Cabozantinib Prostate Cancer Bone Scans – Part 2 of an interview with Dr Maha Hussain
This is part 2 of my interview with Dr Maha Hussain, Professor of Medical Oncology at the University of Michigan. You can read part 1 about cabozantinib and pain here.
At the 2011 ASCO annual meeting, Dr Hussain presented data from a non-randomized phase 2 trial with cabozantinib that showed dramatic improvements in bone scans before and after treatment.
Bones are living tissues that are constantly being remade, a dynamic process that involves formation of new bone and taking up of old bone, a process known as bone resorption. Cancer cells can interfere with bone remodeling, resulting in increased new bone formation (osteoblastic response) or excessive bone resorption (osteoclastic response).
Bone scans involve the injection of radioactive tracers such as technetium-99m-MDP. In simple terms, the radioactive material detects bone turnover and areas of high bone metabolism. These show up as darker “hot spots” where the tracers accumulate.
Bone scans have poor specificity because tumors, fractures and infection all lead to hot spots. Also, not all tumors or lesions are detected by a bone scan. Bone scans have a sensitivity of around 62-89%.
At the 2011 Society for Translational Oncology Prostate Cancer Symposium, Professor Johann de Bono (The Institute for Cancer Research) noted that bone scans do not accurately reflect the activity of the disease in men with prostate cancer.
This raises the question as to what we should conclude from the bone scans seen with cabozantinib. I put this question to Professor Hussain.
BSB: What is the significance of the bone scans that we see and what should we interpret from them given that bone scans don’t accurately reflect the disease?
Dr Hussain: I will refer you back to my presentation at ASCO originally and my recent AACR presentation.
I have specifically put a slide (together) to address, is what we are seeing a fluke, a function of a technique issue because you are targeting the osteoblasts? Consequently if you inhibit osteoblastic function, you are not going to see much changes on the scan, or is there more too it?
The specific slide actually puts in columns the (percentage of) patients who had a partial or a complete resolution on the bone scan, versus those who had stable or progressive disease, and then matches it with other evidence of an anti-tumor effect as in target lesion regressions, progression free survival at I think the 6 month mark if I recall correctly, as in the pain improvement, narcotic use.
Recognizing that by the way the pain and narcotic use, both of these were post-hoc assessments that were done. Once we saw the observation, the sponsor went back and began asking all the investigators to record these things. Clearly, the ALK phosph going down, the bone turnover markers going down.
Dr Hussain’s conclusion is interesting from a marketing strategy perspective. She does not position cabozantinib as a bone targeted drug such as Xgeva or a bone targeted radiopharmaceutical such as Alpharadin. Instead, her view is that cabozantinib should be developed as a “prostate cancer specific drug that does have the added advantage of significant anti-tumor effect in the bone” ie an anti-cancer tyrosine kinase inhibitor (TKI).
This is at odds with how Exelixis appear to be positioning it. The corporate presentation at the Cowen Annual Healthcare Conference on March 6, 2012 had a strong focus on bone metastases: “Cabozantinib demonstrates unique ability to resolve bone metastases and decrease bone pain in CRPC,” one slide said.
If Dr Hussain is correct and we should consider cabozantinib as a prostate cancer specific drug, then it will need to compete on endpoints with other drugs that have shown an impact on overall survival.
Cabozantinib will likely not obtain regulatory approval on the basis of the bone scans, whatever they may show.
Without demonstrating a significant effect on overall survival, it’s hard to believe that cabozantinib will be able to compete effectively in what is fast becoming a very competitive prostate cancer market.
The final installment of the Biotech Strategy Blog interview with Dr Hussain will cover her perspective on the mechanism of action of cabozantinb, and where the drug, theoretically, might be expected to have most impact in prostate cancer.
One Response to “Cabozantinib Prostate Cancer Bone Scans – Part 2 of an interview with Dr Maha Hussain”
Interesting interview! I think the recent paper that came out in Cancer Discvery that PSB summarized, indeed suggests that cabo also has cell-autonomous effects on cancer growth. It was interesting that the paper also showed cabo could inhibit liver mets in their mouse model, suggesting that the anti-metastatic effect is not solely due to effects on bone metabolism, but might also have direct effects on the cancer cell. Exelixis probably hurt themselves slightly by focusing so much on the anti-bone effect, and with comparisons to Xgeva, people are skeptical the drug will have any PFS/OS benefit.
I’m a little confused by the graph that is attempting to make a correlation between bone scan and other clinical effects—yellow and grey bars don’t add up to 100% (shouldn’t they). And wouldn’t also be informative (and make the point) by comparing to ‘negative’ clinical effects too? (ie. no lesion regression/PFS/pain improvement, etc.)
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