Research Spotlight

Hurvitz, S. A., A. Goncalves, H. S. Rugo, K. H. Lee, L. Fehrenbacher, L. A. Mina, S. Diab, J. L. Blum, J. Chakrabarti, M. Elmeliegy, L. DeAnnuntis, E. Gauthier, A. Czibere, I. C. Tudor, R. G. W. Quek, J. K. Litton and J. Ettl (2019). “Talazoparib in Patients with a Germline BRCA-Mutated Advanced Breast Cancer: Detailed Safety Analyses from the Phase III EMBRACA Trial.” Oncologist Nov 25. [Epub ahead of print].

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BACKGROUND: In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression-free survival (PFS) compared with physician’s choice of chemotherapy (PCT) in germline BRCA1/2-mutated HER2-negative advanced breast cancer (ABC). Herein, the safety profile of talazoparib is explored in detail. MATERIALS AND METHODS: Overall, 412 patients received >/=1 dose of talazoparib (n = 286) or PCT (n = 126). Adverse events (AEs) were evaluated, including timing, duration, and potential overlap of selected AEs. The relationship between talazoparib plasma exposure and grade >/=3 anemia was analyzed. Time-varying Cox proportional hazard models assessed the impact of dose reductions on PFS. Patient-reported outcomes (PROs) in patients with common AEs and health resource utilization (HRU) were assessed in both treatment arms. RESULTS: The most common AEs with talazoparib were hematologic (195 [68.2%] patients) and typically occurred within the first 3-4 months of receiving talazoparib. Grade 3-4 anemia lasted approximately 7 days for both arms. Overlapping grade 3-4 hematologic AEs were infrequent with talazoparib. Higher talazoparib exposure was associated with grade >/=3 anemia. Permanent discontinuation of talazoparib due to hematologic AEs was low (<2%). A total of 150 (52.4%) patients receiving talazoparib had AEs associated with dose reduction. Hematologic toxicities were managed by supportive care medication (including transfusion) and dose modifications. Among patients with anemia or nausea and/or vomiting AEs, PROs favored talazoparib. After accounting for the treatment-emergent period, talazoparib was generally associated with a lower rate of hospitalization and supportive care medication use compared with chemotherapy. CONCLUSION: Talazoparib was associated with superior efficacy, favorable PROs, and lower HRU rate versus chemotherapy in gBRCA-mutated ABC. Toxicities were manageable with talazoparib dose modification and supportive care. IMPLICATIONS FOR PRACTICE: Talazoparib was generally well tolerated in patients with germline BRCA-mutated HER2-negative advanced breast cancer in the EMBRACA trial. Common toxicities with talazoparib were primarily hematologic and infrequently resulted in permanent drug discontinuation (<2% of patients discontinued talazoparib due to hematologic toxicity). Hematologic toxicities typically occurred during the first 3-4 months of treatment and were managed by dose modifications and supportive care measures. A significant efficacy benefit, improved patient-reported outcomes, lower rate of health resource utilization and a tolerable safety profile support incorporating talazoparib into routine management of germline BRCA-mutated locally advanced/metastatic breast cancer.E

Hebeler, K. R., G. Filardo and J. M. DiMaio (2019). “Serum albumin and 1-year mortality in patients with transcatheter aortic valve replacement therapy (Reply).” Ann Thorac Surg Nov 28. [Epub ahead of print].

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We thank Dr. Kawada for the comments related to our study. The aim of our study was to assess the predictive ability of combining widely used frailty markers and sarcopenia measurements with the STS-PROM for 1-year mortality after TAVR and not to make inference on the magnitude of single point estimates. We agree that the relatively small number of events would have limited this latter analysis but this was beyond the purpose of our study. Nonetheless, the very large p-values estimated for all frailty markers (with the exception of albumin) [gait speed (Model 3: 0.54, Model 4: 0.59), grip strength (Model 3: 0.24, Model 4: 0.13), Katz ADL (Model 3: 0.43, Model 4: 0.43), and psoas muscle area (Model 4: 0.53)] suggest that a higher number of events would have not affected our results and conclusions regarding the poor prediction of these markers for 1-year mortality after TAVR. Likewise, we agree that the area under the curve of model 4 is not very high but again, the goal of the study was to present the predictive ability of combining widely used frailty markers and sarcopenia measurements with the STS-PROM for 1-year mortality. In fact, we stated in the conclusion of our manuscript that “…commonly used pre-TAVR risk assessments are poorly predictive of 1-year mortality.” In summary, we are confident that albumin was the only frailty marker that was associated with higher mortality. Future studies should investigate whether optimization of nutritional status can improve outcomes after TAVR. (Text of authors’ response to comments on their article, Hebeler KR, Baumgarten H, Squiers JJ, et al. “Albumin is predictive of 1-year mortality after transcatheter aortic valve replacement.” Ann Thorac Surg 2018;106:1302-7.)

Hamandi, M., A. T. Lanfear, J. Fan, M. L. Bolin, J. M. DiMaio, R. L. Smith and C. Dib (2019). “Incidental finding of giant coronary artery aneurysm.” J Card Surg Nov 25. [Epub ahead of print].

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A 58‐year‐old asymptomatic man presented to our institution after a routine cardiac computed tomography (CT) for calcium scoring. He did not have any history of connective tissue disorders or Kawasaki disease. CT angiogram confirmed the presence of a coronary artery aneurysm (CAA) measuring 10.3 × 6.8 cm arising from the right coronary artery (RCA) with true lumen enhancement. The rest of the aneurysm was thrombosed, and distal calcification of the RCA was also noted. Management for patients with CAA is not standardized, as CAAs appear in only 0.3% to 5.3% of patients undergoing coronary angiographies, while “giant” CAAs (>5 cm) appear in less than 0.02%. Surgical or percutaneous intervention and antiplatelet/anticoagulation therapy are commonly reported. Due to the rarity of giant coronary aneurysms, there is no standardized management strategy supported by controlled trials. Data assessing the risk of mortality associated with these management options is sparse. The patient was referred for aneurysm ligation with distal bypass grafting due to the size and potential high risk of rupture and the risk of distal embolization which can result in myocardial ischemia or infarction. His perioperative risk of mortality and morbidity was deemed to be extremely low. Following the median sternotomy, the aneurysm was opened and the large orifice of the main right coronary artery was noted. The right coronary ostium was ligated and the old mural thrombus within the aneurysm was removed. The patient underwent coronary artery bypass grafting. The clinical course was uneventful and he was discharged on postoperative day 4. In conclusion, the management of a giant coronary artery aneurysm should be guided by the patient’s clinical presentation and perioperative risk, the size of the aneurysm, and the final decision should be made by an experienced Heart Team approach. (Full text of this image study.)

Grace, E., O. Goldblum, L. Renda, N. Agada, K. See, C. Leonardi and A. Menter (2019). “Injection Site Reactions in the Federal Adverse Event Reporting System (FAERS) Post-Marketing Database Vary Among Biologics Approved to Treat Moderate-To-Severe Psoriasis.” Dermatol Ther (Heidelb) Nov 16. [Epub ahead of print].

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INTRODUCTION: Biologics used to treat moderate-to-severe plaque psoriasis may cause injection site reactions (ISRs) characterized by erythema, edema, itch, and sometimes pain. The Federal Adverse Event Reporting System (FAERS) is a repository of spontaneous post-marketing reports of adverse events (AEs) that are reported to the US Food and Drug Administration (FDA). Our objective was to perform a pharmacovigilance analysis of FAERS reports of ISRs associated with the use of subcutaneously administered biologic products approved to treat moderate-to-severe plaque psoriasis. METHODS: The products included in our assessment were adalimumab, etanercept, ixekizumab, secukinumab, and ustekinumab. Reports from the date of US approval for each biologic as treatment for plaque psoriasis through 2 years were included using the search term “injection site.” RESULTS: The results show that the FAERS database contained reports of ISRs for all of the included biologics during the 2 years following FDA approval. The most common reports on ISRs were on pain, irritation, and erythema for adalimumab; reaction, pain, and erythema for etanercept; erythema, pain, and reaction for ixekizumab; bruising, pain, hemorrhage for secukinumab; and pain, induration, and swelling for ustekinumab. FAERS does not include data on total patient exposure; therefore, ISR rates could not be calculated. CONCLUSIONS: Specific ISRs varied among the biologic therapies assessed. The findings presented could be helpful when patients consider switching therapies due to ISRs. FUNDING: Eli Lilly and Company.

Goraya, N. and D. E. Wesson (2019). “Novel dietary and pharmacologic approaches for acid-base modulation to preserve kidney function and manage uremia.” Curr Opin Nephrol Hypertens Nov 15. [Epub ahead of print].

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PURPOSE OF REVIEW: We review mechanisms for chronic kidney disease (CKD) progression that might be addressed with nonpharmacologic and novel pharmacologic interventions as strategies by which to slow or even prevent CKD progression. RECENT FINDINGS: Evolving data support the contribution of the broad spectrum of disorders of acid (H) accumulation, which we refer to as ‘H stress’, to CKD progression. Recent studies support that amelioration of H stress, including spectra of H accumulation that are insufficient to cause metabolic acidosis, is kidney-protective. In addition, gut-derived toxins appear to contribute to CKD progression and to the well described increased cardiovascular disease (CVD) risk in patients with CKD. Dietary and novel pharmacologic interventions hold promise as strategies to slow CKD progression through reducing levels of these gut-derived toxins. In addition, oxidative stress appears to mediate CKD progression and contributing factors like diet and cigarette smoking can exacerbate oxidative stress. Dietary changes and smoking cessation hold promise to favorably affect CKD progression by reducing kidney oxidative stress. SUMMARY: The urgent need to add to the traditional armamentarium of blood pressure control and antiangiotensin II pharmacologic therapy for kidney protection has led to investigations into additional kidney-protective strategies. Acid stress, a disordered gut microbiome, and oxidative stress each appear to contribute to CKD progression and can be potentially addressed by nonpharmacologic and novel pharmacologic interventions.