MDV3100 was selected for clinical development based on potent anti-tumour effects in castration-resistant and bicalutamide-resistant xenograft models of prostate cancer. The clinical results reported here establish that MDV3100 has significant antitumor activity in men with chemotherapy-naive and chemotherapy-treated CRPC, thereby validating the preclinical models.
Antitumor effects were observed at all dosages studied, beginning with the first six patients treated at the lowest dosages, one of whom has remained on treatment for more than 2 years. In addition to substantial and sustained PSA declines, many patients had regressions of soft-tissue disease, no progression in bone disease, and prolonged times to PSA and radiographic progression. Overall, two-thirds of patients had partial remissions or stable disease in radiographically-evident soft tissue and bone lesions. The degree and proportion of patients showing PSA declines were dose-dependent from 30 mg to 150 mg/day, but reached a plateau between 150 and 240 mg/day, above which no additional antitumor effects were seen. The presentation of post-therapy PSA change data with waterfall plots (as suggested by the PCWG2 guidelines22
) rather than with discrete percent PSA decline cutoff values was particularly helpful in recognizing the plateau in the dose-response relationship.
The time to PSA progression is presented using both the protocol specified definition of a 25% rise from baseline as well as the PCWG2 definition of a confirmed 25% or greater rise from nadir.22
Use of the PCWG2 criteria is important because it provides consistency in reporting outcomes that allows for relative comparisons between different treatment approaches. As expected, the time to PSA progression using the less conservative definition allows patients a longer exposure to the drug. The role of using PSA progression criteria alone to determine the need to discontinue treatment of an anti-androgen in CRPC remains controversial, as it known that that the relationship between PSA progression and survival is modest in this setting.26
Whether continued suppression of androgen signalling with an anti-androgen that has no agonist activity is warranted in patients who have responded and are now progressing solely on the basis of a rising PSA (versus discontinuing the treatment) is unknown and will require prospective testing. The approach is consistent with standard practice to continue androgen suppression and a new therapy for men with progressive CRPC,27
and to continue trastuzumab and add a new therapy for women with progressive breast tumors.28
In addition to conventional endpoints, we explored experimental biomarkers of AR inhibition and tumour response in subsets of the patients. Notably, FDHT PET scans revealed that MDV3100 substantially displaced FDHT binding at all dosages evaluated, with an apparent maximal effect seen at 150 mg despite the higher serum MDV3100 levels achieved at higher dosages. This suggests that AR binding by MDV3100 may be saturated at serum levels of ~5-15 μg/mL, which were achieved consistently in patients receiving 150 mg/day but not at lower dosages. FDG-PET scans performed on the same 22 patients to assess early treatment response revealed declines of SUVmax of 25% or more in 45% of cases, showing that FDHT response (which occurred in essentially all patients) does not predict for FDG response, as would be expected for a pharmacodynamic biomarker.
A second early indicator of treatment efficacy was CTC number. Recent retrospective data from phase 2 clinical trials of prostate,29
and colorectal cancer31
have shown that baseline CTC number is prognostic in patients about to start a new line of chemotherapy. In a recent trial, changes in CTC counts after treatment were more predictive of survival than were changes in PSA, with a favourable CTC count post-treatment associated with a 21-month median survival.29
In this study, unfavourable counts were observed in 40% of patients at baseline including 27% of the chemotherapy-naive and 51% of the post-chemotherapy patients. Early post-treatment conversions from unfavourable to favourable were observed in 75% of chemotherapy-naïve and 37% of post-chemotherapy patients. Declines in PSA were generally associated with parallel declines (or lack of progression) in CTCs, but not universally so, suggesting that these measures assess different aspects of the malignant process. PSA declines may in some cases reflect the mechanism of action of MDV3100 as an AR antagonist rather than an actual anti-tumor effect. However, the benefit of MDV3100 on multiple assessments, including CTCs and radiologic time to progression, suggest that in fact MDV3100 does have a true anti-tumor effect.
The predominant adverse event attributable to MDV3100 was fatigue that represented a clear change from the patient's baseline. In most patients, the fatigue appeared after 4 weeks, matching the time when drug concentrations reached steady state and resolved within two to four weeks of dose reduction. Although there was no other obvious cause to the fatigue such as depression, adrenal insufficiency was not formally excluded, although the mechanism of action of the drug does not suggest adrenal insufficiency as a possible side effect. Although dosages up to 480 mg/day were tolerated for 4 weeks, we determined the maximal tolerated dose to be 240 mg/day based on the frequency of treatment discontinuations required at higher doses.
Based on the declines in PSA, regressions of soft-tissue disease, CTC conversion rates, time to progression, and the safety profile demonstrated in this phase 1-2 study, a phase 3 randomized trial has been initiated to examine MDV3100 vs. placebo in men with progressive advanced prostate cancer, with a primary endpoint of overall survival. The results of the present trial validate in man preclinical studies implicating sustained AR signaling as a driver in CRPC and establish that a substantial fraction of tumours that progress despite multiple hormonal treatments and are currently treated with chemotherapy remain dependent on AR signaling for growth. MDV3100 may have the potential to significantly alter treatment options in metastatic disease, even in the post-chemotherapy setting where hormonal manipulations may have more utility than previously thought.