New combination therapies for castration-resistant prostate cancer

17 Background: Metabolic consequences of potent AR suppression with enzalutamide and apalutamide are unresolved. Endocrine perturbations induced by potent AR antagonists may promote adverse effects and impinge on the potential efficacy of combination therapies, including for example, immunotherapies. We hypothesized that enzalutamide and apalutamide will block 11β-HSD2, the major enzyme that inactivates cortisol in peripheral tissues and results in increased systemic exposure to endogenous active glucocorticoids. We further hypothesized that AR is co-expressed with 11β-HSD2, suggesting a mechanism of suppression. Methods: Cortisol and cortisol/cortisone ratio (substrate/product of 11β-HSD2) were measured in serum using mass spectrometry before and on-treatment in 3 clinical trials: 1) neoadjuvant apalutamide + leuprolide 2) enzalutamide +/- PROSTVAC for metastatic castration-resistant prostate cancer 3) enzalutamide +/- PROSTVAC for non-metastatic castration-sensitive prostate cancer. AR and 11β-HSD2 expression were assessed in kidneys of 13 men and 9 women. Results: A rise in cortisol concentration and cortisol/cortisone ratio occurs uniformly across all 3 trials of potent AR antagonists. For example, a rise in cortisol/cortisone ratio occurred in 23/25 (92%) patients (p<0.001), 30/38 (79%) patients (p=0.051), and 36/64 (67%) patients (p<0.001), in the 3 respective trials. AR is only expressed alongside 11β-HSD2 in the kidneys of men but not women. Conclusions: Treatment with enzalutamide or apalutamide increases systemic exposure to active glucocorticoids. This effect is likely mediated by AR suppression of 11β-HSD2 in the kidney. These findings have potential consequences for immune suppression, the efficacy of treatment combinations using next-generation AR antagonists, and adverse effects of these drugs.

Download Full-text

The New Combination Docetaxel, Prednisone and Curcumin in Patients with Castration-Resistant Prostate Cancer: A Pilot Phase II Study

Oncology ◽

10.1159/000441148 ◽

2016 ◽

Vol 90 (2) ◽

pp. 69-78 ◽

Cited By ~ 51

Author(s):

Hakim Mahammedi ◽

Eloise Planchat ◽

Mélanie Pouget ◽

Xavier Durando ◽

Hervé Curé ◽

...

Keyword(s):

Prostate Cancer ◽

Phase Ii ◽

Phase Ii Study ◽

New Combination ◽

Castration Resistant Prostate Cancer ◽

Pilot Phase ◽

Castration Resistant

Download Full-text

Impact of Time to Castration Resistance on Survival in Metastatic Hormone Sensitive Prostate Cancer Patients in the Era of Combination Therapies

Frontiers in Oncology ◽

10.3389/fonc.2021.659135 ◽

2021 ◽

Vol 11 ◽

Author(s):

Mike Wenzel ◽

Felix Preisser ◽

Benedikt Hoeh ◽

Maria Schroeder ◽

Christoph Würnschimmel ◽

...

Keyword(s):

Prostate Cancer ◽

Patient Characteristics ◽

Combination Therapies ◽

Castration Resistant Prostate Cancer ◽

Castration Resistance ◽

Logistic Regression Models ◽

Castration Resistant ◽

Hormone Sensitive ◽

The Impact ◽

Multivariable Adjustment

BackgroundTo evaluate the impact of time to castration resistance (TTCR) in metastatic hormone-sensitive prostate cancer (mHSPC) patients on overall survival (OS) in the era of combination therapies for mHSPC.Material and MethodsOf 213 mHSPC patients diagnosed between 01/2013-12/2020 who subsequently developed metastatic castration resistant prostate cancer (mCRPC), 204 eligible patients were analyzed after having applied exclusion criteria. mHSPC patients were classified into TTCR <12, 12-18, 18-24, and >24 months and analyzed regarding OS. Moreover, further OS analyses were performed after having developed mCRPC status according to TTCR. Logistic regression models predicted the value of TTCR on OS.ResultsMedian follow-up was 34 months. Among 204 mHSPC patients, 41.2% harbored TTCR <12 months, 18.1% for 12-18 months, 15.2% for 18-24 months, and 25.5% for >24 months. Median age was 67 years and median PSA at prostate cancer diagnosis was 61 ng/ml. No differences in patient characteristics were observed (all p>0.05). According to OS, TTCR <12 months patients had the worst OS, followed by TTCR 12-18 months, 18-24 months, and >24 months, in that order (p<0.001). After multivariable adjustment, a 4.07-, 3.31-, and 6.40-fold higher mortality was observed for TTCR 18-24 months, 12-18 months, and <12 months patients, relative to TTCR >24 months (all p<0.05). Conversely, OS after development of mCRPC was not influenced by TTCR stratification (all p>0.05).ConclusionPatients with TTCR <12 months are at the highest OS disadvantage in mHSPC. This OS disadvantage persisted even after multivariable adjustment. Interestingly, TTCR stratified analyses did not influence OS in mCRPC patients.

Download Full-text