Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure.

BACKGROUND: Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11ß-hydroxysteroid dehydrogenase-2 (11ß-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences. PATIENTS AND METHODS: Human kidney tissues were stained for AR and 11ß-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide ± PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide ± PROSTVAC for non-metastatic castration-sensitive prostate cancer] were analyzed for cortisol and its metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Progression-free survival was determined in the metastatic CRPC study of enzalutamide ± PROSTVAC for those with glucocorticoid changes above and below the median. RESULTS: Concurrent AR and 11ß-HSD2 expression occurs only in the kidneys of men. A statistically significant rise in cortisol concentration, cortisol/cortisone ratio and tetrahydrocortisol/tetrahydrocortisone ratio with AR antagonist treatment occurred uniformly across all three trials. In the trial of enzalutamide ± PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed. CONCLUSION: Enzalutamide and apalutamide treatment toggles renal 11ß-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.

Long-term follow-up of prostate cancer patients treated with vaccine and definitive radiation therapy.

BACKGROUND: Vaccine therapy in combination with radiation therapy may improve distant and/or local control in prostate cancer. We present long-term follow-up data on the secondary and exploratory endpoints of safety and biochemical failure, respectively, from patients with clinically localized prostate cancer treated definitively with a poxviral vector-based therapeutic vaccine combined with external beam radiation therapy (EBRT). METHODS: Thirty-six prostate cancer patients received definitive EBRT plus vaccine. A total of 18 patients were treated with adjuvant standard-dose interleukin-2 (S-IL-2) (4 MIU m(-2)) and 18 were treated with very low-dose IL-2 (M-IL-2) (0.6 MIU m(-2)). Seven patients were treated with EBRT alone. Twenty-six patients treated with EBRT plus vaccine returned for follow-up, and we reviewed the most recent labs and clinical notes of the remaining patients. RESULTS: Median follow-up for the S-IL-2, M-IL-2 and EBRT-alone groups was 98, 76 and 79 months, respectively. Actuarial 5-year PSA failure-free probability was 78%, 82% and 86% (P=0.58 overall), respectively. There were no significant differences between the actuarial overall survival and the prostate cancer-specific survival between the two vaccine arms. Of the 26 patients who returned for follow-up, Radiation Therapy Oncology Group grade ≥2 genitourinary (GU) and gastrointestinal (GI) toxicity was seen in 19% and 8%, respectively, with no difference between the arms (P=1.00 and P=0.48 for grade ≥2 GU and GI toxicity, respectively). In all, 12 patients were evaluated for PSA-specific immune responses, and 1 demonstrated a response 66 months post-enrollment. CONCLUSIONS: We demonstrate that vaccine combined with EBRT does not appear to have significant differences with regard to PSA control or late-term toxicity compared with standard treatment. We also found limited evidence of long-term immune response following vaccine therapy.

Impact of tumour volume on the potential efficacy of therapeutic vaccines.

With the recent approval by the U.S. Food and Drug Administration of the first therapeutic vaccine for cancer, the long-awaited goal of harnessing a patient's immune system to attack cancer through this modality is finally realized. However, as researchers in the field of cancer immunotherapy continue to perform randomized definitive studies, much remains to be learned about potential surrogate endpoints and appropriate patient populations for therapeutic vaccines. The present review addresses available data from clinical trials of immunotherapeutic agents relevant to the selection of appropriate patient populations. We believe that the weight of evidence supports the use of immunotherapy earlier in the disease course and in patients with less aggressive disease, and that the relevant findings have important implications for the design of clinical trials with therapeutic vaccines.

Long-term survival and PSA control with radiation and immunotherapy for node positive prostate cancer.

We describe a patient with node positive prostate cancer treated with radiation, androgen deprivation, and immunotherapy with long-term overall survival and PSA control. ELISPOT immunoassay studies demonstrated PSA specific T-cells prior to starting vaccine therapy suggesting that this positive response may be related to an improved antitumor immune response of the patient, increased immunogenicity of the tumor, or decreased activation of immune escape pathways. Further evaluation of therapeutic cancer vaccines in combination with radiation and hormonal therapy in the definitive management of prostate cancer is warranted.

A retrospective analysis of cardiovascular morbidity in metastatic hormone-refractory prostate cancer patients on high doses of the selective COX-2 inhibitor celecoxib.

This data were previously presented in February 2007 at the American Society of Clinical Oncology's Prostate Cancer Symposium in Orlando, FL, USA. COX-2 inhibition has shown promise in treating prostate cancer, but concerns exist regarding the risk profile associated with this class of drugs. This study analyzes the cardiovascular and cerebral vascular morbidity associated with high doses of the COX-2 inhibitor, celecoxib, in patients with metastatic hormone-refractory prostate cancer (mHRPC). We retrospectively reviewed 67 patients with mHRPC who were treated at our institution between 1999 and 2005. All charts were reviewed for cardiac risk factors and the clinical course whilst on therapy and post-treatment was analyzed. This study included 34 patients who were on protocols that involved celecoxib 400 mg b.i.d.. Treatment ranged from 21 to 355 days, with a median of 118.5 days. There were three myocardial infarctions (MIs)--two in the study group and one in the control group. One patient had a MI while on treatment, but he had a significant cardiac disease history. There were also two cerebral vascular accidents (CVAs) in each group, although none in any patient who was on-study. Although this is a small study, these findings, in the context of other published data, suggest that some patients with advanced malignancies may still benefit from therapies involving COX-2 inhibitors without clinically significant increase in risk for MI or CVA.