Prostate Cancer: New MET, VEGFR Inhibitor Produces Impressive Response in Bone

Chemotherapy Foundation SymposiumNEW YORK CITY—A remarkable response seen in bone scans of men with prostate cancer after treatment with cabozantinib (XL184), a tyrosine kinase inhibitor that blocks MET and VEGFR in vivo, was a highlight of the prostate cancer session at the Chemotherapy Foundation Symposium here. Bone metastases, the main cause of mortality in men with metastatic castration-resistant prostate cancer, are associated with high levels of MET expression, and simultaneous inhibition of MET and VEGFR may block the progression of osteolytic and osteoblastic bone lesions, said David C. Smith, MD, Professor of Medicine at the University of Michigan Comprehensive Cancer Center. Dr. Smith presented data on cabozantinib from the Phase II multi-cohort randomized discontinuation trial (XL 184-203), but first he discussed the case of the first patient treated with cabozantinib for metastatic prostate cancer. “We saw a dramatic effect, including complete resolution of bone scan uptake, a confirmed partial response by RECIST criteria, and a response indicated by both alkaline phosphatase and PSA levels.” That response led to the XL 184-203 trial, which enrolled 171 patients with multiple solid tumors. Randomization was suspended after 122 patients because of early clinical benefit. At 12 weeks there were seven partial responses, but importantly there were also 135 patients experiencing stable disease, and only 12 with progressive disease, for a “no progression” rate of 68%.WILLIAM K. OH, MD: “If those are really, truly cancer regressions, then I think this is a brand new paradigm in prostate cancer treatment and we should be prepared to see more of [cabozantinib] in the future....The caution here is that it is a sunitinib-like drug, and about half of the patients required some dose reductions. But those are some of the best bone scans some of us have seen in our whole careers.”Bone metastases, the main cause of mortality in men with metastatic castration-resistant prostate cancer, are associated with high levels of MET expression, and simultaneous inhibition of MET and VEGFR may block the progression of osteolytic and osteoblastic bone lesions, explained DAVID C. SMITH, MD, in presenting data on cabozantinib from the Phase II multi-cohort randomized XL 184-203 discontinuation trial.Among 108 patients with evaluable bone scans, there was complete resolution in 19%, partial resolution in 56%, stable disease in 21%, and progressive disease in 3%. “All in all, 98% of the men appeared to have some evidence of activity on bone scan if you included the stable disease population,” Dr. Smith said. Progression-free survival for 14 patients randomized to cabozantinib was 21 weeks, compared with only six weeks for the 17 patients receiving placebo. Dr. Smith said the agent has activity in patients whether they received prior docetaxel or not. “Clearly this is a remarkable response on the bone scans that we've never seen before – and may never see again,” said the co-moderator of the session, Anna Ferrari, MD, Professor, Department of Medicine and Co-Director of the GU Research Program at New York University School of Medicine. She asked Dr. Smith if there may have been soft tissue progression instead even as the bone involvement diminished. Dr. Smith replied that there had been no major tissue progression, and also that the bone scans showed rapid progression after the drug was stopped at 12 weeks. In an overview of the session afterwards, the other co-moderator, William K. Oh, MD, Chief of the Division of Hematology and Medical Oncology at Mount Sinai Medical Center, Associate Director for Clinical Research at Mount Sinai Tisch Cancer Institute and Professor of Medicine and Urology and the Ezra M. Greenspan, MD, Professor in Clinical Cancer Therapeutics, said he had some mechanism questions about this drug: “The caution here is that it is a sunitinib-like drug, and about half of the patients required some dose reductions. But those are some of the best bone scans some of us have seen in our whole careers.” Cabozantinib is a VEGF inhibitor and MET inhibitor, he continued, “and it seems to overcome resistance to VEGF inhibitors. It also targets the microenvironment, and we're starting to see this theme that maybe just killing cancer cells alone is not going to be enough.” The partial response rate was 4%, Dr. Oh said, but as in the case in many renal cancer studies, the majority of patients had some stabilization or shrinkage of cancer during treatment. “If those are really, truly cancer regressions, then I think this is a brand new paradigm in prostate cancer treatment and we should be prepared to see more of that drug in the future,” he said. Intermittent Androgen Deprivation Intermittent androgen deprivation should be the standard of care for most patients with PSA recurrence after radiotherapy, said another speaker, Laurence Klotz, MD, Professor of Surgery at the University of Toronto and Chief of the Division of Urology at Sunnybrook Health Sciences Center.LAURENCE KLOTZ, MD, said that intermittent androgen deprivation should now be the standard of care for most prostate cancer patients with PSA recurrence after radiotherapy. “Reduced costs, improved quality of life, and a possible benefit in bone mineral density preservation also make this treatment more appealing.”ANNA FERRARI, MD, called the bone scan response clearly remarkable.Dr. Klotz based this statement on the latest data from the large, randomized PR.7 Canadian trial of intermittent androgen deprivation versus continuous therapy in men with hormone-sensitive nonmetastatic prostate cancer. PR.7, he explained, was designed to be the pivotal trial answering the question of survival and duration of response to anti-androgen therapy. The primary endpoint was overall survival among the 1,386 patients enrolled. The trial found that intermittent treatment was not inferior to continuous therapy with respect to overall survival, and also improved the time to castration resistance. Mortality was higher in the continuous-treatment group—9% higher prostate cancer deaths and 8% higher non-prostate cancer deaths. Adverse events were similar between the two groups, although there were fewer hot flashes in the intermittent group. “Reduced costs, improved quality of life, and a possible benefit in bone mineral density preservation also make this treatment more appealing,” Dr. Klotz said, adding that the PR.7 results suggest that more potent androgen receptor-directed therapies be used during the induction period. In his overview of the session, Dr. Oh said the PR.7 study had demonstrated that “intermittent androgen deprivation is a fair, reasonable option to offer patients with a rise in PSA after localized treatment.” Patients were only on androgen deprivation therapy about 27% of the time compared with those on continuous androgen deprivation, he said: “That's a tremendous cost savings and also leads to a higher quality of life in terms of sexual function and hot flashes, with really no substantive difference in survival.”

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