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Simple Summary: Patients with moderate to severe cancer-related pain are frequently treated with oxycodone, a strong-acting opioid. However, treatment with oxycodone does not always lead to sufficient analgesic action. In order to determine which factors affect treatment outcomes, we performed an observational study and developed a population pharmacokinetic model. The model described oxycodone, nor-oxycodone and nor-oxymorphone pharmacokinetics. The association between oxycodone or oxycodone metabolites' exposure with pain scores and adverse events was not significant. The combined oxycodone, nor-oxycodone and nor-oxymorphone model is a good starting point for further unravelling the factors that affect the pharmacokinetic/pharmacodynamic relation of oxycodone and its metabolites. Oxycodone is frequently used for treating cancer-related pain, while not much is known about the factors that influence treatment outcomes in these patients. We aim to unravel these factors by developing a population-pharmacokinetic model to assess the pharmacokinetics of oxycodone and its metabolites in cancer patients, and to associate this with pain scores, and adverse events. Hospitalized patients with cancer-related pain, who were treated with oral oxycodone, could participate. Pharmacokinetic samples and patient-reported pain scores and occurrence and severity of nine adverse events were taken every 12 h. In 28 patients, 302 pharmacokinetic samples were collected. A one-compartment model for oxycodone and each metabolite best described oxycodone, nor-oxycodone, and nor-oxymorphone pharmacokinetics. Furthermore, oxycodone exposure was not associated with average and maximal pain scores, and oxycodone, nor-oxycodone, and nor-oxymorphone exposure were not associated with adverse events (all p > 0.05). This is the first model to describe the pharmacokinetics of oxycodone including the metabolites nor-oxycodone and nor-oxymorphone in hospitalized patients with cancer pain. Additional research, including more patients and a more timely collection of pharmacodynamic data, is needed to further elucidate oxycodone (metabolite) pharmacokinetic/pharmacodynamic relationships. This model is an important starting point for further studies to optimize oxycodone dosing regiments in patients with cancer-related pain. [ABSTRACT FROM AUTHOR]

(1) Background: Markers identifying which patients with metastatic, castration-resistant prostate cancer (mCRPC) will benefit from cabazitaxel therapy are currently lacking. Therefore, the aim of this study was to identify markers associated with outcome to cabazitaxel therapy based on counts and gene expression profiles of circulating tumor cells (CTCs). (2) Methods: From 120 mCRPC patients, CellSearch enriched CTCs were obtained at baseline and after 6 weeks of cabazitaxel therapy. Furthermore, 91 genes associated with prostate cancer were measured in mRNA of these CTCs. (3) Results: In 114 mCRPC patients with an evaluable CTC count, the CTC count was independently associated with poor progression-free survival (PFS) and overall survival (OS) in multivariable analysis with other commonly used variables associated with outcome in mCRPC (age, prostate specific antigen (PSA), alkaline phosphatase, lactate dehydrogenase (LDH), albumin, hemoglobin), together with alkaline phosphatase and hemoglobin. A five-gene expression profile was generated to predict for outcome to cabazitaxel therapy. However, even though this signature was associated with OS in univariate analysis, this was not the case in the multivariate analysis for OS nor for PFS. (4) Conclusion: The established five-gene expression profile in CTCs was not independently associated with PFS nor OS. However, along with alkaline phosphatase and hemoglobin, CTC-count is independently associated with PFS and OS in mCRPC patients who are treated with cabazitaxel. [ABSTRACT FROM AUTHOR]

Many patients have advanced esophageal cancer at diagnosis. However, the most optimal treatment has not been identified. Therefore, we evaluated a weekly regimen of carboplatin (area under the curve (AUC)) of 4 and paclitaxel at 100 mg/m2 as an induction or palliative treatment. All patients with advanced (gastro)esophageal cancer treated with this regimen between 2002–2018 were included. Exclusion criteria were previous radiotherapy or treatment elsewhere. Data on toxicity, response, and survival were collected. Analyses were performed in two groups: induction (iCT) or palliative chemotherapy (pCT). Median progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan–Meier method. A total of 291 patients was included (iCT: 122; pCT: 169). Most patients had T3 carcinoma (iCT: 54%; pCT: 66%) and stage IV disease (iCT: 42%; pCT: 91%). A toxicity grade ≥3 occurred mainly as hematological toxicity (iCT: 71%; pCT: 73%) and gastrointestinal toxicity (iCT: 3%; pCT: 5%). Response rates were 48% (iCT) and 44% (pCT). Esophagectomy or definitive chemoradiotherapy followed in 42% of iCT, resulting in a PFS of 22.1 months (interquartile range (IQR): 12.4–114.2) and OS of 26.8 months (IQR: 15.4–91.7). For pCT, PFS was 8.2 months (IQR: 5.1–14.5) and OS 10.9 months (IQR: 6.5–18.3). This retrospective cohort study demonstrated that weekly carboplatin (AUC4) and paclitaxel (100 mg/m2) is a well-tolerated and effective induction or palliative treatment regimen for patients with locally advanced or metastatic disease. Future research should directly compare this treatment regimen with other first-line treatment options to determine its true value for clinical practice. [ABSTRACT FROM AUTHOR]

Extragonadal androgens play a pivotal role in prostate cancer disease progression on androgen receptor signaling inhibitors (ARSi), including abiraterone and enzalutamide. We aimed to investigate if germline variants in genes involved in extragonadal androgen synthesis contribute to resistance to ARSi and may predict clinical outcomes on ARSi. We included ARSi naive metastatic prostate cancer patients treated with abiraterone or enzalutamide and determined 18 germline variants in six genes involved in extragonadal androgen synthesis. Variants were tested in univariate and multivariable analysis for the relation with overall survival (OS) and time to progression (TTP) by Cox regression, and PSA response by logistic regression. A total of 275 patients were included. From the investigated genes CYP17A1 , HSD3B1 , CYP11B1 , AKR1C3 , SRD5A1 and SRD5A2 , only rs4736349 in CYP11B1 in homozygous form (TT), present in 54 patients (20%), was related with a significantly worse OS (HR = 1.71, 95% CI 1.09 – 2.68, p = 0.019) and TTP (HR = 1.50, 95% CI 1.08 – 2.09, p = 0.016), and was related with a significantly less frequent PSA response (OR = 0.48, 95% CI 0.24 – 0.96, p = 0.038) on abiraterone or enzalutamide in a multivariable analysis. The frequent germline variant rs4736349 in CYP11B1 is, as homozygote, an independent negative prognostic factor for treatment with abiraterone or enzalutamide in ARSi naive metastatic prostate cancer patients. Our findings warrant prospective investigation of this potentially important predictive biomarker. • A germline variant in CYP11B1 is related to response to abiraterone or enzalutamide. • In homozygous form, this germline variant is related with worse outcomes of treatment. • With a global prevalence of 20%, the homozygous variant is highly frequent. [ABSTRACT FROM AUTHOR]

Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose. This cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC 0–12 h) within no-effect boundaries. These boundaries were set at 0.57–1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets. Of 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC 0–12 h was 1.45 (90% CI 1.27–1.65). No grade ≥3 adverse events were reported during the study. Boosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established. • Pharmacokinetic boosting increases olaparib exposure despite 3-fold dose reduction. • Pharmacokinetic boosting of olaparib does not lead to undertreatment. • Short-term boosted olaparib is well-tolerated. [ABSTRACT FROM AUTHOR]

Abstract Introduction Nivolumab treatment is subject to large interpatient variability in both efficacy and toxicity, which may partly be explained by differences in nivolumab exposure. Exposure–response relationships in regular healthcare have not been extensively investigated for nivolumab. Therefore, we aimed to identify possible exposure–response relationships in nivolumab-treated patients with non–small-cell lung cancer (NSCLC). Methods Patients with NSCLC who started second-line nivolumab therapy (3 mg/kg Q2W) between May 5th 2016 and August 1st 2017, and from whom serial blood samples, toxicity data and outcome data were prospectively collected, were included. Follow-up was carried out until November 1st 2017. Patients were classified according to the best overall response (BOR) based on the Response Evaluation Criteria in Solid Tumours, v1.1, and toxicities according to the Common Terminology Criteria for Adverse Events. Nivolumab trough concentrations were measured after 2, 4 and 10 weeks of treatment, excluding dose delays, and calculated geometric means were tested versus BOR or toxicity using analysis of variance and an independent samples t -test, respectively. Overall survival (OS) and progression-free survival were compared between high and low trough concentration groups. Results Seventy-six patients were evaluable for analyses. Responders (n = 15) had higher mean trough concentrations than patients with progression (n = 33): 47% higher after 2 weeks (p = 0.001), 53% higher after 4 weeks (p = 0.008) and 73% higher after 10 weeks (p = 0.002). Higher trough concentrations were associated with longer OS (p = 0.001). Conclusions This study shows that patients with NSCLC with a response to nivolumab had a higher nivolumab exposure than patients with progression, indicating a potential exposure–response relationship. Further clinical research should focus on clarifying these exposure–response relationships. Highlights • Responders to nivolumab treatment had higher nivolumab exposure than progressors. • No difference in exposure was seen in patients with and without toxicity. • Factors influencing exposure should be clarified in future research. [ABSTRACT FROM AUTHOR]

Background Imatinib 400 mg per day is first-line therapy for patients with gastrointestinal stromal tumours (GISTs). Although clinical benefit is high, progression-free survival (PFS) is variable. This study explores the relationship of single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacokinetics and pharmacodynamics and PFS in imatinib-treated patients with advanced GIST. Methods In 227 patients a pharmacogenetic pathway analysis was performed. Genotype data from 36 SNPs in 18 genes were tested in univariate analyses to investigate their relationship with PFS. Genetic variables which showed a trend (p < 0.1) were tested in a multivariate model, in which each singular SNP was added to clinicopathological factors. Results In univariate analyses, PFS was associated with synchronous metastases (p = 0.0008) and the mutational status (p = 0.004). Associations with rs1870377 in KDR (additive model, p = 0.0009), rs1570360 in VEGFA (additive model, p = 0.053) and rs4149117 in SLCO1B3 (mutant dominant model, 0.027) were also found. In the multivariate model, significant associations and trends with shorter PFS were found for synchronous metastases (HR 1.94, p = 0.002), KIT exon 9 mutation (HR 2.45, p = 0.002) and the SNPs rs1870377 (AA genotype, HR 2.61, p = 0.015), rs1570360 (AA genotype, HR 2.02, p = 0.037) and rs4149117 (T allele, HR 0.62, p = 0.083). Conclusion In addition to KIT exon 9 mutation and synchronous metastases, SNPs in KDR , VEGFA and SLCO1B3 appear to be associated with PFS in patients with advanced GIST receiving 400-mg imatinib. If validated, specific SNPs may serve as predictive biomarkers to identify patients with an increased risk for progressive disease during imatinib therapy. [ABSTRACT FROM AUTHOR]

Aim of the study As a rise in mean corpuscular volume (MCV) of the erythrocyte is frequently seen during treatment with imatinib and sunitinib, we investigated whether macrocytosis (MCV > 100 fl) also occurs as a class effect in other tyrosine kinase inhibitors (TKIs) and whether occurrence of macrocytosis is associated with outcome. Materials and methods In 533 patients, using 5 TKIs, we investigated if macrocytosis and an increase in MCV were associated with progression-free survival and overall survival (OS) in specific tumour-treatment combinations. Results Macrocytosis as well as an increase in MCV from baseline of >10 fl (ΔMCV +10 fl), when included as a time-dependent covariate, were associated with improved OS in patients with renal cell cancer (RCC) treated with sunitinib (macrocytosis, hazard ratio [HR] = 0.61, p = 0.031, and ΔMCV +10 fl, HR = 0.58, p = 0.016). Conclusion In sunitinib-treated patients with RCC, the occurrence of macrocytosis, or a substantial increase in MCV levels after start of treatment, could potentially serve as a positive prognostic factor for survival, if validated prospectively. [ABSTRACT FROM AUTHOR]