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Joel
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Since it FDA approval in 2004, docetaxel (a taxane based chemotherapy) has been the standard first-line chemotherapy for men with metastatic prostate cancer (mCRPC).
Other than the trial of Provenge all the successful phase III trials conducted in mCRPC focused on men experiencing cancer progression after first-line docetaxel chemotherapy. The implication is that improving the outcome of these men was the most critical unmet need facing men with prostate cancer. Additionally, men at this stage provided an opportunity to demonstrate an overall survival improvement more rapidly over a shorter time frame.
Since the approval of docetaxel four different drugs have been shown to provide an overall survival benefit on top of other clinical improvements for men whose disease progressed after their having had docetaxel: cabazitaxel (Jevtana), abiraterone (Zytiga), radium-223 (Xofigo), and enzalutamide (Xtandi).
Prior to 2010 the best standard of care after docetaxel failure was considered another round of docetaxel a few months after the initial failure (there is no evidence that this second round provided any survival advantage). Then mitoxantrone with prednisone was used which only provided palliative benefit (no survival advantage).
Now, given the fact that they supply a survival advantage, it is clear that these other, new drugs should be the next treatment steps after docetaxel failure.
Cabazitaxel (Jevtana), which is a newly approved “second-generation” taxane was shown to improve overall survival when added to prednisone compared with mitoxantrone plus prednisone in the TROPIC trial (hazard ratio [HR] 0.72, 95% CI 0.61 to 0.84; median overall survival, 15.1 vs. 12.7 months; p < 0.0001) in 745 patients with mCRPC progressing after treatment with docetaxel. Progression-free survival (PFS) was also improved with cabazitaxel and prednisone (HR 0.75, 95% CI 0.65 to 0.87).
Additionally, preliminary data suggested that some antitumor activity from cabazitaxel remained in men whom both docetaxel and abiraterone failed, with a prostate-specific antigen (PSA) response rate of approximately 50%.
Not surprising there are now two ongoing phase III trials with the goal of evaluating the use of cabazitaxil in men with mCRPC compared with docetaxel in the first-line chemotherapy setting (FIRSTANA, NCT01308567).
There is also another large phase III trial (PEACE 2) scheduled to evaluate cabazitaxel in men with localized prostate cancer and at a very high-risk of relapse.
To date, all prior attempts to development of non-taxane chemotherapy have ended in failures.
Clearly, despite the development of new drugs to treat mCRPC, taxane based chemotherapy still has a major role in the treatment protocol. Additionally, the very real possibility is that taxane based therapy could take on an even larger role in the future.
Joel T. Nowak, M.A., M.S.W.
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Joel
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I want to share that I am hopeful that we have made progress with Bayer Healthcare and the issues I have written about surrounding the newly approved treatment for men with castrate resistant prostate cancer, Xofigo.
I have shared that they failed to support the early access trials because of what they claimed were supply problems. Now that they have been approved by the FDA these supply issues could become worse with the increase in demand for the drug.
I have also become aware of the lack of understanding by clinicians and survivors that this treatment is meant to be used along side of other treatments, not in a sequence.
The good news is that Bayer Healthcare, due to the hard work of Jan Manarite (PCRI), has agreed to starting to speaking with the advocates of the prostate cancer community about these issues and others surrounding this new treatment. They have organized a conference call for tomorrow, Friday where I am hopeful that a dialogue can start.
Our goal is simple; we want to hear solutions to the problems. We want to hear what Bayer has done to ameliorate problems and specifically what they are going to do tomorrow to get a head of the curve.
Bayer Healthcare is a great company, but it needs to understand that it has to respond to the survivor community. Bayer baby aspirin is a trusted brand, now they need to find ways of fostering trust form the adult prostate cancer community. This is a good first step, I thank Bayer for recognizing the problem and putting a step forward in building the much needed trust.
Joel T Nowak, M.A., M.S.W.
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Joel
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More great news for men with advanced prostate cancer that is castrate resistant and who also have symptomatic bone metastases and no known visceral metastatic disease. Today, Bayer HealthCare announced that the U.S. Food and Drug Administration (FDA) has approved (radium Ra 223 dichloride).
Xofigo (zo-FEE-go) is the first and only alpha particle-emitting radioactive therapeutic agent approved by the FDA that has demonstrated improvement in overall survival (OS) and delay in time to first symptomatic skeletal event (SSE) compared to placebo, as shown in their pivotal Phase III ALSYMPCA trial.
Bayer says that the commercial production of Xofigo is underway, and first doses are expected to be ready for patient treatment within a few weeks. Bayer has worldwide exclusive marketing rights for Xofigo. It looks to me that my earlier statements about the prior slow down in product availability for the early access trials was correct. However, I can only hope now that the FDA has approved Xofigo® that the product will flow easily to men in need.
Oliver Sartor, MD, North American Principal Investigator for the pivotal trial and medical director of the Tulane Cancer Center said that “Xofigo has demonstrated an antitumor effect on bone metastases and will be an important addition to the treatment of this cancer.” I cannot agree more with him.
We know that bone is the most common site in the body to be affected by metastatic prostate cancer and that bone metastases are particularly prevalent. In reality, approximately 90% of men with metastatic prostate cancer show evidence of bone metastases. Bone metastases can lead to an increase in frequency of skeletal events and are shown to be the main cause of morbidity and death in men with CRPC.
The most common (greater than or equal to 10%) adverse side effects reported from the ALSYMPCA trial were nausea, diarrhea, vomiting and peripheral edema. The most common hematologic laboratory abnormalities (greater than or equal to 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia and neutropenia.
Now we wait to see if Bayer is able to deliver the product.
Joel T Nowak, M.A., M.S.W.
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Joel
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The committee to start the early access clinical trials for drugs and treatments for men with advanced prostate cancer has been very hard at work. Based on the leadership and tenacity of Jan Manarite of the Prostate Cancer Research Institute (PCRI) we have managed to encourage, beg and cajole a number of pharmaceutical (pharma) companies to work with the FDA to provide their investigational treatment to men in serious need of them prior to receiving FDA approval.
This is done under the auspices of gathering additional data, especially safety data for the consideration of the FDA. Since it is a clinical trial and the trial uses unapproved treatments the pharmaceutical is not able to charge for the treatment or its administration.
So, why should a pharma be willing to give away for no enumeration their drug?
First, as I mentioned they will be able to gather additional data on both safety and efficacy. Secondly, they will be able to create good will among the patient and doctor communities. The third reason is that it will broaden the communities knowledge of the treatment so that the second they receive FDA approval they will already have a market penetration. Additionally, all the companies claim that they are concerned about the patients who need their treatment to survive.
Bayer Healthcare and Algeta have one drug, radium 223 dichloride, under an Early Access Program (EAP). They were very difficult when it came to our trying to obtain their cooperation in setting up trial sites. Now we have managed to get them to set up a number of sites, but they fail on a regular basis in providing adequate supply of the radium 223. Their response has been a great disappointment.
One of the men I work with has run out of treatment options, radium 223 is the only treatment left him. When rejected from the trial because of lack of supply he wrote a letter to the pharma. He received back the following answer:
Dear Mr. XXX
I am Dr. XXXX, Vice President Medical Affairs at Bayer Healthcare. I would like to thank you for your letter dated April 19,2013, directed to Algeta which has been forwarded to me.
On behalf of Algeta and Bayer, I would like to address the status of the Expanded Access Program (EAP) for our investigational product, radium 223 dichloride.
Radium 223 dichloride is currently provided to patients through several clinical trials worldwide, including a large expanded access program (EAP). However, we are experiencing high demand worldwide from patients who need treatment, and recent demand for radium 223 dichloride has exceeded the maximum production capacity of the currently available clinical supply at the production site in Norway. We are working very hard to get another line running as quickly as possible so that we can supply this demand from patients worldwide. As a result, it will be necessary during the next few weeks to limit enrollment of new patients until we can produce sufficient quantities to accommodate additional patients. We recognize that this can be upsetting to patients, their families and health care providers. Unfortunately, due to the high demand for the product, this decision was necessary to ensure that those patients already enrolled in the EAP Program and on therapy could continue to receive their required treatments.
The production of radium 223 dichloride occurs in a Norwegian facility and the current production line, designed for clinical trials, has limited capacity. Bayer and its partner Algeta have been working diligently to initiate production of radium 223 dichloride through a new, larger manufacturing line which has substantially greater capacity than the current clinical supply line. Such a manufacturing line must undergo rigorous testing and secure the necessary worldwide regulatory approvals prior to commencement of production. We are working with the authorities to do this as quickly as possible.
While the new manufacturing line is in the final stages of securing the regulatory approvals necessary to start production, Bayer and Algeta could not be assured that this would be accomplished in time to prevent a shortfall in supply if new patients were allowed to enroll into the program. Accordingly, the companies took the difficult step of limiting enrollment into the Program until the new manufacturing line is able to produce radium 223 dichloride. We understand that this would be difficult for patients; unfortunately, we felt that we had no other option. Once the new, larger manufacturing line is producing greater quantities of radium 223 dichloride, the sites will be notified immediately and enrollment will resume so that patients can receive this new therapy. Manufacturing authorization for the new production line is expected in the near future, which will enable full production in the next few weeks.
Bayer and Algeta are deeply committed to ensuring that this treatment is available to physicians and patients through the Program and we are working to resolve this matter as quickly as possible. We recognize that many patients around the world would like treatment under the EAP program and we are working hard to make this happen. We shall ask that your center contact you as soon as additional supply of radium 223 dichloride is assured.
I do hope that this information addresses the concerns that you raised. Should you have any additional questions, please feel free to contact me.
Sincerely,
XXXX XXXX, MD PhD
Vice President US Medical Affairs Specialized Therapeutics
Come on Bayer, you knew of the pent up demand. I find it hard to just accept that the demand has just overwhelmed the supply. You knew this was going to happen and you made no attempt to expand production before today.
Bayer and Algeta, we have men who need this treatment NOW. For many men this is their one and only last option. How can you tell them that they have to stand on line and wait? These men will not survive long enough to see you through your failure to produce product. This line you have created is not like standing on line waiting to get into the movies or buy the popcorn.
You are making ill will in the community and you are allowing men to die sooner than they need to die!
Joel T. Nowak, M.A., M.S.W.
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Joel
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Ra-223 (Alpharadin)is an alpha-pharmaceutical targeting bone metastases (mets) with high-energy, short-range (< 100 ?m) alpha-particles. Currently it has been submitted to the FDA for approval, which we hope will happen by August 2013.
In the phase 3, double-blind, randomized, multinational ALSYMPCA study, Ra-223 significantly improved overall survival (OS) in men with castrate resistant advanced prostate cancer (CRPC) having bone mets by a median increase of 3.6 months compared to placebo. The median OS: 14.9 vs 11.3 mo; P < 0.001; HR = 0.69; 95% CI: 0.58-0.83). An updated analysis of the SRE secondary endpoint is presented.
The men in the study men had progressive, symptomatic CRPC with
? 2 bone mets on scintigraphy (a diagnostic test used in nuclear medicine, wherein radioisotopes called radiopharmaceuticals are taken internally, and the emitted radiation is captured by external detectors (gamma cameras) to form two-dimensional images and no known visceral mets (mets in organs or soft tissue). The subjects either previously received docetaxel, or did not because they were docetaxel ineligible, or refused docetaxel. The subjects were randomized 2:1 to receive 6 injections of Ra 223 (50 kBq/kg IV) q4wk or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use.
Nine hundred and twenty one (921) men were randomized
(Ra-223, n = 614; placebo, n = 307); 40% had >20 mets.
Ra-223 significantly delayed time to first skeletal related event (SRE) versus placebo by a median increase of 5.8 months (median time to SRE: 15.6 vs 9.8 mo; P < 0.001; HR = 0.66; 95% CI: 0.52-0.83).
Ra-223 significantly delayed time to first SRE with a reduction in risk observed for all 4 SRE components. Despite the longer time at risk, Ra-223 patients had an approximately 50% reduction in risk for spinal cord compression. Ra-223 is an effective therapy with a highly favorable safety profile.
U-235 may provide a new standard of care for treatment of CRPC patients with bone mets.
Clinical trial information: NCT00699751.
J Clin Oncol 31, 2013 (suppl 6; abstr 11); Nicholas J. Vogelzang, Chris Parker, Sten Nilsson, Robert Edward Coleman, C. Gillies O’Bryan-Tear, Minghua Shan, A. Oliver Sartor; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; Karolinska University Hospital, Stockholm, Sweden; Weston Park Hospital, Sheffield, United Kingdom; Algeta ASA, Oslo, Norway; Bayer HealthCare, Montville, NJ; Tulane Cancer Center, New Orleans, LA
Joel T Nowak, M.A., M.S.W.
