Last October at the European Cancer Congress 2013 there was a release of data from a phase 3 study of Ipilimumab (CA 184-043) that showed that it might be effective in treating castration-resistant prostate cancer in men who have a low burden of disease; however it failed to show at the required 95% confidence level required for FDA approval that it was a generally effective treatment for prostate cancer.
Ipilimumab (Ipi or Yervoy) is already approved and commonly used for the treatment of Melanoma. Ipi is an immune therapy that differs in its mode of action from the already approved immunologic therapy Provenge (approved for the treatment of prostate cancer). Provenge sensitizes the immune system to fight prostate cancer by training the immune system to recognize cancer cells while Ipi removes the breaks on the immune system allowing it to generally attack the cancer.
The reported data was derived from the CA 184-043 trial, a Phase 3, multicenter, randomized, double blind trial of 799 men with castration-resistant prostate cancer treated with ipilimumab or placebo after docetaxel and a single radiation dose (8 Gy). The subject men had to have one or more symptomatic bone metastases that could be irradiated with a single dose of radiotherapy (8 Gy).
After the irradiation, 399 of the men were randomized to receive ipilimumab at an intravenously infused dose of 10 mg/kg on weeks 1, 4, 7 and 10, and then every 12 weeks until progression or intolerable toxicity. Four hundred (400) men were also randomized to receive a matching placebo.
An actual review of the final data showed a failure:
1- Median overall survival was 11.2 months in men treated with ipilimumab and 10 months for men in the placebo group (hazard ratio [HR] = 0.85, P = .0053)
2- Overall survival rates of 47% and 40% at 1 year, and 26% and 15% at 2 years.
However, a break down of the data into subgroups tells a different story and a more interesting story.
In men whose disease progressed within 6 months of having chemotherapy (docetaxel), the primary endpoint of overall survival just missed reaching statistical significance in the CA184-043 trial at a median of 11.2 months in men treated with Ipi and of 10 months for those given placebo (hazard ratio [HR] = 0.85, P = .0053).
Overall survival at 1 year was 47% and 40% in each group, respectively, and 26% and 15% at 2 years.
Men without visceral metastases were more likely to benefit than were those with visceral metastases, reported Dr. Winald Gerritsen of Radboud University Medical Center in Nijmegen, the Netherlands. The HR for overall survival according to the absence or presence of visceral metastases was 0.73.
They also reported that the overall survival was better with Ipi in men with an ECOG performance status of 0 rather than 1 (HR = 0.72), alkaline phosphatase levels less than 1.5 times the upper limit of normal rather than higher (HR = 0.78), hemoglobin levels of 11 g/dL rather than lower values (0.79), and normal rather than elevated lactate dehydrogenase levels (HR = 0.82).
In other words analysis showed a greater overall survival benefit for immunotherapy with Ipi in men with a better prognostic profile, based on alkaline phosphatase level, hemoglobin level, and the absence of visceral metastases. Overall survival was 22.7 months in these men and 15.8 months for men in the placebo group (HR = 0.62). This translates into a better survival advantage for men at an earlier disease stage, not dissimilar to our findings with Provenge.
Progression-free survival was also significantly improved at 4 months for ipilimumab therapy and 3 months for placebo (HR = 0.70; P less than .0001). Further, a higher percentage of men had a prostate-specific antigen response if they were given the immunotherapy with Ipi (13.1% vs. 5.3%).
Unfortunately, this really should not have come as a surprise. Immune therapy belongs in the early disease stages and needs to be evaluated at earlier disease stages. Why would there be any difference with Ipi? Why did we lose this drug, or at least delay its availability to men with prostate cancer given our universal understanding about using immune therapy in earlier disease stages. Why was Ipi tested in the post-chemotherapy stage of the disease?
We should be using the knowledge we already have and make better trials that will reflect what we know. If we have a reasonable belief that a drug will be more effective at a certain disease stage lets test it there and then worry about evaluating it at other disease stages.
Does this make sense, what do you think?
Joel T. Nowak, M.A., M.S.W.
On March 4th I wrote a post which included a suggestion that combining Provenge and the clinical trial of Prostvac-VF might provide an interesting one-two punch against advanced prostate cancer. In the post I suggested that it could be interesting to have Provenge and then move immediately on to Prostvac.
This was an error, I reversed the suggested order and instead should have recommended that first you enter the Prostvac trial and then upon its completion take Provenge.
Why these important changes in the sequencing order? Simple, to qualify for the Prostvac trial you must be Provenge naïve (never had Provenge). Taking Provenge first will disqualify you from entering the Prostvac trial.
Bottom line, talk with your doctor about trying this one two attack on your cancer, but make sure you start with the clinical trial with Prostvac then moving immediately to Provenge. Learn more about the Prostvac trial at: www.clinicaltrials.gov and search for Prostvac.
Remember, Prostvac is an investigation treatment in clinical trial.
Joel T. Nowak, M.A., M.S.W.
Over the last several years’ prostate cancer treatment options for men with advanced prostate cancer has gone from rags to riches. We now have multiple options for treatment and there is every indication that the number of options will continue to grow.
However, we do see that not all men will respond to all treatments. Given that all of these treatments are very costly and all come with the promise of significant side effects it would be beneficial to be able to know in advanced without having to administer a treatment if a particular treatment will actual benefit a man.
“Enzalutamide (Xtandi) has been hailed as a miracle drug for many patients with advanced prostate cancer, but a significant proportion of men do not receive any clinical benefit from this agent,” said Emmanuel Antonarakis, M.D., an assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore. “Our data show that AR-V7 seems to predict resistance to enzalutamide in virtually all cases. These findings are clinically relevant and could save patients time and money because oncologists could identify those men that are unlikely to respond to enzalutamide before they receive it and direct them to alternative therapies.”
According to research conducted by Dr. Antonarakis, men with metastatic, castration-resistant prostate cancer who started treatment with enzalutamide and had a molecule called AR-V7 present in their circulating tumor cells (CTCs) prior to starting treatment had a worse response to The enzalutamide compared with those who had no detectable AR-V7. These results were presented at the AACR Annual Meeting 2014 where I was in attendance, thus I have not had the opportunity to post over the last week.
According to Antonarakis and many others our hormones (androgens), such as testosterone, are the main drivers of prostate cancer. These androgens work by binding to a protein called the androgen receptor (AR), which then attaches to certain regions of the DNA of the prostate cancer cell, fueling its growth and division. This AR-V7 protein in question is a shortened form of the AR protein. It is missing the part of AR that testosterone binds, which is the same part that enzalutamide binds, but it can still attach to DNA and fuel cell growth and division, even when testosterone is not bound to it.
This was a small study enrolling only 31 men with metastatic, castration-resistant prostate cancer who were about to begin enzalutamide treatment. Blood samples were obtained from each man prior to starting treatment with enzalutamide, at the time of the man’s maximum response to treatment, and at the time of disease progression. CTCs were isolated from blood samples and analyzed for the presence of AR-V7 mRNA, an intermediate between the AR gene and the AR-V7 protein.
The researchers found that 12 of the 31 men had AR-V7 mRNA detectable in CTCs obtained prior to the start of enzalutamide treatment. These AR-V7-positive men had worse responses to enzalutamide compared with men who had no AR-V7 mRNA detected in CTCs.
Levels of prostate-specific antigen (PSA), a measure of prostate cancer disease activity, failed to drop in the blood of all 12 AR-V7-positive men, whereas PSA levels dropped by 50 percent or more in 10 of the 19 AR-V7-negative men.
They also found that AR-V7 positive men also had their disease progress sooner (as assessed by bone scan or computed tomography) compared with those who were AR-V7-negative: Time to radiographic progression was 2.1 months compared with 6.1 months.
Antonarakis also said “Before we can conduct the large-scale prospective trials needed to verify our results, we need to have the test that we used to detect AR-V7 mRNA in CTCs certified in a Clinical Laboratory Improvement Amendments (CLIA) setting to ensure the necessary quality control. We are currently in the process of doing this and we hope that things will run smoothly so we can continue to move forward.”
He also added that, “We are also conducting a small study to see whether AR-V7 might predict resistance to another AR-targeted therapy, abiraterone [Zytiga] ….We hope to be able to present the results from that study later this year.”
Joel T Nowak, M.A., M.S.W.
Today, Malecare posted our latest teleconference with Dr. Neal Shore, M.D. The conference, which was recorded last week, is about Bone Health and Prostate Cancer. It discusses the importance of maintaining healthy bones and methods to accomplish this task when facing advanced prostate cancer. This teleconference was made possible by the generous support of Bayer.
This teleconference joins the following, all of which are available to listen to and to read the transcript:
1- New Prostate Cancer Tests with Drs. Daniel Lieber and Steve Hershman. The teleconference explored the current state of affairs of genetic testing and prostate cancer.
2- All About New Options for Men with Advanced Prostate Cancer with Dr. James Gulley from the National Cancer Institute (NCI). Dr. Gulley talked about advanced prostate cancer treatments, immunotherapy and clinical trials.
3- All About Provenge was discussed by Dr. Neal Shore. Provenge, the only approved immunotherapy to treat advanced prostate cancer.
4- Dr. James McKiernan provided us with a general conversation abour advanced prostate cancer.
All of these teleconferences are available for you to listen and to read their transcript at: www.malecare.org/teleconferences
Joel T. Nowak, M.A., M.S.W.