We have previously reported the results of the first stage of this phase II trial of sorafenib [6
] in metastatic castration resistant prostate cancer. Of the 22 patients in the first stage, 13 patients progressed by PSA alone and of all patients with bony lesions, only 4 had progressive disease. In vitro
experiments showed that sorafenib treatment in LNCaP prostate cancer cell lines showed growth inhibition but increased cumulative PSA secretion over time. The observed discordance between the PSA increase and improvement in bone scans brought about a protocol amendment that resulted in further accrual of the trial to investigate the effect of targeting the Ras/Raf/Extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling pathway and vascular endothelial growth factor (VEGF) in metastatic CRPC.
Indeed, the interpretation of post-therapy PSA changes as a measure of response in the era of targeted agents is of unclear clinical significance, especially since noncytotoxic agents may modulate PSA secretion independent of its activity on tumor suppression [10
]. Two other clinical studies using sorafenib for prostate cancer has shown similar results with sorafenib exhibiting limited activity using PSA-defined criteria for progression [11
]. In the first study, the primary endpoint of progression-free survival of ≥ 12 weeks using sorafenib was achieved with 4 of 55 evaluable patients achieving SD by RECIST criteria, 2 patients with PSA response, and 11 patients with stable PSA [11
], while a 3.8% PSA response was seen in the study by Chi et. al. [12
], thereby not meeting the primary end point of > 20% possibility of a PSA response as defined by 50% decline in ≥ 4 weeks. The conclusion for both of these trials, including our previous published first stage, was that while sorafenib did exhibit some activity in prostate cancer, PSA was not a reliable marker for disease progression. However, no reliable surrogate marker has yet been established. Analysis of phospho-ERK levels did not show a correlative reduction in the obtained samples of patients treated with sorafenib [6
]. Therefore, subsequent bone marrow biopsies were not performed. Of note, the two previous clinical studies using sorafenib enrolled patients who were chemotherapy-naïve [11
]. In comparison, the majority of patients in the second stage of this trial had prior docetaxel (21 of 24 patients) since the accrual began in January 2006, long after docetaxel and prednisone had become standard of care [13
Second line treatment after docetaxel failure has been studied using several agents including mitoxantrone [14
], ixabepilone [15
], carboplatin [16
], and satraplatin [17
], with reported median overall survival using these agents in the range of 9.8 months to 17 months. The median overall survival for sorafenib is 18.3 months in this study, comparable to other 2nd
line cytotoxic regimens. In addition, there was one PR and 10 patients with SD. The modest activity seen warrants further study of sorafenib, perhaps in the docetaxel-failure population.
Sorafenib is fairly well tolerated, although an increase in patients who had to discontinue treatment in the second stage compared to the first stage was noted. More patients experienced hand-foot skin reaction (HFSR) with Grade 3 toxicity occurring in 3 patients and Grade 2 toxicity in 9 patients in contrast to the first stage in which only one patient each developed Grade 2 and 3 HFSR. Further explorations of risk factors associated with the dermatologic toxicities are reported elsewhere (personal communication). Although high variability was observed in rate and extent of sorafenib absorption for the second stage of this trial, this was consistent with the first stage and other reported pharmacokinetics trials [18
] where geometric mean on exposure and Cmax
ranges from 9.76–71.7 hr*mg/L and 1.28–9.35 mg/L, respectively and the corresponding % CV ranges from 43–90% and 44–106%. The variability in exposure and Cmax does not account for the higher frequency of HFSR observed in the second stage. Exploration of covariate factors that might explain variability in individual response or toxicity to sorafenib is ongoing. One possible example of sources of variability is polymorphism in UGT1A9 enzyme which may influence the sorafenib blood levels by altering its elimination. In the current analysis, the patient with UGT1A9*3/*3 polymorphism (only 1) had significantly higher exposure and was the only patient who had grade 3 skin rash/desquamation toxicity.