Conference Highlights 2007/2008 - Prostate Cancer Research Institute

Conference Highlights 2007/2008 from The ASCO Genitourinary Cancers Symposium, the Prostate Cancer Foundation Scientific Retreat, and the Upcoming American Urological Association Meeting

Reported by Mark Scholz, M.D. Prostate Oncology Specialists

Edited from PCRI Insights May, 2008 v 11.2

Every year in the United States new research on prostate cancer is presented at three conferences: The ASCO Genitourinary Cancer Symposium (GCS) in February, the American Urological Association (AUA) meeting in May, and the Prostate Cancer Foundation Scientific Retreat (PCFSR) in October. The AUA meeting in May is pending at the time of this article, but abstracts from the upcoming conference have been released and are reviewed in this article.

The effectiveness of Abiraterone, a new and more powerful oral agent for men with hormone-resistant prostate cancer (link hormone refractory PC), has been established in several clinical trials. At the GCS, Abiraterone was evaluated (Abstract #3) in a pilot trial of 29 hormone resistant men previously treated with Taxotere. The median starting PSA was 115. Twelve men (41%) had a greater than 50% decline in PSA. Measurement of circulating tumor cells (CTC) was performed, and the number of cancer cells circulating in the blood decreased substantially in the men who responded. Dr. Johann De Bono from the Royal Marsden presented the results of another trial of Abiraterone in a group of men with an average PSA of 75 at the PCFSR. The PSA response rate was 61%, and one-fourth of the men had a greater than a 90% decline in PSA. Interestingly they also reported that five of the 16 patients who initially responded to Abiraterone and who later developed progression of disease, subsequently achieved another remission if a potent form of cortisol called Dexamethasone was added to the Abiraterone.

A phase III trial of Abiraterone is being initiated in the United States and Canada. Approximately 70 sites around the United States and Canada are conducting the trial including Prostate Oncology Specialists (where I work). The eligibility criteria for men who want to participate in the trial are (1) hormone resistance, (2) a PSA greater than five, and (3) previous exposure to Taxotere therapy. This trial is designed to obtain FDA approval for Abiraterone.

The ability of Abiraterone to induce responses in Taxotere and castration-resistant men confirms recent reports that what has traditionally been called hormone resistance is really nothing of the kind. In other words, research is showing that prostate cancer cells, even the "hormone resistant" ones, still require testosterone to grow. Hormone-resistant cancer cells use two mechanisms to proliferate in the face of low blood testosterone levels. First, by synthesizing an over abundance of testosterone receptors (GCS Abstract #18), they can magnify the androgen effect of the tiny amount of residual testosterone present after castration (with Lupron or Zoladex). Or second, they obtain the necessary testosterone by manufacturing their own testosterone inside the cancer cell. The reason Abiraterone works in a hormone-resistant cell is because, unlike Lupron or Casodex, Abiraterone blocks testosterone synthesis inside the cancer cells.

These new discoveries about the root causes of hormone resistance have resurrected old and unanswered questions about whether combination hormone blockade is superior to monotherapy (Lupron plus Casodex vs. Lupron alone). This question was addressed in a Japanese study presented at the GCS (Abstract #180) where 160 men with metastatic disease were randomly allocated to treatment with either an LHRH agonist (Lupron, Trelstar, or Zoladex) or an LHRH agonist in combination with the oral antiandrogen flutamide (which is very similar to Casodex). The time to cancer progression was twice as long in the men on combination therapy and there was also a 20% improvement in survival.

The PCRI has previously reported in the medical journal Urology that Proscar, a 5 alpha-reductase inhibitor prolongs the holiday time between cycles of hormone therapy in men with newly-diagnosed or relapsed cancer. A group in Italy is reporting a similar beneficial effect with the use of a Cox-2 inhibitor Etoricoxib in men with relapsed disease. (A comparable Cox-2 inhibitor on the market in the United States is Celebrex.) This finding (AUA Abstract 1445) confirms the results of previously published studies demonstrating an inhibitory effect on the rate of PSA rise using Celebrex in men who have a rising PSA after surgery.

Dutasteride is a new 5-alpha reductase inhibitor that may be more potent than finasteride (Proscar). Like Proscar, Avodart is approved by the FDA for the treatment of urinary problems in men with benignly enlarged prostate glands. In this study, twenty-four men with prostate cancer and a rising PSA after surgery were treated with 0.5 mg of Avodart daily. The average starting PSA was 4.2. Ten of the 24 men (42%) had a greater than 50% decline in PSA. A decrease in PSA (but less than a 50% decline) was seen in an additional six men (24%). There were essentially no side effects other than a rash in one man (AUA Abstract 514).

Even though this study indicated a reduced incidence of heart attacks, hormone therapy should be used with greater caution in men with obesity and diabetes. While on therapy, men need to be monitored for increases in blood sugar, weight, or blood pressure so that timely countermeasures can be implemented.

Continuing on the subject of heart attacks in men with prostate cancer, Dr. Fang presented convincing data from Iceland that simply being informed that you have prostate cancer increases the risk of heart attack by a factor of 10 during the first week after initial diagnosis (Abstract #12). These findings further emphasize the need for appropriate counseling of men before a prostate biopsy to defuse the prevailing wrong belief that a prostate cancer diagnosis is a death sentence. Remember, studies have unequivocally established that the chance for a positive biopsy showing cancer is about one in four â€“ even in men with normal PSA levels and no symptoms. Unfortunately many ill-informed, newly-diagnosed men believe that prostate cancer, like colon cancer or lung cancer, is imminently life-threatening. The excessive and inappropriate fear engendered by this typically low-grade disease is further emphasized in another study by Dr. Fang (Abstract #104) that showed suicide risk increased 22 fold during the week after the initial diagnosis of prostate cancer. The men at highest risk for suicide were younger (less than 65), had a lower education level, and were without a partner (single, widowed or divorced).

It is hoped that new data will help reduce the exaggerated fears of imminent death. A study from the Mayo Clinic involved 1500 men with high-risk prostate cancer who were treated with radical prostatectomy. The study showed that the mortality rate from prostate cancer ten years after diagnosis was only 5%. (AUA Abstract 1618). High risk was defined as a PSA over 20, a Gleason score of 8-10, or a large cancerous mass in the prostate. Other studies reported in reputable journals (such as the Journal of Clinical Oncology Vol. 23 page 441) have indicated that in men with low or intermediate-risk prostate cancer, the ten-year cancer-specific mortality is zero percent.

Over a million prostate biopsies are performed annually in the United States looking for prostate cancer. About two-thirds of prostate biopsies are negative, causing substantial amounts of unnecessary discomfort, inconvenience and cost. One-to-two percent of biopsies cause serious bleeding or infections. PSA is the main indicator used to monitor for underlying prostate cancer. The problem is that PSA can be elevated in men with non-malignant conditions such as benign prostatic hypertrophy. PCA-3 is an FDA-approved urine test that is not influenced at all by the size of the prostate gland. Research from the AUA (Abstract 2046) indicates that PCA-3 is approximately twice as accurate as PSA for determining whether or not underlying cancer is present.

Another tumor marker, EPCA-2, made the news last year with claims of being more than 90% accurate for detecting the presence of underlying prostate cancer. A follow-up study using a slight variation on the same test seems to confirm the initial results reported last year (AUA Abstract 2044). It is to be hoped that this very accurate test will get rapid FDA approval. Last year EPCA-2 was reported to be so accurate it could even tell the difference between organ-confined prostate cancer and extra-capsular prostate cancer.

AUA Abstract 192 reports that 471 men who underwent radical prostatectomy and had baseline cholesterol levels done prior to surgery were evaluated for their risk of cancer relapse. Men who had cholesterol levels in the top 25% (cholesterol >217) had a risk of relapse that was two-and-a-half times higher than that of the men with cholesterol levels in the lowest 25% (cholesterol <167). These findings remained predictive, even after compensating for the impact of other significant factors like body mass index, age, PSA, and surgical stage.

Men undergoing prostate surgery frequently have positive margins (indicating that while endeavoring to remove the prostate, the surgeon cut through cancer, leaving some cancer behind). Recently published studies demonstrate that immediate radiation sharply reduces relapse rates in such men. However, since not all men with positive margins relapse, it is not desirable to do immediate preventative radiation in everyone because radiation increases the risk of impotence and/or incontinence.

Dr. Peter Carroll and the researchers from University of California, San Francisco studied 402 surgically treated men with low intermediate and high-risk prostate cancer (AUA Abstract 154). They found that the five-year relapse rates were dramatically lower for men with an undetectable PSA from one-to-three months after surgery. Most importantly, positive or negative margin status did not significantly impact relapse rates when ultrasensitive PSA levels were taken into account. In men with undetectable PSA levels one-to-three months after surgery, the average cure rate for men with negative margins was 91%. Most remarkable was that with undetectable PSA after surgery, the average cure rate with positive margins was 94%! The rate of relapse based on risk category is presented in Table 1. These findings suggest that men with positive margins after surgery and an undetectable PSA may be able to safely forgo immediate radiation while those with detectable PSA should receive immediate therapy (the type of radiation to be used - fossa alone; fossa plus pelvic; or fossa, plus pelvic, plus hormone therapy - is an important but unanswered question). The technology for delivering pelvic radiation is also rapidly progressing.

Risk	Undetectable PSA	Detectable PSA
Low	96%	60%
Intermediate	93%	44%
High	90%	56%

Table 1. Average Cure Rates Five Years after Surgery

Radiation technology over the last ten years has advanced faster than any other field in prostate cancer. Intensity Modulated Radiation Therapy (IMRT) dramatically improves cure rates compared to older radiation technologies while at the same time sharply reducing the dreaded possibility of a rectal burn. These improvements occur because IMRT conforms accurately to curved targets (such as prostates) thus minimizing radiation exposure to the sensitive surrounding structures like the bladder and rectum. In selected men with high-risk prostate cancer, extending the radiation field to cover the pelvic lymph nodes can reduce relapse rates by 20% (Journal of Clinical Oncology Vol. 21 page 1904).

However, the old-style radiation used in Dr. Mack Roach's study induces irreversible bowel damage about 5% of the time. Though there are no studies to prove it, most experts believe that the risk of bowel damage can be substantially reduced with IMRT because IMRT can curve around the lymph nodes and miss the intestines. Very recently, one eminent radiation therapist, Dr. Colleen Lawton, convened a conference of ten major radiation centers to hammer out a consensus on the optimal method for administering pelvic lymph node radiation with IMRT (GCS Abstract #6). The details of this suggested approach are published on the American Society of Therapeutic Radiation Oncology (ASTRO) website.

Another abstract from this year's AUA highlights an additional potential risk of radiation (beside bowel problems) - the development of secondary cancers (AUA abstract #318). In this study, they found a three-fold higher incidence of bladder cancer and a 1.7 times higher risk of rectal cancer in men previously treated with radiation. Clearly, the risk of secondary cancers needs to be factored into the decision-making process when selecting treatment.

Avastin is a FDA approved angiogenesis inhibitor for the treatment of colon cancer. A large phase III trial is in progress comparing Taxotere alone to Taxotere plus Avastin. If, when this trial is completed, it demonstrates improved survival with the combination of Avastin plus Taxotere, the FDA will approve Avastin for use in prostate cancer.

Last year Dr. William Figg from the NCI reported stellar anti-cancer results in a pilot trial of Avastin combined with Taxotere and Thalidomide, which is another angiogenesis inhibitor. This year, Dr. Figg has updated his findings, reporting on 55 men with a very aggressive type of prostate cancer (The Baseline PSA was 99 and the PSA doubling time was 1.6 months). Forty-eight of these men (87%) responded to the combination of these three drugs. Forty of these men (72%) had more than an 80% decline in PSA. Only two of the 55 patients failed to have some degree of PSA decline. The average time to progression in this group of men who had a very severe type of prostate cancer was 18 months! However, 5-10% of this group suffered significant side effects including fevers, fainting, blood clots and fistulas (GCS Abstract 164)

It is believed that inhibiting a cell receptor called endothelin can reduce cancer proliferation and cancer invasiveness. Abbott Laboratories spent tens of millions of dollars evaluating an endothelin antagonist called Xinlay. The drug had activity, but it failed in FDA review due to problems with design of their research study. At the GCS, AstraZeneca released preliminary data on the results of a 312-patient study of ZD 4054, another agent that blocks endothelin (Abstract 7). Men treated with ZD 4054 lived 40% longer compared to men treated with placebo. Side effects were similar to what was reported with Xinlay: headaches, runny nose and ankle swelling.

Single-agent Taxotere has become the standard treatment for men with hormone resistant prostate cancer. But what should be the next step if Taxotere is not working? At Prostate Oncology Specialists, we are seeing good results with combinations of Taxol and Carboplatin or with medications such as Avastin or Xeloda used in combination with Taxotere. A research institute in Houston, however, has suggested that a combination of three drugs (Novantrone, Ketoconazole and Leukine) is quite active. (Actually, Dr. Eric Small from UCSF has already reported favorable responses with the combination of Ketoconazole and Leukine at a previous meeting.) In any case, in the Houston study of 25 men treated with all three drug (GCS Abstract 174), 15 had more than a 50% decline in PSA, and 20% had greater than a 90% decrease. Low white blood cell counts and low platelet counts were the most common side effects.

PRX 302 is a potent cellular toxin that has been genetically altered so that it attacks PSA producing cells. It is hoped that when this drug is injected into the prostate, it will have a potent anticancer effect without damaging important structures like the bladder and rectum. In a multi-center study presented at the GCS, men with recurrent cancer in their prostates after radiation, a notoriously difficult condition to treat, were given injections of PRX 302 directly into their prostate glands (Abstract 136). Twenty-four men were treated. No side effects were noted. PSA levels declined in 15 of the men (63%), and repeat prostate biopsies improved in 18 men (75%). These results are very preliminary but the lack of any side effects offers hope that PRX 302 may have a future not only in relapsed disease but also in men with early stage disease that has never been treated.

A monoclonal antibody that targets the PSMA surface receptor by carrying a highly radioactive Lutetium molecule to latch on to the surface of the cancer cell has been in development for several years. Dr. Neil Bander, a prime mover in this field, performed a dose-finding study in 32 patients. More than half of the patients had been previously treated with Taxotere and had become resistant. Eighteen patients (57%) responded to the radioactively tagged PSMA antibody when it was used at the higher dose level. The main side effect of the treatment was low platelet counts requiring platelet transfusions in nine of the 32 patients. The researchers feel that the treatment would be more effective and less toxic in men with less advanced disease and are planning further studies (AUA Abstract 724).

Obviously this article only touches upon all the ongoing research that was presented at these three meetings. There were many more fascinating abstracts about scientific endeavors that are at an earlier stage of development. There were also numerous abstracts presenting small but important refinements of previously known technologies. Fortunately, we see bigger and better breakthroughs every year that goes by. We expect this pattern of accelerating technological progress to continue for the foreseeable future.