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Understanding Prostate Cancer

August 2010 Advances

Findings from the American Society of Clinical Oncology (ASCO) Annual Meeting

June 4 – June 8, 2010

OVERVIEW

The 46th American Society of Clinical Oncology (ASCO) Annual Meeting featured 160 papers focused on prostate cancer. Overall, the society had 37,000 total attendees, including exhibitors from the pharmaceutical and biotech industries, and drew attendees from 121 countries. This meeting is the annual “oncology platform” for the release of about 4,500 scientific abstracts. Many are highly anticipated research findings for patients, oncologists, oncology nurses, the FDA, biotech, pharma companies, and the general public. ASCO was founded as an “American” society in 1965 when the use of cancer medicines in oncology was an emerging field. Yet the major clinical-practice-changing papers presented this year in prostate cancer were notably international studies with U.S. patients in the majority of total patients treated.

Of the 160 prostate cancer papers presented, more than 20 oral presentations were presented by beneficiaries of 2006-2009 PCF Young InvestigatorCreativity or Challenge Awards. About an equal number of short papers were presented in phase I poster sessions, many of which were supported by PCF funding. Of these posters, a large number focused on biomarkers such as circulating tumor cells, new agents and new combinations of one new and one “old” drug in small clinical trials of 30 to 80 patients. Many papers were presented by investigators who are supported and funded by the Prostate Cancer Foundation and Department of Defense Prostate Cancer Clinical Trials Consortium.

It was an uneventful and thus somewhat disappointing ASCO in terms of findings that would suddenly lengthen the survival of men with advanced prostate cancer in 2011. There were no “breakthrough” drugs announced that we had not heard of for prostate cancer. However there were real breakthroughs for ALK-4 lung cancer and BRAF melanoma that do change the care of patients with advanced disease.

The annual ASCO meeting usually presents the culmination of science into larger stage (phase III) clinical trials that are large enough to gain acceptance and change the standard of care for patients. All ASCO results “look backward” in time to the state of science when a large trial was started – as it can take many years for large clinical trials to be completed – and to see the benefits eight to nine years after treatment. Most phase III prostate cancer trials presented were from circa 2002-2004. At the same time, the scientific and translational discoveries march onwards and there can seem to be a disconnect between what is known now, and what was done in trials. For example, all the major clinical trial work presented in radiation oncology was initiated before the recently announced 23+1 gene fusions discovery made at the University of Michigan by Arul Chinnaiyan, MD, PhD and colleagues Scott A. Tomlins, Christopher Maher and Daniel Hamstra, MD, PhD, PCF Young Investigator award recipients involved in the clinical work.

All of the above being said, ASCO is always valuable because those who take care of oncology patients took new concepts, knowledge, medicines, and diagnostics back to their clinics and patients.

The following “Highlights that Change Practice” are my thoughts on new clinical data and research findings that were presented at ASCO. The following clinical research reportings provide hope around new data for current patients in regards to survival and treatment options.

HIGHLIGHTS THAT CHANGE PROSTATE CANCER PRACTICE

1. FDA Approval for Cabazitaxel to Provide Prolonged Survival for Metastatic Prostate Cancer Patients

Only days after the cabazitaxel data was presented at ASCO, the FDA approved the chemotherapy agent, which is the first drug to demonstrate a survival benefit for men whose cancers first respond, and then become refractory to, docetaxel chemotherapy. The significance of the study from Johann De Bono, MD, DSc, PhD, senior lecturer at Royal Marsden Hospital, London is prolonged survival for men with metastatic prostate cancer.

Cabazitaxel - Prostate Cancer DrugCabazitaxel is the first chemotherapy to provide a survival benefit in “second-line” metastatic hormone-refractory prostate cancer. The drug itself was “rationally synthesized” by chemists to avoid being pumped out of cancer cells - as one form of resistance to docetaxel is that tumor cells pump it back out. Cabazitaxel has not yet been used at the “front-line” or compared to docetaxel to determine if it confers more remissions or if those remissions are more durable.

The large phase III trial was conducted in over 700 patients, most of who were in Europe. Patients were treated with the intravenous drug and received up to 10 doses every three weeks. Cabazitaxel was given with 10mg per day prednisone administered orally. The median survival with cabazitaxel was 15.1 months, compared to 12.7 months for mitoxantrone and prednisone. Patients experienced reductions in white blood cell counts and anemia. Many patients did not benefit from treatment; however an important minority of repeatedly treated patients did show a significant clinical improvement and lived weeks longer than those treated with Novantrone.

Published papers in the late 20th century said that “hormone-refractory prostate cancer was resistant to chemotherapy;” however, this is no longer the case. For example, the phase III trial of cabazitaxel had patients who clearly tolerated treatment and lived additional months with quality of life, but there were no complete remissions from the disease. It could be that these drugs are being tested far too late in the clinical course of the disease. It could also be that they block the microtubules and cause tumor cell death in a minority population of exceptionally fast-growing metastatic tumor cells – enough to slow, but not stop the disease. (Microtubules serve as structural components within cells and are involved in many cellular processes.) Microtubule drugs like Taxotere and cabazitaxel, and microtubules in prostate cancer treatment science, need additional research – even though the first approval of this class of drug (taxol) was in 1992.

Many researchers are still unclear as to why this class of drugs works in some prostate cancers. Next steps for PCF researchers, and funding partners, include studying tumor cells (liquid biopsies) and their responses to cabazitaxel. Currently, PCF has engaged senior scientists, particularly at the LeFrak Prostate Cancer Center at Cornell University, in the cabazitaxel discussions. PCF is continuing to try to stimulate work towards discoveries on how microtubules shuttle proteins in hormone-refractory prostate cancer cells and how they permit cells to divide.

2. Androgen Receptor Targeted Therapy   

Just as cabazitaxel may prolong survival for metastatic prostate cancer patients, androgen receptor targeted therapies may play a critical role in extending patient survival by decreasing the proliferation of prostate cancer cells, and are an important driving force in castration-resistant prostate cancer cells. Additionally, investigators are defining new mutations in androgen receptors and identifying protein interactions that can lead to the design of targeted therapies.

Abiraterone - Prostate Cancer DrugCurrently, primary therapies included Lupron and Casodex and secondary therapies included research with abiraterone and MDV3100. The introduction of these drugs by Charles Ryan, MD at the University of California, San Francisco, is a product of PCF research support through Challenge Awards and National Cancer Institute (NCI) funding. FDA review is currently pending for abiraterone and MDV3100.

Efficacy studies on abiraterone reveal that the drug is highly active in some patients, with response portions ranging from 45 percent in heavily pretreated patients to 75 percent in patients without extensive secondary hormone therapy or chemotherapy. The dosage used is once a day at 1000mg continuously for 28 day cycles.
 
Investigators have also shown that MDV3100 has clinical activity even in heavily pretreated patients, and it is now being tested in phase III studies. Clinical trials that answer the question of whether MDV3100 should be moved up and be used as initial primary androgen receptor targeted therapy, and whether its use would be beneficial in a noncastrate setting.

Some MDV3100 responses from scans are impressively durable and a few complete responses do occur at several US centers. New research, with funding from PCF, is attempting to answer questions about this therapy, including whether it can be used with hormone therapy to prolong survival in symptomatic metastatic disease, and whether it should be continued even after progression of disease to protect against tumor growth exacerbation.

3. Short-Term Hormone Therapy with Radiation Therapy

Radiation therapy in combination with targeted androgen receptor is synergistic in a Petri dish. A 1994 – 2001 North American study was designed by David G. McGowan, MBchB, Cross Cancer Institute, Edmonton, Canada, to determine whether a four-month short-course of hormone therapy, plus radiation, could improve overall survival in men with early stage, organ-confined, prostate cancer – compared with potentially curative radiation alone.

The data demonstrated that men with high-risk disease that is still confined to the prostate should receive long-term androgen deprivation therapy greater than four months – and those at intermediate risk should receive short-term androgen deprivation therapy. Patients with low-risk prostate cancer don’t appear to need androgen deprivation therapy.

1,979 of these patients were randomly assigned to receive either radiation, with or without four months of hormone therapy; hormone therapy was begun two months prior to radiation therapy to improve the killing of tumor cells. If the hypothesis is correct, hormone therapy radio sensitizes some prostate cancer cells that would otherwise be resistant to the same dose of external beam radiation alone. Patients received 66.6 Gy of radiation in both study arms.

A significant increase in overall survival occurred with the addition of adjuvant hormone therapy – 62 percent compared with 57 percent at 10 years. Survival from prostate cancer, even if the disease reoccurred, was also increased with a hazard ratio for survival of 1.84 for patients treated with hormone therapy and radiation compared with radiation alone. Re-biopsy was done in 439 of 987 patients in the H+RT arm; 344 (78 percent) of these were negative. Potential side effects associated with hormone therapy included impotence and hot flashes.

To better understand the potential benefit, investigators retrospectively divided patients according to prognosis groups, based on Gleason score, PSA levels at diagnosis and tumor stage by exam and CT scans. The average age of these patients was 71 years-old and most were not thought to be ideal candidates for surgery.

In 655 low-risk patients (Gleason score of six or lower, PSA of 10 ng/mL or lower) the overall survival at 10 years was estimated to be 73 percent with radiation alone and 76 percent with radiation and hormone therapy. In this group, hormone treatment probably didn’t add much to the curative capability of radiation.

In contrast, a significant improvement in overall survival was found in the 1,068 intermediate-risk patients (Gleason score of 7 or Gleason at or below 6 and either a PSA score between 10 and 20) with 72 percent of patients predicted to be alive at 10 years in the combination-therapy arm compared with 66 percent in the radiation-only arm.  The 226 patients with highest-risk disease (Gleason score of 8 or higher) did not show a statistically significant improvement in survival with the addition of hormone plus radiation, with the 10-year estimated survival rate of 66 percent in the combination therapy arm compared with 58 percent in the radiation-only arm.

For practitioners and patients, the survival benefit appeared to be greatest in those with Gleason 7 disease and a PSA between 10 and 20, but with organ confined disease. No benefit of hormone use was seen in the low-risk group and previous studies have shown that men with high-risk disease need more than four months of androgen deprivation.

4. Improved Survival Shown when Adding Radiation to Hormone Therapy

Just as short-term hormone therapy with radiation therapy can improve overall survival in men with early stage, organ-confined, prostate cancer, improved survival was shown when adding radiation to hormone therapy for men with locally advanced prostate cancer that extends outside the prostate.

Radiologic Responses to Abiraterone AcetateLocally advanced disease was defined as a T3 tumor, where the cancer has spread to the connective tissue near the prostate (T3a), or to the seminal vesicles as well (T3b). T4 tumors occur when the cancer has spread within the pelvis to tissue next to the prostate – such as the bladder, sphincter, rectum or the wall of the pelvis. The trial tested this combination in patients with T3 and T4 stage cancers.

Most oncologists already sensed, or expected to hear at ASCO that androgen deprivation plus external beam radiation therapy should be the standard treatment approach for men with locally advanced prostate cancer. Technological changes covering the past decade have enabled oncologists to deliver much higher doses of radiation, with fewer side effects, into the prostate than previously done before. The study was coordinated by the NCI of Canada included the participation of radiation oncologists in Great Britain and the U.S. and was led by Dr. Padraig R. Warde, MB, of Princess Margaret Hospital, Canada.

Results from the international phase III trial demonstrated that adding radiotherapy to androgen deprivation therapy reduced the risk of death from prostate cancer by 43 percent in men with locally advanced disease.

Between 1995 and 2005, 1,205 men were randomly assigned to receive ADT plus radiation or ADT alone. After six years of follow-up, 51 of the 603 men who received the combination modality therapy had died, compared with 89 of the 602 men who received ADT alone. Treatment was very well tolerated for a time. Fewer than two percent of patients in either group experienced significant gastrointestinal toxicities. However, patients receiving radiation had more low-grade diarrhea for a time and some rectal bleeding.

Researchers projected that fewer men who received hormone therapy plus radiation would die from prostate cancer over 10 years, than those men who received anti-androgen therapy alone (15 percent versus 23 percent). Final results are still coming in and are expected in the next few years.

Disease-specific Survival

Radiotherapy was given as 45 Gy, in 25 treatments, over five weeks to the pelvis plus 20 to 24 Gy in 10 to 12 fractions over 2.0 to 2.5 weeks to the prostate. PCF funded investigator Anthony D’Amico, MD, PhD, of Harvard Medical School, discussed the findings for the entire field and recommended that standard practices for locally advanced prostate cancer take into account both the patient’s life expectancy and comorbidities.  D’Amico noted that men with life expectancies of more than five years should be candidates for combined therapy, whereas older men and men at risk for early death may benefit from androgen deprivation without the need for radiation exposure.

5. Delaying Skeletal Fracture Events in Prostate Cancer with Patients on ADT – Denosumab Superior to Zometa

The Prostate Cancer Foundation has supported significant laboratory research on drug tests to prevent fractures and perhaps, slow down disease in bone metastases. Much of that data in the late 1990’s finally entered clinical trials and updated data was reported in Chicago.

Bone metastases from castration-resistant prostate cancer (CRPC), also known as hormone-refractory prostate cancer, are associated with osteoclast activation medicated by receptor activator of nuclear factor kappaB ligand (RANKL). This can result in bone destruction and skeletal-related event (SREs). Denosumab is a human monoclonal antibody against RANKL and the only bisphosphonate currently approved to prevent delay of SREs is denosumab. In an earlier study, it delayed time to first SRE by 5 months.

Karim Fizazi, MD, PhD, of the Institute Gustave-Roussy, France, reported at ASCO that in patients who had CRPC metastasized to the bone, denosumab delayed the time to a SRE by 3.6 months over Zometa.

Fizazi’s study randomly assigned 1,901 patients with CRPC and at least one bone metastasis to both subcutaneous denosumab 120 mg and intravenous placebo (950 patients) or subcutaneous and intravenous Zometa 4mg (951 patients) every 4 weeks. The study was designed to compare denosumab and Zometa head-to-head.

Accelerated normal bone resorption is extremely common in metastatic sites of prostate cancer, despite sclerotic radiographic appearances, and the morbidity associated with sclerotic disease is common, and again, more common than many clinicians appreciate. Bone targeted treatments do have a major impact on important clinical outcomes. They may not improve survival, but they do play a role in the quality of survival.

6. Ipilimumab 

Ipilimumab research has received significant PCF funding with James Allison at University of California, Berkley and Memorial Sloan Kettering Cancer Center. Ipilimumab is a monoclonal antibody that inhibits the T-cell suppressor protein CTLA4 and is suggested to be combined with anti-androgen therapy to improve clinical outcomes in patients with advanced prostate cancer. Bristol-Myers Scribb (BMS) acquired ipilimumab with its acquisition of Medarex in 2009. Matthew K. Tollefson, MD, a fellow in the Urologic Oncology Department at the Mayo Clinic, presented the abstract at ASCO after assigning 108 patients with advanced prostate cancer to receive a single dose of ipilimumab with anti-androgen therapy or anti-androgen therapy alone.

In the phase II study, patients randomized to receive anti-androgen therapy alone could cross over to ipilimumab upon PSA progression. In terms of safety, the team found that the combination was well tolerated. The most common Grade immune-related adverse events were bowel symptoms like colitis and diarrhea, each affecting 4.5 percent of the patients treated with the combination. Side effects like diarrhea could be managed as outpatients in most cases.

Ipilimumab and anti-androgen treated patients were more likely to have undetectable PSA by three months compared with patients treated with hormone therapy alone (55 percent vs. 38 percent) – not a statistically significant difference. In some patients it took a number of months before the PSA began to fall. These findings suggest it may take weeks, or even months, before the immune system is fully activated to attack in prostate cancer cells. It is still very unclear why Ipilimumab works in some patients and not others.

Investigators also looked at the impact of therapy on measureable disease and found responses by RECIST criteria (Response Evaluation Criteria In Solid Tumors are published rules that define when cancer patients improve ["respond"], stay the same ["stabilize"], or worsen ["progression"] during treatments).  Of the 54 patients initially treated with the combination, 24 patients (44 percent) did not have measureable disease, two (4 percent) showed disease progression, five (9 percent) had stable disease, 13 (26 percent) had a partial response, and seven (13 percent) had complete responses. Of the 54 patients treated with anti-androgen therapy, 32 crossed over to the combination. Of the crossover patients, 14 (42 percent) did not have measurable disease, seven (21 percent) had stable disease, three (12 percent) had stable disease, six (18 percent) had partial responses, and two (6.1 percent) had a complete response.

They used both MRI and CT scans to measure shrinkage of tumors as small as a quarter of an inch in diameter.

In a separate report, the Mayo team presented data on a subset of the patients treated in the randomized trial who subsequently opted for a radical prostatectomy off study after treatment. All 15 of the men in this subset initially presented with advanced disease and had a complete clinical regression of their prostate cancer under the microscope following treatment with the combination therapy ADT and ipilimunmab, based on PSA, prostate exam, and follow-up imaging. Eight of the patients had down staged diagnosis based on final pathologic review.

According to Dr. Tollefson, the next step will be combining both studies and designing a study that looks specifically at “tissue down staging” – in other words, attacking the tumor in the prostate prior to removing it. Tollefson also stated that there was good biological rationale for this combination – with anti-androgen therapy killing tumor cells and increasing T cell activity and ipilimumab stoking that response – and new data strengthening that notion. Though the jury has not reached a decision, results at this point are promising and worthy of further study.

7. Old Diabetes Drug May Get New Role 

An emerging question in prostate cancer research: is there a subset of prostate cancer that resembles breast cancer enough that metformin would slow down prostate cancer? As reported at ASCO, metformin as a treatment concept is designed to slow down breast cancers, not act as a chemotherapeutic drug that kills them. Metformin, a commonly prescribed drug for the treatment of Type 2 diabetes, affects the liver and then affects the level of circulating insulin in the entire body which is an energy saver for metastatic cancer cells.

Metformin

A PubMed literature search featured 67 research articles suggesting that metformin may slow down breast cancer cells by depriving them of a valuable source of energy needed to divide. In addition, the National Cancer Institute is sponsoring a 3,000 enrolled/patient women’s clinical trial to test metformin as an agent to slow down breast cancer progression.

Cristiano Ferrario, MD, clinical fellow at the Lady Davis Institute at McGill University in Montreal, is evaluating the likelihood that metformin might have an effect on prostate cancer progression and its impact on prostate cancer cells in vitro. Ferrario and colleagues also examined prostate cancer tumors for expression of the insulin receptor, which is targeted by the drug.  Ferrario is being mentored by a PCF 2007-2010 Challenge Award recipient, Dr. Michael Pollak, who has been one of the leaders in studying how insulin and insulin-like growth factor-1 (IGF-1) control the ability of prostate cancer cells to use energy.

To determine whether the insulin receptor (IR) is expressed in prostate cancers, the researchers stained 644 tissue samples from 161 patients on tissue microarrays with an anti-IR antibody. The higher the Gleason score on average, the higher the insulin receptor is expressed, and potentially the greater the likelihood metformin might have a positive treatment effect.

Growth declined in a dose-dependent manner when the team treated prostate cancer cells in culture with metformin. Metformin treatment activated AMPK, which inhibits the mTOR complex. The effects of metformin on cells could be largely reversed by reducing the amount of AMPK in the cell with small interfering RNAs, indicating that the drug is working through AMPK.

Dr. Ferrario and other scientists plan to test metformin in patients with castrate-resistant metastatic prostate cancer and look for an impact on PSA progression and attempt to find which types of prostate cancer respond to metformin and which do not.  A key effort will be defining and further researching the 23+1 types of prostate cancers discovered at the University of Michigan, Ann Arbor.

CLOSING OBSERVATIONS

Presentations in Chicago answered a major and lingering question on the value of radiation therapy with short or full anti-androgen. Chicago also taught us the importance, and immediate needs for more agents in the pipeline. What was entering phase III trials five years-ago may seem ancient compared to our current molecular understandings provided in the past two-years (i.e.: 23 + 1 types of prostate cancer discovery including the need for targeted agents SPINK1, EZH2, ATK1, etc.).  Avastin (a first-generation anti-androgenesis treatment) was shown conclusively not to have a survival benefit in a large phase III trial for prostate cancer. However, second generation agents are now testing.

PCF will continue fast-forwarding prostate specific targeted treatments – as the repeated phrase heard time and time again in Chicago was targeted treatments. The Prostate Cancer Foundation’s vital role in funding new treatment research has never been more important.

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