The impact of mammalian target of rapamycin inhibition on bone health in postmenopausal women with hormone receptor-positive advanced breast cancer receiving everolimus plus exemestane in the phase IIIb 4EVER trial

Abstract

BackgroundBreast cancer and its treatments are associated with a detrimental effect on bone health. Here we report the results of an exploratory analysis assessing changes in levels of biomarkers of bone metabolism in patients enrolled in the phase IIIb 4EVER study.MethodsThe 4EVER trial investigated everolimus in combination with exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. In this prespecified exploratory analysis, changes in biomarkers of bone turnover were assessed in patients from baseline to weeks 4, 12, and 24. The serum bone markers assessed were procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTX), osteocalcin, parathyroid hormone (PTH), and 25-hydroxyvitamin D (25-OH-vitamin D). On-treatment changes in bone markers over time were described per subgroup of interest and efficacy outcomes.ResultsBone marker data were available for 241 of 299 enrolled patients. At the final assessment, P1NP, osteocalcin, PTH, 25-OH-vitamin D (all P < 0.001), and CTX (P = 0.036) were significantly decreased from baseline values per the Wilcoxon signed-rank test. At the last assessment (24 weeks or earlier), levels of serum CTX and PTH were significantly lower (P = 0.009 and P = 0.034, respectively) among patients with vs. without prior antiresorptive treatment (ART). Serum CTX levels were significantly lower (P < 0.001), and 25-OH-vitamin D concentrations significantly higher (P = 0.029), at the last postbaseline assessment in patients receiving concomitant ART vs. those without ART. Changes from baseline in PTH and 25-OH-vitamin D concentrations to the final assessment were significantly smaller in patients with prior ART. Lower baseline serum concentrations of osteocalcin and PTH were associated with clinical response (partial vs. non-response) at 24 weeks. High serum levels of CTX and P1NP at baseline were risk factors for progression at 12 weeks.ConclusionsThese exploratory analyses support use of everolimus plus exemestane for the treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, and add to the body of evidence suggesting a potentially favorable impact of everolimus on bone turnover.Trial registrationNCT01626222. Registered 22 June 2012, https://clinicaltrials.gov/ct2/show/NCT01626222.

mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

“…Furthermore, significantly worse outcomes were recorded in baseline VD-deficient patients (≤20 ng/mL) compared to patients with baseline VD levels in the normal ranges. The PROVIDENCE trial, a multicentric and prospective trial, is underway, which aims to investigate the role of hypovitaminosis D and the integration of VD on treatment outcome in patients with advanced cancer subjected to immunotherapy (primary endpoint: failure of treatment over time) [60]. Assessing 25-VD levels and the VDBP rs7041 genotype, before starting therapy, and quantifying nivolumab concentrations at 15 days, to eventually change the immunotherapeutic dosage or predict VD supplementation, could reduce the risk of progression of the tumor [38].…”

Optimizing treatment selection, and sequencing decisions for Management of HR-Positive, HER2-Negative advanced breast cancer – Proceedings from breast cancer expert group meeting

“…Further, the safety of this combination was evaluated in the European phase IIIb, expanded-access, multicenter, BALLET study conducted among 2131 heavily pretreated patients with HR + HER2 − mBC (26.4% elderly). The safety profile of the combination in BALLET was found to be consistent with that noted for the combination in BOLERO-2 trial, with no new safety signals [ 89 ]. This combination has also been noted to have a favorable impact on bone turnover [ 87 ].…”

The effect of rapamycin and its analogues on age-related musculoskeletal diseases: a systematic review

“…While the safety analysis set is not the basis for the conclusions in the study, the high dropout rates are noteworthy. The sirolimus group contains ~ 102% more participants for analysis vs. the placebo group - No differences in characteristics in bone metastases and bisphosphonate use at baseline - Possible detection bias where local investigators could order additional scans or surveys at their discretion - Sponsored by Novartis, a major pharmaceutical company Hadji et al [ 27 ] The impact of mammalian target of rapamycin inhibition on bone health in postmenopausal women with hormone receptor-positive advanced breast cancer receiving everolimus plus exemestane in the phase IIIb 4EVER trial Moderate (ROBINS-I) - No difference in measured parameters of CTX, osteocalcin, P1NP, PTH, 25-OH-vitamin D at baseline between groups - Study design allowed anti-resorptive therapy to be used among participants. Although well-addressed in the analysis, the participants received different treatment dosages, negatively impacting the analyses Bryun et al [ 34 ] Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomized, placebo-controlled, parallel-group, proof-of-concept study High (Cochrane RoB 2.0) - No difference in measured parameters of a tender or swollen joint count, pain, patient, physician global disease activity, HAQ physical function, ESR or CRP - Some concerns with subjectivity in measurement, e.g., visual pain scale - Unclear justification in the grouping of some results, i.e., those that dropped out early grouped with those that used steroids - The average cumulative dose of systemic steroids over the 12-week treatment period was not significantly different, but dose adjustments were also allowed at investigators' discretion, given specific blood results Wen et al [ 35 ] Low-dose sirolimus immunoregulation therapy in patients with active rheumatoid arthritis: a 24-week follow-up of the randomized, open-label, parallel-controlled trial High (Cochrane RoB 2.0) - Sirolimus group contains 110% more participants for analysis vs. the conventional group.…”

“…Participants that discontinued the study due to several reasons. Notable ones possibly relating to the use of the mTOR inhibitor include: Leukopenia -Thrombocytopenia -Hypercholesterolemia/hyperlipidaemia -Increased liver enzymes Key adverse events (sirolimus vs cyclosporin A) -Hypertriglyceridemia (51% vs 12%, P < 0.01) -Hypercholesterolemia (44% vs 14%, P < 0.01) -Hyperglycaemia (20% vs 7%) -Insulin dependent diabetes (2% vs 2%) -SGOT (aspartate aminotransferase) elevation (17% vs 0, P < 0.05) -Hypokalaemia (34% vs 0, P < 0.01) -Hypophosphatasaemia (15% vs 0, P < 0.05) -Thrombocytopenia (37% vs 0, P < 0.01) -Leukopenia (39% vs 14%, P < 0.05) -Anaemia (37% vs 24%) -Arthralgia (20% vs 0, P < 0.05) -Pneumonia (17% vs 2%, P < 0.05) Sirolimus group also experienced a higher number of infections, but numbers were still similar (n = 25 vs n = 22) Study 2 Some discontinuations of participants in the sirolimus group were due to agranulocytosis and hyperlipidaemia Key adverse events (sirolimus vs cyclosporin A) -Hypertriglyceridemia (73% vs 50%) -Hypercholesterolemia (65% vs 45%) -Hyperglycaemia (15% vs 16%) -Insulin dependent diabetes (3% vs 3%) -SGOT (aspartate aminotransferase) elevation (13% vs 5%) -Creatinine increase (18% vs 39%, P < 0.05) -Hyperuricemia (3% vs 18%, P < 0.05) -Thrombocytopenia (45% vs 8%, P < 0.01) -Leukopenia (28% vs 18%) -Anaemia (43% vs 29%) -Diarrhoea (38% vs 11%, P < 0.01) Westenfeld et al [24] Impact of sirolimus, tacrolimus and mycophenolate mofetil on osteoclastogenesis-implications for post-transplantation bone disease Key metabolic effects in sirolimus vs calcineurin inhibitor -Cholesterol (Elevated, P = 0.001) -Triglycerides (Elevated, P = 0.002) -Haemoglobin (Decreased, P = 0.048) -Intact parathyroid hormone (Elevated, P = 0.032) Study explained no change in platelets or leucocyte count between groups Sessa et al [25] Immunosuppressive agents and bone disease in renal transplant patients with hypercalcemia Key adverse events at all grades (everolimus vs placebo) -Hyperglycaemia (14% vs 1%) -Pneumonitis (16% vs 0) -Stomatitis (59% vs 12%) -Rash (39% vs 7%) -Fatigue (37% vs 27%) -Diarrhoea (34% vs 19%) -Nausea (31% vs 29%) -Decreased weight (28% vs 7%) Most common grade 3-4 adverse events (everolimus vs placebo) -Stomatitis (8% vs < 1%) -Hyperglycaemia (5% vs < 1%) -Fatigue (4% vs 1%) Bone-related adverse events were reported to be low and similar across treatment arms, though fewer fractures were reported in the everolimus arm (2.3% vs 3.8%) The population in the everolimus arm was twice that in the placebo arm (n = 428 vs n = 238) Hadji et al [27] The impact of mammalian target of rapamycin inhibition on bone health in postmenopausal women with hormone receptor-positive advanced breast cancer receiving everolimus plus exemestane in the phase IIIb 4EVER trial…”

“…Five studies included the effects of rapamycin and rapalogues on bone as an outcome [23][24][25][26][27]. Campistol et al [23] investigated the effects of rapamycin on bone metabolism in renal transplant patients, using serum osteocalcin and urinary N-telopeptide (i.e., bone-associate collagen degradation) as proxy markers of bone anabolism and catabolism.…”