Movement of Poly-ADP Ribose (PARP) Inhibition into Frontline Treatment of Ovarian Cancer.

The use of poly (ADP-ribose) polymerase (PARP) inhibitors in the front-line management of advanced ovarian cancer has recently emerged as an exciting strategy with the potential to improve outcomes for patients with advanced ovarian cancer. In this article, we review the results of four recently published Phase III randomised controlled trials evaluating the use of PARP inhibitors in the primary treatment of ovarian cancer (SOLO1, PRIMA, PAOLA-1, and VELIA). Collectively, the studies suggest that PARP maintenance in the upfront setting is most beneficial among patients with BRCA-associated ovarian cancers (hazard ratios range from 0.31 to 0.44), followed by patients with tumours that harbour homologous recombination deficiencies (hazard ratios range from 0.33 to 0.57). All three studies that included an all-comer population were able to demonstrate benefit of PARP inhibitors, regardless of biomarker status. The FDA has approved olaparib for front-line maintenance therapy among patients with BRCA-associated ovarian cancers, and niraparib for all patients, regardless of biomarker status. In determining which patients should be offered front-line maintenance PARP inhibitors, and which agent to use, there are multiple factors to consider, including FDA indication, dosing preference, toxicity, risks versus benefits for each patient population, and cost. There are ongoing studies further exploring the front-line use of PARP inhibitors, including the potential downstream effects of PARP-inhibitor resistance in the recurrent setting, combining PARP-inhibitors with other anti-angiogenic drugs, immunotherapeutic agents, and inhibitors of pathways implicated in PARP inhibitor resistance.

Niraparib maintenance in frontline management of ovarian cancer: a cost effectiveness analysis.

OBJECTIVES: Niraparib maintenance after frontline chemotherapy for advanced ovarian cancer extends progression free survival. The objective of this study was to determine the cost effectiveness of niraparib maintenance therapy in patients with newly diagnosed ovarian cancer. METHODS: Decision analysis models compared the cost of observation versus niraparib maintenance following chemotherapy for five groups: all newly diagnosed ovarian cancer patients (overall), those with homologous recombination deficiency, those harboring BRCA mutations (BRCA), homologous recombination deficiency patients without BRCA mutations (homologous recombination deficiency non-BRCA), and non-homologous recombination deficiency patients. Drug costs were estimated using average wholesale prices. Progression free survival was estimated from published data and used to estimate projected overall survival. Incremental cost effectiveness ratios per quality adjusted life year were calculated. Sensitivity analyses varying the cost of niraparib were performed. The willingness-to-pay threshold was set at US$100 000 per quality adjusted life year saved. RESULTS: For the overall group, the cost of observation was US$5.8 billion versus $20.5 billion for niraparib maintenance, with an incremental cost effectiveness ratio of $72 829. For the homologous recombination deficiency group, the observation cost was $3.0 billion versus $14.8 billion for niraparib maintenance (incremental cost effectiveness ratio $56 329). Incremental cost effectiveness ratios for the BRCA, homologous recombination deficiency non-BRCA, and non-homologous recombination deficiency groups were $58 348, $50 914, and $88 741, respectively. For the overall and homologous recombination deficiency groups, niraparib remained cost effective if projected overall survival was 2.2 and 1.5 times progression free survival, respectively. CONCLUSIONS: For patients with newly diagnosed ovarian cancer, maintenance therapy with niraparib was cost effective. Cost effectiveness was improved when analyzing those patients with homologous recombination deficiency and BRCA mutations. Efforts should continue to optimize poly-ADP-ribose polymerase utilization strategies.

Real world experience of poly (ADP-ribose) polymerase inhibitor use in a community oncology practice.

OBJECTIVE: This study aims to describe the real-world experience, including the clinical and financial burden, associated with PARP inhibitors in a large community oncology practice. METHODS: Retrospective chart review identified patients prescribed olaparib, niraparib or rucaparib for maintenance therapy or treatment of recurrent ovarian, primary peritoneal or fallopian tube cancer across twelve gynecologic oncologists between December 2016 and November 2018. Demographic, financial and clinical data were extracted. One PARP cycle was defined as a single 28-day period. For patients treated with more than one PARPi, each course was described separately. RESULTS: A total of 47 patients and 506 PARP cycles were identified (122 olaparib, 24%; 89 rucaparib, 18%; 294 niraparib, 58%). Incidence of grade ≥ 3 adverse events were similar to previously reported. Toxicity resulted in dose interruption, reduction and discontinuation in 69%, 63% and 29% respectively. Dose interruptions were most frequent for niraparib but resulted in fewer discontinuations (p-value 0.01). Mean duration of use was 7.46 cycles (olaparib 10.52, rucaparib 4.68, niraparib 7.34). Average cost of PARPi therapy was $8018 per cycle. A total of 711 phone calls were documented (call rate 1.4 calls/cycle) with the highest call volume required for care coordination, lab results and toxicity management. CONCLUSIONS: Although the toxicity profile was similar to randomized clinical trials, this real-world experience demonstrated more dose modifications and discontinuations for toxicity management than previously reported. Furthermore, the clinical and financial burden of PARP inhibitors may be significant and future studies should assess the impact on patient outcomes.

Cost-effectiveness of niraparib, rucaparib, and olaparib for treatment of platinum-resistant, recurrent ovarian carcinoma.

BACKGROUND: Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease. METHODS: Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non­platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations. RESULTS: Non­platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non­platinum-based regimens. CONCLUSION: High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.

Cost-Neutral Optimization of Pazopanib Exposure by Splitting Intake Moments: A Prospective Pharmacokinetic Study in Cancer Patients.

BACKGROUND AND OBJECTIVE: Pazopanib is an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and soft-tissue sarcoma. At the approved dose of 800 mg once daily (QD), 16-20% of patients are being underdosed and at risk of decreased efficacy. This study aimed to show whether splitting intake moments, as a cost-neutral alternative to a dose increase, leads to an increased exposure. METHODS: We performed a cross-over trial comparing the pharmacokinetics of pazopanib 800 mg QD with pazopanib 400 mg twice daily. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. RESULTS: Nine evaluable patients were included. At the 800 mg QD dosing schedule, median minimum plasma concentration (Cmin), area under the concentration-time curve from 0 to 24 h (AUC0-24h), and maximum plasma concentration (Cmax) were 23.2 mg/L (interquartile range 18.5-27.6), 773 mg h/L (557-1009), and 40.6 mg/L (36.4-56.4) compared with 41.6 mg/L (30.5-55.8, p = 0.004), 942 mg h/L (885-1419, p = 0.027), and 50.2 mg/L (46.8-72.5, p = 0.074) at 400 mg twice daily. One patient experienced a grade 3 event (i.e., diarrhea). CONCLUSIONS: This study demonstrates that splitting intake moments of pazopanib leads to a 79% increase in Cmin, with acceptable tolerability. Therefore, this new dosing schedule offers a cost-neutral opportunity to optimize treatment in patients with low exposure. CLINICAL TRIAL REGISTRATION: NL6137 ( http://www.trialregister.nl ).

Cost-Effectiveness of Niraparib Versus Routine Surveillance, Olaparib and Rucaparib for the Maintenance Treatment of Patients with Ovarian Cancer in the United States.

OBJECTIVES: The aim was to evaluate the cost-effectiveness of niraparib compared with routine surveillance (RS), olaparib and rucaparib for the maintenance treatment of patients with recurrent ovarian cancer (OC). METHODS: A decision-analytic model estimated the cost per quality-adjusted life-year (QALY) gained for niraparib versus RS, olaparib, and rucaparib from a US payer perspective. The model considered recurrent OC patients with or without germline BRCA mutations (gBRCAmut and non-gBRCAmut), who were responsive to their last platinum-based chemotherapy regimen. Model health states were: progression-free disease, progressed disease and dead. Mean progression-free survival (PFS) was estimated using parametric survival distributions based on ENGOT-OV16/NOVA (niraparib phase III trial), ARIEL3 (rucaparib phase III trial) and Study 19 (olaparib phase II trial). Mean overall survival (OS) benefit was estimated as double the mean PFS benefit based on the relationship between PFS and OS observed in Study 19. Costs included: drug, chemotherapy, monitoring, adverse events, and terminal care. EQ-5D utilities were estimated from trial data. RESULTS: Compared to RS, niraparib was associated with an incremental cost-effectiveness ratio (ICER) of US$68,287/QALY and US$108,287/QALY for gBRCAmut and non-gBRCAmut, respectively. Compared to olaparib and rucaparib, niraparib decreased costs and increased QALYs, with a cost saving of US$8799 and US$22,236 versus olaparib and US$198,708 and US$73,561 versus rucaparib for gBRCAmut and non-gBRCAmut, respectively. CONCLUSIONS: Niraparib was estimated to be less costly and more effective compared to olaparib and rucaparib, and the ICER fell within an acceptable range compared to RS. Therefore, niraparib may be considered a cost-effective maintenance treatment for patients with recurrent OC.

Micelle System Based on Molecular Economy Principle for Overcoming Multidrug Resistance and Inhibiting Metastasis.

The high mortality of cancer is mainly attributed to multidrug resistance (MDR) and metastasis. A simple micelle system was constructed here to codeliver doxorubicin (DOX), adjudin (ADD), and nitric oxide (NO) for overcoming MDR and inhibiting metastasis. It was devised based on the "molecular economy" principle as the micelle system was easy to fabricate and exhibited high drug loading efficiency, and importantly, each component of the micelles would exert one or more active functions. DOX acted as the main cell killing agent supplemented with ADD, NO, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). MDR was overcome by synergistic effects of mitochondria inhibition agents, TPGS and ADD. A TPGS-based NO donor can be used as a drug carrier, and it can release NO to enhance drug accumulation and penetration in tumor, resulting in a positive cycle of drug delivery. This DOX-ADD conjugate self-assembly system demonstrated controlled drug release, increased cellular uptake and cytotoxicity, enhanced accumulation at tumor site, and improved in vivo metastasis inhibition of breast cancer. The micelles can fully take advantage of the functions of each component, and they provide a potential strategy for nanomedicine design and clinical cancer treatment.

Real-world costs and outcomes in metastatic renal cell carcinoma patients treated with targeted therapies: a cohort study from the French health insurance database.

OBJECTIVES: The objective of this study was to describe treatment patterns, survival, healthcare use and costs in patients with metastatic renal cell carcinoma (mRCC) in a real-world setting. RESEARCH DESIGN AND METHODS: We used the National Health Insurance (NHI) claims database for the Ile-de-France region to perform a retrospective cohort analysis of patients with mRCC treated by a first-line targeted therapy. Treatment naïve patients were identified combining the 10th revision of the International Classification of Diseases (ICD-10) codes (C64 & C77-C79) and a first prescription of targeted therapies. Descriptive analyses were performed on treatment patterns and patients' characteristics. Progression free survival (PFS) and overall survival (OS) were determined using Kaplan-Meier actuarial survival analysis. All healthcare resource use and costs were estimated on a per patient per month (PPPM) basis (€2016). RESULTS: A total of 327 treatment naïve patients with mRCC were included. Median follow-up was 13.4 months. Sunitinib accounted for 73% of first-line treatments. The most frequently observed treatment sequence for the first two lines was sunitinib-everolimus (16%; n = 137) and for the first three lines sunitinib-everolimus-axitinib (20%; n = 49). First-line PFS for sunitinib, everolimus, pazopanib, sorafenib and other was 8.7, 6.2, 10.7, 5.7 and 11.2 months, respectively. Median OS for patients treated by first-line sunitinib, everolimus, pazopanib, sorafenib and other was respectively 14.7, 8.1, 21.1, 8.9 and 14.0 months. From the NHI's perspective, the mean PPPM was €5546. The average PPPM in pre-progression was €5597 compared to €5541 beyond progression of the disease. Oral targeted therapies accounted for 53% of the total PPPM. CONCLUSION: This descriptive study showed that the economic burden of mRCC is substantial with oral targeted therapies accounting for 53% of the PPPM. OS and PFS in real life are poorer than observed in clinical trials.

Assessment of Efficacy, Safety, and Quality of Life of 124 Patients Treated With Axitinib as Second-Line Therapy for Metastatic Renal-Cell Carcinoma: Experience in Real-World Clinical Practice in Japan.

PURPOSE: To comprehensively analyze the efficacy of axitinib for metastatic renal-cell carcinoma (mRCC) patients. PATIENTS AND METHODS: This study included 124 consecutive Japanese patients treated with axitinib as second-line systemic therapy for mRCC in a routine clinical setting. RESULTS: In addition to 4 indeterminate patients (3.2%), 0 (0%), 21 (16.9%), 87 (70.2%), and 12 (9.7%) were judged to show complete response, partial response, stable disease, and progressive disease, respectively, as the best responses to axitinib. The median progression-free survival (PFS) and overall survival (OS) after initiating treatment with axitinib were 9.3 and 27.0 months, respectively. Multivariate analyses of several parameters identified the following independent predictors of PFS and OS: Memorial Sloan Kettering Cancer Center (MSKCC) classification and C-reactive protein level for PFS; and MSKCC classification, C-reactive protein level, bone metastasis, and liver metastasis for OS. Common grade 3 or higher adverse events associated with axitinib were hypertension in 41 (33.1%), proteinuria in 14 (11.3%), and hand-foot syndrome in 14 (11.3%). Quality-of-life analysis using the Medical Outcomes Study 36-Item Short Form showed that 2 scores were significantly improved 12 weeks after the administration of axitinib, while there were no significant differences in the remaining 6 scores between surveys administered before and 12 weeks after the treatment with axitinib. CONCLUSION: Favorable disease control could be achieved with acceptable tolerability by introducing axitinib as second-line systemic therapy, resulting in improvement of the prognosis and quality of life of Japanese patients with mRCC.

Clinical and Translational Assessment of VEGFR1 as a Mediator of the Premetastatic Niche in High-Risk Localized Prostate Cancer.

Preclinical studies have suggested that VEGFR1-positive cells potentially foster the development of metastases by establishing a "premetastatic niche." We sought to test this hypothesis in high-risk localized prostate cancer and assess potential niche modulation by the VEGFR1-targeting drug axitinib. Formalin-fixed, paraffin-embedded tissue derived from benign lymph nodes was collected and VEGFR1-positive cell clustering was assessed in benign lymph nodes via IHC. Recursive partitioning was used to define a threshold for VEGFR1 clustering that could segregate patients based on time to biochemical recurrence (TTBR). Multivariate analyses were used to determine whether VEGFR1 clustering, age, pathologic T-stage, Gleason score, or baseline PSA could independently predict TTBR. A randomized, phase II clinical trial comparing axitinib for 28 days followed by radical prostatectomy and pelvic lymph node dissection (RP/PLND) to RP/LND alone was then conducted, with the primary endpoint of demonstrating downregulation of VEGFR1-positve cell clustering in benign lymph nodes. Our retrospective analysis assessed a cohort of 46 patients. A threshold of 1.65 VEGFR1-positive cells per high power field was identified, below which TTBR was delayed. VEGFR1 clustering was an independent predictor of TTBR in a multivariate analysis. Only 11 out of the planned 44 patients were accrued to the phase II trial. While preoperative axitinib was safe and well tolerated, there was no sign of clinical activity or VEGFR1 downregulation. Our results validate previous findings that suggest VEGFR1-positive cells in benign lymph nodes can predict clinical outcome. Further work is needed to develop a viable clinical strategy for modulating VEGFR1 in these tissues.

The European Medicines Agency approval of axitinib (Inlyta) for the treatment of advanced renal cell carcinoma after failure of prior treatment with sunitinib or a cytokine: summary of the scientific assessment of the committee for medicinal products for human use.

Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3. Based on the positive opinion from the European Medicines Agency (EMA), a marketing authorization valid throughout the European Union (EU) was issued for the treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. The demonstration of clinical benefit for axitinib was based on a phase III, randomized, open-label, multicenter study of axitinib compared with sorafenib in patients with advanced RCC after failure of a prior systemic first-line regimen containing one or more of the following agents: sunitinib, bevacizumab plus interferon-α, temsirolimus, or cytokines. In the primary analysis, a 2-month increase in median progression-free survival (PFS) was observed for axitinib compared with sorafenib (hazard ratio [HR]: 0.665; 95% confidence interval [CI]: 0.544-0.812; p < .0001). In the subgroup of patients with a prior cytokine-containing regimen, the increase in median PFS associated with axitinib was 5.4 months (updated analysis, HR: 0.519; 95% CI: 0.375-0.720; p < .0001). In the subgroup of patients with prior sunitinib treatment, the increase in median PFS was 1.4 months (updated analysis, HR: 0.736; 95% CI: 0.578-0.937; p = .0063). The analysis of overall survival showed no statistically significant survival benefit of axitinib over sorafenib in patients previously treated with cytokine-containing regimens (HR: 0.813; 95% CI: 0.556-1.191) or sunitinib (HR: 0.997; 95% CI: 0.782-1.270). The most common treatment-related adverse events associated with axitinib included diarrhea, hypertension, fatigue, nausea, decreased appetite, dysphonia, and palmar-plantar erythrodysesthesia. Most of these events were mild or moderate in severity. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

Combined use of pharmacokinetic modeling and a steady-state delivery approach allows early assessment of IkappaB kinase-2 (IKK-2) target safety and efficacy.

NF-kappaB activation is clearly linked to the pathogenesis of multiple inflammatory diseases including arthritis. The prominent role of IkappaB kinase-2 (IKK-2) in regulating NF-kappaB signaling in response to proinflammatory stimuli has made IKK-2 a primary anti-inflammation therapeutic target. PHA-408, a potent and selective IKK-2 inhibitor, was identified internally and used for our studies to assess this target. In early in vivo studies, PHA-408 demonstrated efficacy at high doses; however, the correlation between PHA-408 exposure and efficacy could not be established using standard dosing paradigms for the rat disease models. Similar concerns arose from early in vivo safety studies where appropriate NOAEL margins were not achieved. Following a full investigation of the physicochemical properties of the molecule and pharmacokinetic modeling, an oral steady-state delivery strategy was designed to administer PHA-408 to the rat for both efficacy and safety studies. Using this steady-state delivery, a clear dose-response relationship was established between plasma concentrations of PHA-408 and efficacy in the rat arthritis model. The same steady-state delivery approach was used to demonstrate the target safety. In summary, a combination of pharmacokinetic modeling with a steady-state delivery approach allowed us to establish confidence in both the mechanism and safety of the target.

Carcinogenicity assessment of lonidamine by dietary administration to Sprague-Dawley rats.

Following chronic dietary administration of 20, 60 and 180 mg/kg per day of lonidamine for 2 years to groups of Sprague-Dawley rats, treatment-related non-tumour findings seen microscopically included the following: atrophy of the testis with associated changes in epididymis and pituitary at all dosages; neuropathy in the sciatic nerve accompanied by skeletal muscle atrophy which was dose-related, particularly in male animals. Neither the incidence of tumour-bearing animals, nor the spectrum of tumours seen, was significantly changed. In the females given 180 mg/kg per day an overall reduction in tumour incidence was noted, which was reflected in a significant reduction (P < 0.001) in mammary tumours.