Supplementary Material for: Amiloride Is Effective in the Management of Abiraterone-Induced Mineralocorticoid Excess Syndrome without Interfering with Its Antineoplastic Activity

<p><b><i>Background:</i></b> The administration of abiraterone acetate (abiraterone) leads to an adrenocorticotropic hormone (ACTH)-driven increase in mineralocorticoid hormones, requiring glucocorticoid supplementation that may stimulate the growth of prostate cancer (PCa). Amiloride is a drug that selectively reduces the aldosterone-sensitive Na+/K+ exchange and could be effective in the management of mineralocorticoid excess syndrome (MCES). <b><i>Methods:</i></b> The efficacy of amiloride + hydrochlorothiazide (HCT) in the clinical management of abiraterone-induced MCES was assessed in 5 consecutive patients with castration-resistant PCa (CRPC). Then, using the in vitro experimental model of PCa cell lines, the possible effects of drugs usually used in the clinical management of CRPC patients on PCa cell viability were investigated. <b><i>Results:</i></b> Amiloride/HCT led to a complete disappearance of all clinical and biochemical signs of abiraterone-induced MCES in the 5 treated patients. The in vitro study showed that abiraterone treatment significantly decreased cell viability of both androgen receptor (AR)-expressing VCaP (vertebral-cancer of the prostate) and LNCaP (lymph node carcinoma of the prostate) cells, with no effect on AR-negative PC-3 cells. Prednisolone, spironolactone, and eplerenone increased LNCaP cell viability, while amiloride reduced it. The non-steroid aldosterone antagonist PF-03882845 did not modify PCa cell viability. <b><i>Conclusions:</i></b> The combination of amiloride/HCT was effective in the management of abiraterone-induced MCES. Amiloride did not negatively interfere with the abiraterone inhibition of PCa cell viability in vitro.</p

Supplementary Material for: Efficacy and Safety of Lanreotide Autogel and Temozolomide Combination Therapy in Progressive Thoracic Neuroendocrine Tumors (carcinoid): Results from the Phase 2 ATLANT Study

Introduction: Lanreotide autogel (LAN) and temozolomide (TMZ) are guidelines-recommended monotherapies for thoracic neuroendocrine tumors (carcinoids; T-NETs) but prospective data for both combined and monotherapies are lacking. ATLANT (NCT02698410) evaluated efficacy and safety of LAN/TMZ in progressive T-NETs. Methods: ATLANT was a 12-month, Italian, phase 2, single-arm, open-label, multicenter pilot study. Eligible patients had unresectable, locally-advanced/metastatic, well-/moderately-differentiated T-NETs with radiological progression. Patients received subcutaneous LAN 120 mg every 28 days and oral TMZ 250 mg/day for 5 consecutive days every 28-day cycle. Main endpoints: disease control rate (DCR) at 9 months (primary; investigator-assessed), median progression-free survival (PFS), biomarkers and safety. Results: Patients: n=40; 60% male. Primary tumor site: lung (90%); thymus (10%). Carcinoid type: typical (20.0%), atypical (52.5%). DCR at 9 months was 35.0% (95% confidence interval [CI] 20.63–51.68) (non-acceptability threshold ≤10%, p<0.0001; not significantly above clinically relevant threshold ≥30%, p=0.2968). DCR between 7.5 and 10.5 months (sensitivity analysis) was 45.0% (95%CI 29.26–61.51) and clinically relevant (p=0.0320 at ≥30% threshold). Median PFS was 37.1 (95%CI 24.1–52.9) weeks. No association was observed between biomarker variations (chromogranin A, neuron-specific enolase, somatostatin receptor type-2, Ki-67, 6-O-methylguanine-DNA-methyl-transferase) and DCR or PFS. Most patients (97.5%) had treatment-emergent adverse events (TEAEs); 72.5% had treatment-related TEAEs. TEAEs were mainly grade 1/2. No unanticipated TEAEs were reported. Conclusions: This study showed that LAN/TMZ combination has promising efficacy in progressive T-NETs, and was well tolerated. Larger studies are warranted to support the clinical benefits of LAN/TMZ in patients with T-NETs

Supplementary Material for: Efficacy and Safety of Lanreotide Autogel and Temozolomide Combination Therapy in Progressive Thoracic Neuroendocrine Tumors (carcinoid): Results from the Phase 2 ATLANT Study

Introduction: Lanreotide autogel (LAN) and temozolomide (TMZ) are guidelines-recommended monotherapies for thoracic neuroendocrine tumors (carcinoids; T-NETs) but prospective data for both combined and monotherapies are lacking. ATLANT (NCT02698410) evaluated efficacy and safety of LAN/TMZ in progressive T-NETs. Methods: ATLANT was a 12-month, Italian, phase 2, single-arm, open-label, multicenter pilot study. Eligible patients had unresectable, locally-advanced/metastatic, well-/moderately-differentiated T-NETs with radiological progression. Patients received subcutaneous LAN 120 mg every 28 days and oral TMZ 250 mg/day for 5 consecutive days every 28-day cycle. Main endpoints: disease control rate (DCR) at 9 months (primary; investigator-assessed), median progression-free survival (PFS), biomarkers and safety. Results: Patients: n=40; 60% male. Primary tumor site: lung (90%); thymus (10%). Carcinoid type: typical (20.0%), atypical (52.5%). DCR at 9 months was 35.0% (95% confidence interval [CI] 20.63–51.68) (non-acceptability threshold ≤10%, p<0.0001; not significantly above clinically relevant threshold ≥30%, p=0.2968). DCR between 7.5 and 10.5 months (sensitivity analysis) was 45.0% (95%CI 29.26–61.51) and clinically relevant (p=0.0320 at ≥30% threshold). Median PFS was 37.1 (95%CI 24.1–52.9) weeks. No association was observed between biomarker variations (chromogranin A, neuron-specific enolase, somatostatin receptor type-2, Ki-67, 6-O-methylguanine-DNA-methyl-transferase) and DCR or PFS. Most patients (97.5%) had treatment-emergent adverse events (TEAEs); 72.5% had treatment-related TEAEs. TEAEs were mainly grade 1/2. No unanticipated TEAEs were reported. Conclusions: This study showed that LAN/TMZ combination has promising efficacy in progressive T-NETs, and was well tolerated. Larger studies are warranted to support the clinical benefits of LAN/TMZ in patients with T-NETs