GU Cancers 2019 | Cabozantinib plus docetaxel and prednisone in mCRPC

Our trial looked at the addition of cabozantinib in addition to docetaxel and prednisone for the treatment of patients with metastatic castrate resistant prostate cancer. I’m sure as you know the overall survival of patients treated with those attacks on docetaxelin and prednisone is around a year and a half. So there’s definitely room to improve upon that and one strategy is to do that would be to use combination-based treatments so the drug that we investigated I think was cabozantinib which is a small molecule inhibitor of Met, VEGF, AXL and RET and it’s been shown in two Phase 3 clinical trials to have some clinical efficacy in prostate cancer with CTC conversion improvement in bone scan response. So, this is why we decided to add it to the backbone of docetaxel and prednisone which is the standard treatment for patients with metastatic castrate business and prostate cancer.

So, our study was divided into two phases. There was a Phase 1 portion and Phase 2 portion. So, in the Phase 1 portion we enrolled 19 patients and we determined that the maximum tolerated dose of cabozantinib when used in combination with docetaxel and prednisone is 40 milligrams daily. And the Phase 2 portion of the study we enrolled 25 patients. They were randomized in a 1 to 1 ratio to receive either cabozantinib with Docetaxel and prednisone Nissen or C plus DP or to the other group which was docetaxel and prednisone alone which was DP. So essentially both groups received docetaxel and prednisone docetaxel was given at a dose of 75 milligrams per meter squared on day one of a 21-day cycle prednisone was given at a dose of five milligrams twice a day and cabozantinib in the group that received the combination treatment was given at 40 milligrams daily.

So the baseline characteristics of the two groups were fairly balanced with the exception of baseline PSA it was slightly higher and patients who received docetaxel and prednisone alone at 309 versus 63 in patients who received the combination of c plus DP. So, this is just something that needs to be kept in mind when interpreting the data.

As far as the results we found that the combination group C plus DP had significantly higher PSA response rates as well as time to progression. So when we looked at PSA 50 or the proportion of patients who obtained a PSA reduction of greater than 50 percent this was higher in the C plus the DP group at 54 percent versus only 17 percent and those who received DP alone. When we looked at time to progression this was significantly longer as well in patients who received the combination C plus DP at 21 months versus 6.6 Months and patients who received DP alone. And this was significant to the p value of 0.35. Overall survival even though it was numerically higher and patients who received the combination at 23.8 Months it wasn’t statistically significantly longer than the other group of DP who had an overall survival of about 15.6 Months.

With the addition of any treatment we worry about increased adverse effects and tolerability. And so we did find that in the combination group C plus DP there was a significantly higher risk of grade three and four adverse events which remain the neutropenia, leukopenia, some mucocytis and hand and foot syndrome as well. When we look at the needs to discontinue or dose reduced therapy, we see that around 70 percent of patients in the combination group C plus DB had to have a dose reduction of their cabozantinib and about 30 percent of patients we had to discontinue the cabozantinib permanently, a median of about five cycles after the start of therapy. So essentially the conclusions of this study was that the addition of cabozantinib to those stats on prednisone is associated with a superior PSA response as well as time to progression. However, in our study at least it hasn’t panned out as far as overall survival yet and so we think that there needs to be additional study to further confirm this benefit in this patient population.