDA for breast, colon and prostate cancer as being “analytically valid’ (reproducible). A very simplistic cutoff for analysis was used: CTC levels >5 /7.5mls (unfavorable) versus CTC levels <5/7.5mls (unfavorable). For the first time, Dr. Howard Scher presented results of the correlation reducing CTC counts after treatment where an experimental treatment conferred an overall survival improvement. In 972 of 1,195 patients participating in the abiraterone phase III clinical trial called COU-AA-301 CTC, data was generated prospectively.

Here are the key findings:

  • Baseline CTC count and LDH was prognostic for overall survival but PSA was not.
  • Conversion rates from unfavorable to favorable CTC at all specified time points in the trial (4 weeks, 8 weeks, 12 weeks) were higher for abiraterone than placebo and were statistically significant at every time point.

One trial is insufficient evidence, and the current use of “below or above 5/7.5mls” is likely to be improved by better quantification technologies. Nevertheless, it is a big first. “Proof of concept” came at ASCO 2011 that the use of prostate cancer CTC counts can be used as a surrogate to predict “winners” for new drugs for patients. With activism from PCF and the “boost” from ASCO 2011, the sponsors of the following have already agreed to support CTC testing and analysis: MDV3100, dasatinib, ipilimumab, Jevtana and TAK-700.

Summary

ASCO is about more than just papers and tracking progress towards patients. PCF runs a very significant “knowledge exchange” of unpublished data. Expanding on that role this year, PCF’s Chief Science Officer Howard Soule, PhD, met with 13 PCF-funded Young Investigators in addition to another 22+ recipients of PCF funding from 2000-2011. During the 5 days in Chicago, PCF had 16 meetings with leaders in the biotechnology and pharmaceutical fields. The LeFrak PCF-funded Young Investigator Himisha Beltran, MD, presented a paper on a new target in high Gleason grade prostate cancers and expressed a provocative drug target called Aurora Kinase. At least 30 PCF-funded investigators were there in the room taking notes on Aurora Kinase. Dr. Beltran shared: “the new relationships formed during this year's ASCO highlighted the shared enthusiasm amongst prostate cancer researchers as we make new and exciting advancements in the field. Listening to researchers as they share prominent new data is encouraging to one’s own work.”

Anyone in any oncology specialty who read or listened to ASCO papers left this year’s ASCO understanding that advanced, metastatic prostate cancer patients can now be treated with targeted medicines against defined receptors and kinases?and survive longer. This should improve prostate cancer clinical trial participation for advanced prostate cancer patients. In that way, ASCO 2011 represented a watershed for biotech and pharmaceutical executives who will now be told by their business development analysts that effective drugs can be produced profitably for prostate cancer.

As reported in The New York Times:  “Dr. Christopher J. Logothetis, of the MD Anderson Cancer Center, predicted further progress. It’s beyond the individual drugs,” he said. “One sees a manual now on how to go forward.’”

As satisfying as ASCO 2011 was, Dr. Michael Morris of Memorial Sloan-Kettering Cancer Center soberly pointed out to the full genitourinary oncology audience assembled that none of the recent FDA approved medicines by itself has conferred a 12 month survival improvement as a new single agent. Co-targeting and rational combinations of new agents will have to be accelerated. Furthermore, the prostate cancer treatment pipeline is still in danger with federal cancer research funding cutbacks looming at the very moment CTCs may be delivering a speedier and less expensive way to discover “winners” from “losers” in prostate cancer new-drug development.

There is much more for prostate cancer researchers to do and tantalizing new targets and questions. Many promising projects are currently unfunded, but PCF will work to fast forward as many of them as possible.

 

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