No abstract

No abstract

No abstract

15514 Introduction: Sunitinib is a tyrosine kinase inhibitor with activity against VEGFR and PDGFR recently approved by the FDA for the treatment of advanced renal cell carcinoma (RCC). There is no existing literature that details complete responses (CRs) in patients taking sunitinib for metastatic RCC. Methods: Seventy-four patients with metastatic RCC receiving sunitinib at the Cleveland Clinic Taussig Cancer Center on clinical trials were reviewed to determine the number of patients with RECIST-defined CRs. Additionally, patients who achieved near-CRs defined as a greater than 90% reduction in composite tumor volume or residual disease of less than or equal to 1 cm were reviewed. Results: Two patients (2.7%) achieved a RECIST-defined CR lasting >15 months. The patients who obtained CRs had non-bulky pulmonary metastases, favorable or intermediate MSKCC risk profiles, were treated with sunitinib in the first-line setting and had a significant reduction in composite tumor measurements within the first two cycles. An additional 2 patients achieved near-CRs, including one patient that previously progressed on bevacizumab. These 2 near-CR patients remain progression-free for more than 19 months. Finally, 1 patient achieved sufficient downstaging and reduction of tumor volume such that the remaining lesion could be excised, resulting in a surgical CR. This patient is currently off sunitinib and remains progression-free 4 months after surgery. Conclusion: Sunitinib is capable of producing durable CRs in cytokine-naïve metastatic RCC patients with non-bulky pulmonary metastases. Additionally, near-CRs can be seen despite non-pulmonary metastatic sites and prior VEGF-targeted therapy. No significant financial relationships to disclose.

Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Despite the increased survival benefits of these agents, resistance normally occurs and the disease transitions to its lethal form. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations and increased ratio of active to inactive glucocorticoids. We measured cortisol and cortisol/cortisone ratio (substrate/product of 11β-HSD2) in serum using mass spectrometry before and 1 month on-treatment in 3 clinical trials: 1) neoadjuvant apalutamide + leuprolide (n=25) 2) enzalutamide +/- PROSTVAC for metastatic castration-resistant prostate cancer (n=54) and 3) enzalutamide +/- PROSTVAC for non-metastatic castration-sensitive prostate cancer (n=38 patients). Progression-free survival (PFS) was determined in the metastatic CRPC study of enzalutamide +/- PROSTVAC for those with glucocorticoid changes above and below the median. A statistically significant rise in cortisol concentration and cortisol/cortisone ratio with AR antagonist treatment occurred uniformly across all 3 clinical trials. For example, a rise in cortisol/cortisone ratio occurred in 23/25 (92%) patients (p < 0.001), 36/54 (67%) patients (p < 0.001), and 30/38 (79%) patients (p = 0.051), in the 3 respective trials. In the trial of enzalutamide +/- PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved PSA progression-free survival and radiographic progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed. In conclusion, treatment with enzalutamide or apalutamide increases systemic exposure to active glucocorticoids. These findings have potential consequences for immune suppression and the efficacy of treatment combinations using next-generation AR antagonists. On-treatment, glucocorticoid changes might serve as a pharmacodynamic biomarker.