Niraparib treatment for patients with BRCA-mutated ovarian cancer: review of clinical data and therapeutic context.

We reviewed clinical data for niraparib monotherapy in BRCA-mutated (BRCAm) epithelial ovarian cancer (OC), contextualizing results with data from other poly(ADP-ribose) polymerase inhibitors (PARPis). Niraparib reduced the likelihood of progression or death by 60% as first-line maintenance therapy and by 73-78% in recurrent disease. In heavily pretreated OC, efficacy was greater in the BRCAm versus non-BRCAm cohort. Quality-of-life (QoL) was maintained throughout treatment. Adverse events were consistent with the known niraparib safety profile. Cumulative efficacy, safety and QoL evidence demonstrate niraparib maintenance monotherapy has a positive benefit:risk ratio in BRCAm OC. Niraparib significantly improved progression-free survival as first-line maintenance therapy in all patients with OC (i.e., of any biomarker status).

This article reviewed niraparib monotherapy in patients with ovarian cancer (OC) who have mutations in a specific gene (BRCA). Across multiple clinical trials, niraparib maintenance treatment was able to delay further progression of disease or death compared with patients who had received placebo; the tumors of patients who had received extensive prior treatment for OC were also more likely to respond to niraparib treatment. Patients were able to have the same quality-of-life with niraparib as they would if they had not received treatment. Side effects were predictable from previous clinical trial experience. Together, these data show that niraparib, like other inhibitors of poly(ADP-ribose) polymerase, is beneficial in patients with OC who have a deleterious BRCA mutation. A plain language version of this article is available and is published alongside the paper online: www.futuremedicine.com/doi/suppl/10.2217/fon-2022-0206.

Does race predict the development of metastases in men who receive androgen-deprivation therapy for a biochemical recurrence after radical prostatectomy?

BACKGROUND: In this study among men who underwent radical prostatectomy (RP), African American men (AAM) were 28% more likely to develop recurrent disease compared with Caucasian men (CM). However, among those who had nonmetastatic, castration-resistant prostate cancer (CRPC), race did not predict metastases or overall survival. Whether race predicts metastases among men who receive androgen-deprivation therapy (ADT) after a biochemical recurrence (BCR) (ie, before CRPC but after BCR) is untested. METHODS: The authors identified 595 AAM and CM who received ADT for a BCR that developed after RP between 1988 and 2015 in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database. Univariable and multivariable Cox models were used to test the association between race and the time from ADT to metastases. Secondary outcomes included the time to CRPC, all-cause mortality, and prostate cancer-specific mortality. RESULTS: During a median follow-up of 66 months after ADT, 62 of 354 CM (18%) and 38 of 241 AAM (16%) developed metastases. AAM were younger at the time they received ADT (63 vs 67 years; P < .001), had received ADT in a more recent year (2008 vs 2006; P < .001), had higher prostate-specific antigen levels at RP (11.1 vs 9.2 ng/mL; P < .001), lower pathologic Gleason scores (P = .004), and less extracapsular extension (38% vs 48%; P = .022). On multivariable analysis, there was no association between race and metastases (hazard radio, 1.20; P = .45) or any of the other secondary outcomes (all P > .5). CONCLUSIONS: Among veterans who received ADT post-BCR after RP, race was not a predictor of metastases or other adverse outcomes. The current findings suggest that research efforts to understand racial differences in prostate cancer biology should focus on early stages of the disease (ie, closer to the time of diagnosis).

Validating the total illness burden index for prostate cancer (TIBI-CaP) in men with castration-resistant prostate cancer: data from TRUMPET.

AIM: To validate the total illness burden index for prostate cancer (TIBI-CaP) in castration-resistant prostate cancer (CRPC) patients. PATIENTS & METHODS: Baseline comorbidity scores collected using the TIBI-CaP were compared with the baseline patient-reported health-related quality of life using the SF-12v2 and FACT-P questionnaires in 302 patients enrolled in the Treatment Registry for Outcomes in CRPC Patients (TRUMPET). RESULTS: Baseline TIBI-CaP scores were negatively correlated with all baseline SF-12v2 domain/composite (p < 0.001) and FACT-P subscale/total (p < 0.020) scores. There was a significant decreasing linear trend in SF12v2 and FACT-P scores over the categories based on TIBI-CaP quartiles of comorbidity burden (from 'least' to 'severe'). CONCLUSION: The TIBI-CaP is a valid measure of comorbidity burden in patients with CRPC in the real world.

Survival outcomes in patients with chemotherapy-naive metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone acetate.

OBJECTIVE: Evaluation of the comparative effectiveness of enzalutamide and abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) is limited to meta-analyses of randomized trials that exclude patients with significant comorbidities. We evaluated overall survival (OS) in patients with chemotherapy-naive mCRPC treated with enzalutamide or abiraterone acetate (abiraterone) in a real-world single payer setting. METHODS: A retrospective analysis (4/1/2014-3/31/2018) of the Veterans Health Administration (VHA) database was conducted. Patients with mCRPC had ≥1 pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following disease progression on surgical/medical castration, without chemotherapy <12 months prior to index date. Patients had continuous VHA enrollment for ≥12 months pre-index date and were followed until death, disenrollment, or end of study. Kaplan-Meier analysis and multivariable Cox proportional hazards regression models examined the OS treatment effect. RESULTS: Patients with chemotherapy-naive mCRPC (N = 3174; enzalutamide, n = 1229; abiraterone, n = 1945) had mean ages of 74 and 73 years, respectively. Median follow-up was 18.27 and 19.07 months with enzalutamide and abiraterone, respectively. Enzalutamide-treated patients had longer median treatment duration than abiraterone-treated patients (9.93 vs 8.47 months, respectively, p = 0.0008). After baseline comorbidity adjustment, enzalutamide-treated patients had a 16% reduced risk of death (hazard ratio [HR] = 0.84; 95% CI, 0.76-0.94; p = 0.0012). For patients who remained on first line-therapy only, enzalutamide-treated patients had improved OS versus abiraterone-treated patients (HR = 0.71; 95% CI, 0.62-0.82). Enzalutamide-treated patients who crossed over to abiraterone had a comparable risk of death versus abiraterone-treated patients who crossed over to enzalutamide (HR = 1.10; 95% CI, 0.89-1.35). These results were confirmed by sensitivity analysis, which considered prognostic variables. CONCLUSIONS: Retrospective analysis of the VHA database indicated that chemotherapy-naive patients with mCRPC initiating therapy with enzalutamide had improved survival versus abiraterone.

Economic Outcomes in Patients with Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide or Abiraterone Acetate Plus Prednisone.

INTRODUCTION: Prostate cancer (PC) is the second leading cause of cancer death among US men and accounts for considerable healthcare expenditures. We evaluated economic outcomes in men with chemotherapy-naïve metastatic castration-resistant PC (mCRPC) treated with enzalutamide or abiraterone acetate plus prednisone (abiraterone). METHODS: We performed a retrospective analysis on 3174 men (18 years or older) utilizing the Veterans Health Administration (VHA) database from 1 April 2014 to 31 March 2018. Men with mCRPC were included if they had at least one pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following surgical or medical castration, had no chemotherapy treatment within 12 months prior to the index date, and had continuous VHA enrollment for at least 12 months pre- and post-index date. Men were followed until death, disenrollment, or end of study and were 1:1 propensity score matched (PSM). All-cause and PC-related resource use and costs per patient per month (PPPM) in the 12 months post index were compared between matched cohorts. RESULTS: We identified 1229 men with mCRPC prescribed enzalutamide and 1945 prescribed abiraterone with mean ages of 74 and 73 years, respectively. After PSM, each cohort had 1160 patients. The enzalutamide cohort had fewer all-cause (2.51 vs 2.86; p < 0.0001) and PC-related outpatient visits (0.86 vs 1.03; p < 0.0001), with corresponding lower all-cause ($2588 vs $3115; p < 0.0001) and PC-related ($1356 vs $1775; p < 0.0001) PPPM outpatient costs compared with the abiraterone cohort. All-cause total costs (medical and pharmacy) PPPM ($8085 vs $9092; p = 0.0002) and PC-related total costs PPPM ($6321 vs $7280; p < 0.0001) were significantly lower in the enzalutamide cohort compared with the abiraterone cohort. CONCLUSIONS: Enzalutamide-treated men with chemotherapy-naïve mCRPC had significantly lower resource utilization and healthcare costs compared with abiraterone-treated men.

Prostate cancer (PC) is the second leading cause of death among men with cancer in the USA. Healthcare costs associated with PC, including hospitalizations, outpatient visits, and medications prescribed to treat adverse effects, depend on the severity of the disease and intensity of treatment, but are generally very high. Enzalutamide and abiraterone acetate with prednisone (abiraterone) are both approved treatments for men with PC that does not respond to treatments that reduce the male hormone testosterone, known as castration-resistant PC (CRPC). These drugs are associated with varying treatment duration and different adverse effects, and therefore could result in differences in the use of healthcare resources and overall cost of treatment. Here we evaluated the healthcare resource utilization (HCRU), which was calculated as the average number of healthcare encounters, including inpatient stays, outpatient visits, and pharmacy visits, and length of inpatient stays, and treatment costs associated with use of enzalutamide or abiraterone by men with metastatic CRPC (mCRPC), who had not received prior chemotherapy in the Veterans Health Administration. We found that men with chemotherapy-naïve mCRPC treated with enzalutamide used less healthcare resources and incurred lower total healthcare costs than men treated with abiraterone. On average, all-cause total healthcare costs were $1007 per patient per month lower and PC-related total healthcare costs were $959 per patient per month lower for patients treated with enzalutamide than those treated with abiraterone. These results support the hypothesis that the long-term HCRU and costs of enzalutamide may be lower compared with abiraterone.

Treatment Duration, Healthcare Resource Utilization, and Costs Among Chemotherapy-Naïve Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide or Abiraterone Acetate: A Retrospective Claims Analysis.

INTRODUCTION: Enzalutamide and abiraterone acetate (plus prednisone) are new hormonal treatments for metastatic castration-resistant prostate cancer (mCRPC). This study compared treatment duration, healthcare resource utilization (HRU), and treatment costs for chemotherapy-naïve mCRPC patients treated with enzalutamide or abiraterone acetate in the USA. METHODS: Chemotherapy-naïve mCRPC patients initiating treatment with enzalutamide or abiraterone acetate were identified from administrative claims. Continuous enrollment ≥ 6 months before and ≥ 3 months after the index date (initiation date of enzalutamide or abiraterone acetate) was required. Treatment duration, all-cause and prostate cancer-related HRU, and costs were estimated during the post-index period. Multivariable analyses compared HRU and costs between cohorts, adjusting for baseline characteristics. RESULTS: Overall, 920 chemotherapy-naïve patients initiated enzalutamide and 2310 initiated abiraterone acetate (median follow-up, 10.7 and 13.5 months, respectively). More enzalutamide-treated patients had corticosteroid-sensitive comorbidities at baseline. Treatment duration was longer with enzalutamide versus abiraterone acetate (median, 10.7 vs. 8.8 months; P = 0.008). Enzalutamide was associated with fewer all-cause inpatient admissions [adjusted incidence rate ratio (95% confidence interval) 0.87 (0.76, 0.99)], days of hospitalization [0.84 (0.70, 1.02)], and outpatient visits [0.94 (0.90, 0.98)], and fewer prostate cancer-related outpatient visits [0.92 (0.87, 0.96)] compared with abiraterone acetate. Enzalutamide was also associated with lower prostate cancer-related inpatient and emergency department costs [adjusted differences, $122 (P = 0.024) and $28 (P = 0.009), respectively]. CONCLUSION: Chemotherapy-naïve mCRPC patients treated with enzalutamide versus abiraterone acetate had longer treatment duration and incurred lower HRU and prostate cancer-related inpatient and emergency department costs. FUNDING: Astellas Pharma Inc.

Adipocyte differentiation in Sod2(-/-) and Sod2(+/+) murine bone marrow stromal cells is associated with low antioxidant pools.

OBJECTIVE: Adipocytogenesis in bone marrow stromal cells (BMSCs) from manganese-superoxide dismutase-deficient (Sod2(-/-)) and wild-type (Sod2(+/+)) mice and the effect of antioxidant pool size were determined. METHODS: BMSCs from Sod2(-/-) or Sod2(+/+) mice were cultured with and without adipocytogenic supplements including: 10 mug/mL insulin, 1 muM dexamethasone, and 100 muM indomethacin. Oil Red-O-positive cells and reverse-transcriptase polymerase chain reaction measurement of peroxisome proliferator-activated receptor-gamma (PPARgamma) and lipoprotein lipase (LPL) were measured. Antioxidant glutathione levels (GSH) and glutathione peroxidase activity (GPX) were determined. RESULTS: Sod2(-/-) cells demonstrated constitutive adipocytogenesis in basal medium and generated 34% more adipocytes in adipocytogenic media. Growth of cells in the free radical scavenger antioxidant, amifostine (WR2721; 4 mM) decreased numbers of adipocytes in Sod2(-/-) BMSCs in both basal (38.0%, p = 0.037) and adipocytogenic (37.5%, p = 0.021) media and reduced to undetectable the levels of expression of PPARgamma and LPL. In contrast, Sod2(+/+) cells showed no detectable constitutive adipocytogenesis but formed adipocytes in adipocytogenic medium, with a decrease (43.7%, p = 0.001) by addition of WR2721. In basal conditions, Sod2(-/-) cells had lower GSH (78.6%; p = 0.0089) and GPX (52.7%; p < 0.001) levels than did Sod2(+/+) cells, which were increased in either medium by WR2721 treatment of Sod2(-/-) or Sod2(+/+) cells (all p < 0.001). Differentiation of BMSCs to adipocytes was inversely correlated with the level of GSH (r = -0.9427, p = 0.0167). Sod2(-/-) long-term bone marrow cultures had decreased hematopoiesis compared to those from Sod2(+/-) or Sod2(+/+) mice. CONCLUSION: The cellular redox pathway has a role in adipocyte differentiation of cells of the hematopoietic microenvironment.

Antithyroid drug-induced immunomodulation in Graves' disease patients.

The study was so designed as to determine the effect of low to medium daily doses of methimazole (10-20 mg per day) on the number and function of different types of immunocompetent cells in peripheral blood of patients with Graves' disease administered methimazole for the treatment of hyperthyroidism. The study included 127 patients with Graves' disease divided into three groups: group I of 29 thyrotoxic patients before the beginning of treatment; group II of 73 euthyroid patients under antithyroid treatment; and group III of 25 patients who remained euthyroid 8 weeks after therapy discontinuation. In group I, the proportion of CD4+ cells, proportion and number of granulocytes, and their ingestion and microbicidity as well as monocyte phagocytic activity and ingestion were decreased. The mentioned alterations were concluded to most likely be the consequence of the underlying autoimmune process. In group II, the proportion and number of CD8+ cells were increased, while the natural killer cell activity was impaired. Granulocyte microbicidity was suppressed as compared to group I, while the granulocyte phagocytic activity was impaired as compared to normal values. Compared to normal, monocyte microbicidity and phagocytic activity were also suppressed. Monocyte ingestion was suppressed as compared to groups I and III, regardless of the patients' thyroid hormone status. Study results strongly support the hypothesis of a direct immunosuppressive effect of methimazole in patients with Graves' disease rather than the theory favoring concomitant immunomodulation due to thyroid hormone decrease.

Hypoxia inhibition of adipocytogenesis in human bone marrow stromal cells requires transforming growth factor-beta/Smad3 signaling.

Although hypoxia and transforming growth factor-beta (TGF-beta) inhibit differentiation of adipocytes from preadipocytes and bone marrow-derived cells in several species, the relationship between hypoxia and TGF-beta signaling in adipocytogenesis is unknown. In this study, we evaluated the mechanisms of inhibition of adipocyte differentiation by hypoxia and TGF-beta in human and murine marrow stromal cells (MSCs) and the role of TGF-beta/Smad signaling in the inhibition of adipocytogenesis by hypoxia. Both hypoxia-mimetic deferoxamine mesylate (DFO) and TGF-beta1 inhibited adipocyte differentiation (1.0% versus the control at 15 microm DFO and 1.4% versus the control at 1 ng/ml TGF-beta1) and adipocyte gene expression (peroxisome proliferator-activated receptor-gamma2 and lipoprotein lipase) in human MSCs after 21 days of treatment. Hypoxia (2% O(2)) and DFO (but not TGF-beta1) increased hypoxia-inducible factor-1alpha as shown by Western blotting. Macroarrays and Western and Northern blot analyses showed that hypoxia activated the TGF-beta/Smad signaling pathway and that both hypoxia and TGF-beta1 modulated adipocyte differentiation pathways such as the insulin-, peroxisome proliferator-activated receptor-gamma-, phosphatidylinositol 3-kinase-, and MAPK-associated signaling pathways. Studies with mouse marrow stromal cell lines derived from Smad3(+/+) or Smad3(-/-) mice revealed that the TGF-beta type I receptor (ALK-5) and its intracellular signaling molecule Smad3 were necessary for the inhibition of adipocyte differentiation by both TGF-beta and hypoxia-mimetic DFO. Thus, the TGF-beta/Smad signaling pathway is required for hypoxia-mediated inhibition of adipocyte differentiation in MSCs.

Humoral immune response to p53 correlates with clinical course in colorectal cancer patients during adjuvant chemotherapy.

BACKGROUND AND AIMS: Overexpression of p53 protein in malignancies induces an immune response in some cancer patients. We investigated whether production of serum antibodies against p53 (p53-Ab) is associated with pathohistological parameters of colorectal carcinoma and whether p53-Ab can serve as a tumor marker during cancer treatment. PATIENTS AND METHODS: Serum samples from 220 colorectal cancer patients during surgery and adjuvant chemotherapy and 42 healthy controls were tested for the presence of p53-Ab by ELISA. Expression of p53 protein in tumors was determined using mouse anti-human p53-Ab. RESULTS: Serum p53-Ab were detected in 18% of patients while all controls were negative. A strong correlation between p53-Ab production and p53 protein expression was observed: 70% of p53-Ab positive cases had tumors positive for p53 vs. 52% of p53-Ab negative cases. There was also a significant predominance of p53-Ab positive cases in Dukes' stages B and C over stage A. Although surgery alone reduced p53-Ab levels, decreases in p53-Ab titer became significant midterm through chemotherapy compared to both pre- and postoperative values and remained decreased until the completion of treatment. CONCLUSION: The presence of p53-Ab in sera of patients with colorectal cancer indicates tumors in more advanced histopathologic stages (Dukes' B, C). Due to low sensitivity (18%) p53-Ab are not recommendable as a preoperative marker for colorectal cancer. However, due to high specificity (100%), their monitoring after surgery and adjuvant chemotherapy has potential for early diagnosis of tumor relapse in p53-Ab positive cases.

Double-stranded RNA-dependent protein kinase (pkr) is essential for thermotolerance, accumulation of HSP70, and stabilization of ARE-containing HSP70 mRNA during stress.

We have investigated the role of the double-stranded RNA-dependent protein kinase gene (pkr) in the regulation of the heat shock response. We show that the pkr gene is essential for efficient activation of the heat shock response and that pkr disruption profoundly inhibits heat shock protein 70 (HSP70) synthesis and blocks the development of thermotolerance. Despite these profound effects, pkr disruption did not markedly affect the activation of heat shock factor 1 by heat and did not reduce the rate of transcription of the HSP70 gene after heat shock. However, despite the lack of effect of pkr disruption on HSP70 gene transcription, we found a significant decrease in the expression of HSP70 mRNA in pkr-/- cells after heat shock. Kinetic studies of mRNA turnover suggested a block in the thermal stabilization of HSP70 mRNA in pkr-/- cells. As the thermal stabilization of HSP70 mRNA is thought to involve cis-acting A+U rich (ARE) elements in the 3'-untranslated region (UTR), we examined a potential role for pkr in this process. We found that a reporter beta-galactosidase mRNA destabilized by introduction of a functional ARE into the 3'-UTR became stabilized by heat but only in cells containing an intact pkr gene. Our studies suggest therefore that pkr plays a significant role in the stabilization of mRNA species containing ARE destruction sequences in the 3'-UTR and through this mechanism, contributes to the regulation of the heat shock response and other processes.