ANTI-MET TREATMENT FOR BONE METASTASES FROM PROSTATE CANCER

Dramatic resolution of bone metastases occurred in 85% of patients with castration-resistant prostate cancer treated with a wide-spectrum tyrosine kinase inhibitor, according to preliminary study data.
The data, from the open label Lead-in Stage of an ongoing adaptive design phase II randomized discontinuation trial, showed that only one of 62 patients had less than stable disease in bone and soft tissue as best response to cabozantinib (XL184), said David C. Smith, MD, of the University of Michigan in Ann Arbor, and colleagues.
Bone pain and use of narcotic drugs declined, as did markers of bone turnover, investigators in the multicenter trial reported during a poster presentation at the Genitourinary Cancers Symposium here.
And, at 12 weeks of follow-up, three-fourths of the study patients had disease control, Smith and colleagues added.
As a result of the observed activity, the randomized-discontinuation phase of the trial was stopped, and data were unblinded.
Among patients randomized to placebo or to continue treatment with cabozantinib, discontinuation of active therapy was associated with rapid disease progression, Smith and colleagues reported.
Despite their preliminary nature, the team's findings created a stir at the GU cancers meeting.
"The bone scan changes are unprecedented," remarked Oliver Sartor, MD, of Tulane University in New Orleans, who was not involved in the study.
"The scans show that something quite remarkable is going on. This honestly appears to be a whole new mechanism of action," he said.
Added Celestia Higano, MD, of the University of Washington in Seattle, "I have never seen those kind of [bone] changes with any agent."
According to other investigators at the symposium, the bone effects of cabozantinib are not limited to castration-resistant prostate cancer. Benefits have also been observed in breast cancer, melanoma, thyroid cancer, and renal cell cancer.
Bone metastases in castration-resistant prostate cancer are associated with increased expression of MET, which has a key role in tumor cell survival, proliferation, invasion, and metastasis. Studies have shown that osteoblasts and osteoclasts express MET and vascular endothelial growth factor (VEGF) receptors.
Moreover, VEGF type 2 receptor (R2) acts synergistically with MET to stimulate angiogenesis.
Cabozantinib inhibits both MET and VEGFR2, which might block progression of osteolytic and osteoblastic bone lesions, Smith and colleagues noted.
Preclinical studies demonstrated that cabozantinib inhibits progression of prostate cancer xenografts in bone.
Smith's group reported findings from a trial to evaluate the effect of 12 weeks of treatment with cabozantinib, followed by randomized discontinuation, conducted among men with bone and visceral metastases from castration-resistant prostate cancer.
CT/MRI bone scans were performed at baseline and then every six weeks.
The primary endpoint was objective response at 12 weeks. Of 168 patients enrolled to date, 100 had completed 12 weeks of follow-up. Additionally, investigators examined data for 62 patients with known bone metastases and at least one bone scan after baseline.
Of the 100 evaluable patients, about half had progressed on docetaxel. Additionally, about half had visceral disease, 88% had lymph node involvement, 78% had bone metastases, 50% had significant bone pain, and 37% required narcotics for bone pain.
The investigators reported that 26 of the 100 patients dropped out before completing 12 weeks of treatment, primarily because of disease progression (10 patients) and adverse events (nine).
Smith reported that 53 of 62 (85%) patients evaluable by bone scan had complete or partial resolution of bone lesions, and eight others had stable disease. Of 43 evaluable patients with bone metastases and bone pain, 26 (60%) had improvement in pain as early as six weeks after starting cabozantinib.
Among 33 evaluation patients who required narcotics for bone pain, 21 (64%) had improvement in pain at six or 12 weeks, and 13 (46%) decreased the dosage or discontinued narcotics.
Adverse events were common, but severe events were not. The most common adverse events were fatigue (71% of patients), decreased appetite (52%), diarrhea (46%), nausea (40%), constipation (34%), dysphonia (33%), vomiting (29%), hypertension (25%), and dysgeusia (24%).
The most common grade 3+ adverse events were fatigue (15%) and hypertension (8%). Additionally, 5% of patients had severe hand-foot syndrome (19% all grades).
The substantial activity against bone metastases did not translate into similar activity against the primary tumor. Smith reported that only six of 100 patients had objective responses. However, 82 had stable disease. At 12 weeks, 74 of 100 had disease control.
Additionally, a minority of patients had a PSA response to cabozantinib.
The researchers also reported that markers of bone turnover decreased by as much as 80% at 12 weeks.
According to investigators, a nonrandomized expansion-cohort study of cabozantinib in castration-resistant prostate cancer has begun patient accrual.