Plain language summary looking at how long side effects last after treatment with axitinib is stopped in people with advanced renal cell carcinoma.

Axitinib is a medication that stops cancer cell growth by depriving the cancer cell of the nutrients and oxygen that it needs. Axitinib is used to treat advanced renal cell carcinoma (RCC), which is a type of kidney cancer that has spread within or beyond the kidney. Axitinib has been approved for the treatment of RCC as either a first treatment option or a second treatment option. It is used as a first treatment option for RCC when combined with a medication that reactivates the immune system (immunotherapy), either avelumab or pembrolizumab. If the advanced RCC starts growing again it can be used as a second treatment option where it is taken by itself. It is essential to conduct studies to assess how well the drug works and whether it has any side effects in order to understand whether it is safe to give to people. This summary reports the combined results of 5 studies and looks at how long side effects last after treatment is temporarily stopped. Researchers found that side effects generally got better in 3 days or less after people stopped taking axitinib on its own. The time it took for side effects to get better was generally shorter than for other similar drugs or combinations of axitinib and immunotherapy. The results of individual studies may vary from these 5 combined study results. Three of the 5 studies were ongoing at the time of this analysis and the final outcomes of those studies may differ from those described in this summary. The purpose of this plain language summary is to help you understand the findings from recent research. Health professionals should make treatment decisions based on all available evidence. Clinical Trial Registration: NCT00678392, NCT00920816, NCT02493751, NCT02684006, NCT02853331 (ClinicalTrials.gov).

The impact of enzalutamide on quality of life in men with metastatic hormone-sensitive prostate cancer based on prior therapy, risk, and symptom subgroups.

BACKGROUND: Enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival versus ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in ARCHES (NCT02677896). While health-related quality of life (HRQoL) was generally maintained in the intent-to-treat population, we further analyzed patient-reported outcomes (PROs) in defined subgroups. METHODS: ARCHES was a randomized, double-blind, placebo-controlled, phase 3 study. Patients with mHSPC received enzalutamide (160 mg/day) plus ADT (n = 574) or placebo plus ADT (n = 576). Questionnaires, including the Functional Assessment of Cancer Therapy-Prostate, Brief Pain Inventory-Short Form, and EuroQol 5-Dimension, 5-Level (EQ-5D-5L), were completed at baseline, Week 13, and every 12 weeks until disease progression. PRO endpoints were time to first confirmed clinically meaningful deterioration (TTFCD) in HRQoL or pain. Subgroups included prognostic risk, pain/HRQoL, prior docetaxel, and local therapy (radical prostatectomy [RP] and/or radiotherapy [RT]). RESULTS: There were several between-treatment differences in TTFCD for pain and functioning/HRQoL PROs. Enzalutamide plus ADT delayed TTFCD for worst pain in the prior RT group (not reached vs. 14.06 months; hazard ratio [HR]: 0.56 [95% confidence interval: 0.34-0.94]) and pain interference in low-baseline-HRQoL group (19.32 vs. 11.20 months; HR: 0.64 [0.44-0.94]) versus placebo plus ADT. In prior/no prior RP, prior RT, prior local therapy, no prior docetaxel, mild baseline pain, and low-risk subgroups, TTFCD was delayed for the EQ-5D-5L visual analog scale. CONCLUSION: Enzalutamide plus ADT provides clinical benefits in defined patient subgroups versus ADT alone, while maintaining lack of pain and high HRQoL, with delayed deterioration in several HRQoL measures.

Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer by Pattern of Metastatic Spread: ARCHES Post Hoc Analyses.

PURPOSE: Enzalutamide plus androgen deprivation therapy has previously been shown to improve clinical outcomes in men with metastatic hormone-sensitive prostate cancer (ARCHES; NCT02677896). Here, we assessed if and how the pattern of metastatic spread impacts efficacy of enzalutamide plus androgen deprivation therapy in men enrolled in ARCHES. MATERIALS AND METHODS: Men with metastatic hormone-sensitive prostate cancer were randomized 1:1 to enzalutamide (160 mg/day) plus androgen deprivation therapy or placebo plus androgen deprivation therapy, stratified by disease volume and prior docetaxel treatment. The primary end point was radiographic progression-free survival. Secondary end points included time to prostate specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event and castration resistance. Post hoc analyses were performed by pattern of metastatic spread based on study entry imaging. RESULTS: Of the overall population with metastases identified at enrollment (1,146), the largest patient subgroups were those with bone metastases only (513) and those with bone plus lymph node metastases (351); there were fewer men with lymph node metastases only (154) and men with visceral±bone or lymph node metastases (128). Enzalutamide plus androgen deprivation therapy reduced the risk of radiographic progression vs placebo plus androgen deprivation therapy in men with bone metastases only (HR 0.33) and bone plus lymph node metastases (HR 0.31). Similar improvements in secondary end points were also observed in these subgroups. CONCLUSIONS: These findings indicate that treatment with enzalutamide plus androgen deprivation therapy provides improvements in men with bone and/or lymph node metastases but may be less effective in men with visceral patterns of spread.

Enzalutamide with androgen deprivation therapy in Japanese men with metastatic hormone-sensitive prostate cancer: A subgroup analysis of the phase III ARCHES study.

OBJECTIVE: To evaluate the efficacy and safety of enzalutamide plus androgen deprivation therapy in Japanese men with metastatic hormone-sensitive prostate cancer. METHODS: A post-hoc analysis of the Japanese subgroup in the phase III, randomized, multinational ARCHES study (NCT02677896) was carried out. Patients with metastatic hormone-sensitive prostate cancer were randomized to receive enzalutamide or a placebo, plus androgen deprivation therapy, stratified by disease volume and prior docetaxel therapy. The primary end-point was radiographic progression-free survival. Secondary end-points included time to prostate-specific antigen progression and overall survival. RESULTS: Of 1150 patients, 92 Japanese patients were randomized to enzalutamide (n = 36) or a placebo (n = 56), plus androgen deprivation therapy; none received prior docetaxel. Enzalutamide plus androgen deprivation therapy reduced the risk of radiographic progression or death in Japanese patients by 61% versus the placebo, similar to the overall population. Similar results were observed with secondary end-points, showing clinical benefit of enzalutamide plus androgen deprivation therapy in Japanese patients. Overall survival data were immature. Grade 3-4 adverse events were reported in 47% and 25% of the enzalutamide and placebo groups, respectively. Nasopharyngitis, hypertension and abnormal hepatic function were reported more frequently in Japanese patients versus the overall population. CONCLUSIONS: Enzalutamide plus androgen deprivation therapy has clinical benefit with a tolerable safety profile in Japanese men with metastatic hormone-sensitive prostate cancer, consistent with the overall population.

A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors.

LESSONS LEARNED: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. BACKGROUND: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. METHODS: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. RESULTS: No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9-54.3), and progression-free survival was 5.6 months (95% CI, 3.5-not reached). CONCLUSION: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.

Sunitinib in patients with pancreatic neuroendocrine tumors: update of safety data.

AIM: To describe the long-term safety of sunitinib in patients with progressive, well-differentiated, advanced/metastatic pancreatic neuroendocrine tumors. PATIENTS & METHODS: Sunitinib- and placebo-treated patients from the Phase III study continued to receive sunitinib (37.5 mg on a continuous daily-dosing regimen) in two open-label extension studies. RESULTS: Median (range) treatment exposure: 30.2 (0.7-269.4) and 87.1 (3.9-319.4) weeks for medium-term (n = 41) and long-term-treated (n = 61) populations, respectively. All patients experienced ≥1 adverse event (AE); 47 (45.6%) reported serious AEs. Common all-causality AEs: diarrhea (63.1%); neutropenia (43.7%); abdominal pain (40.8%). Fifteen (14.6%) patients discontinued treatment due to treatment-related AEs. CONCLUSION: The safety of extended sunitinib treatment was consistent with the known safety profile of sunitinib in pancreatic neuroendocrine tumors.

First-line axitinib versus sorafenib in Asian patients with metastatic renal cell carcinoma: exploratory subgroup analyses of Phase III data.

AIM: Efficacy/safety of first-line axitinib in Asian patients with metastatic renal cell carcinoma. METHODS: Patients were assigned (2:1) to 5-mg axitinib (n = 48) or 400-mg sorafenib (n = 24) twice daily. Primary end point was progression-free survival. Objective response rate, overall survival and adverse events were also assessed. RESULTS: For axitinib versus sorafenib, hazard ratio for progression-free survival was 0.652 (95% CI: 0.340-1.252; p = 0.0989), objective response rate was higher (35.4 vs 16.7%; p = 0.0495), overall survival longer (hazard ratio: 0.739; 95% CI: 0.397-1.375; p = 0.1683). Palmar-plantar erythrodysesthesia (57.4%), diarrhea (55.3%), hypertension (51.1%) were commonest adverse events with axitinib; palmar-plantar erythrodysesthesia (50.0%) with sorafenib. CONCLUSION: Axitinib improved efficacy in Asian patients with metastatic renal cell carcinoma; adverse events were consistent with previous findings.

Pharmacogenomic analyses of sunitinib in patients with pancreatic neuroendocrine tumors.

Aim: Evaluate associations between clinical outcomes and SNPs in patients with well-differentiated pancreatic neuroendocrine tumors receiving sunitinib. Patients & methods: Kaplan-Meier and Cox proportional hazards models were used to analyze the association between SNPs and survival outcomes using data from a sunitinib Phase IV (genotyped, n = 56) study. Fisher's exact test was used to analyze objective response rate and genotype associations. Results: After multiplicity adjustment, progression-free and overall survivals were not significantly correlated with SNPs; however, a higher objective response rate was significantly associated with IL1B rs16944 G/A versus G/G (46.4 vs 4.5%; p = 0.001). Conclusion: IL1B SNPs may predict treatment response in patients with pancreatic neuroendocrine tumors. VEGF pathway SNPs are potentially associated with survival outcomes.

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.

BACKGROUND: Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. METHODS: In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. FINDINGS: Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). INTERPRETATION: The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). FUNDING: Pfizer Inc.

Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours.

BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial.

BACKGROUND: In previous clinical trials of patients with metastatic renal-cell carcinoma, patients treated with axitinib as second-line therapy had longer median progression-free survival than those treated with sorafenib. We therefore undertook a phase 3 trial comparing axitinib with sorafenib in patients with treatment-naive metastatic renal-cell carcinoma. METHODS: In this randomised, open-label, phase 3 trial, patients with treatment-naive, measurable, clear-cell metastatic renal-cell carcinoma from 13 countries were stratified by Eastern Cooperative Oncology Group performance status, and then randomly assigned (2:1) by a centralised registration system to receive axitinib 5 mg twice daily, or sorafenib 400 mg twice daily. The primary endpoint was progression-free survival, assessed by masked independent review committee in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT00920816. FINDINGS: Between June 14, 2010, and April 21, 2011, we randomly assigned 192 patients to receive axitinib, and 96 patients to receive sorafenib. The cutoff date for this analysis was July 27, 2012, when 171 (59%) of 288 patients died or had disease progression, as assessed by the independent review committee. There was no significant difference in median progression-free survival between patients treated with axitinib or sorafenib (10·1 months [95% CI 7·2-12·1] vs 6·5 months [4·7-8·3], respectively; stratified hazard ratio 0·77, 95% CI 0·56-1·05). Any-grade adverse events that were more common (≥10% difference) with axitinib than with sorafenib were diarrhoea (94 [50%] of 189 patients vs 38 [40%] of 96 patients), hypertension (92 [49%] vs 28 [29%]), weight decrease (69 [37%] vs 23 [24%]), decreased appetite (54 [29%] vs 18 [19%]), dysphonia (44 [23%] vs ten [10%]), hypothyroidism (39 [21%] vs seven [7%]), and upper abdominal pain (31 [16%] vs six [6%]); those more common with sorafenib than with axitinib included palmar-plantar erythrodysaesthesia (PPE; 37 [39%] of 96 patients vs 50 [26%] of 189), rash (19 [20%] vs 18 [10%]), alopecia (18 [19%] vs eight [4%]), and erythema (18 [19%] vs five [3%]). The most common grade 3 or 4 adverse events in patients treated with axitinib included hypertension (26 [14%] of 189 patients), diarrhoea (17 [9%]), asthenia (16 [8%]), weight decrease (16 [8%]), and PPE (14 [7%]); common grade 3 or 4 adverse events in patients treated with sorafenib included PPE (15 [16%] of 96 patients), diarrhoea (five [5%]), and asthenia (five [5%]). Serious adverse events were reported in 64 (34%) of 189 patients receiving axitinib, and 24 (25%) of 96 patients receiving sorafenib. INTERPRETATION: Axitinib did not significantly increase progression-free survival in patients with treatment-naive metastatic renal-cell carcinoma compared with those treated with sorafenib, but did demonstrate clinical activity and an acceptable safety profile. FUNDING: Pfizer Inc.

Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.

BACKGROUND: In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results. METHODS: Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov, number NCT00678392. FINDINGS: Median overall survival was 20.1 months (95% CI 16.7-23.4) with axitinib and 19.2 months (17.5-22.3) with sorafenib (hazard ratio [HR] 0.969, 95% CI 0.800-1.174; one-sided p=0.3744). Median investigator-assessed PFS was 8.3 months (95% CI 6.7-9.2) with axitinib and 5·7 months (4.7-6.5) with sorafenib (HR 0.656, 95% CI 0.552-0.779; one-sided p<0.0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 [17%]), diarrhoea (40 [11%]), and fatigue (37 [10%]) in 359 axitinib-treated patients and hand-foot syndrome (61 [17%]), hypertension (43 [12%]), and diarrhoea (27 [8%]) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20.7 months (95% CI 18.4-24.6) versus 12.9 months (10.1-20.4) in the axitinib group (p=0.0116), and 20.2 months (17.1-32.0) versus 14.8 months (12.0-17.7) in the sorafenib group (one-sided p=0.0020). INTERPRETATION: Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma. FUNDING: Pfizer Inc.

Axitinib and/or bevacizumab with modified FOLFOX-6 as first-line therapy for metastatic colorectal cancer: a randomized phase 2 study.

BACKGROUND: In this multicenter, open-label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first-line treatment of metastatic colorectal cancer (mCRC). METHODS: Patients with previously untreated mCRC were randomized 1:1:1 to receive continuous axitinib 5 mg twice daily, bevacizumab 5 mg/kg every 2 weeks, or axitinib 5 mg twice daily plus bevacizumab 2 mg/kg every 2 weeks, each in combination with modified 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX-6). The primary endpoint was the objective response rate (ORR). RESULTS: In all, 126 patients were enrolled from August 2007 to September 2008. The ORR was numerically inferior in the axitinib arm (n = 42) versus the bevacizumab arm (n = 43; 28.6% vs 48.8%; 1-sided P = .97). Progression-free survival (PFS) (11.0 months vs 15.9 months; 1-sided P = .57) and overall survival (OS) (18.1 months vs 21.6 months; 1-sided P = .69) also were numerically inferior in the axitinib arm. Similarly, efficacy endpoints for the axitinib/bevacizumab arm (n = 41) were numerically inferior (ORR, 39%; PFS, 12.5 months; OS, 19.7 months). The patients who received axitinib had fewer treatment cycles compared with other arms. Common all-grade adverse events across all 3 treatment arms were fatigue, diarrhea, and nausea (all ≥49%). Hypertension and headache were more frequent in the patients who received axitinib. Patients in the bevacizumab arm had the longest treatment exposures and the highest rates of peripheral neuropathy. CONCLUSIONS: Neither the addition of continuous axitinib nor the axitinib/bevacizumab combination to FOLFOX-6 improved ORR, PFS, or OS compared with bevacizumab as first-line treatment of mCRC.

Clinical Outcomes of Enzalutamide in Metastatic Hormone-sensitive Prostate Cancer in Patients Aged <75 and ≥75 Years: ARCHES Post Hoc Analysis.

BACKGROUND: In ARCHES, treatment intensification of androgen deprivation therapy (ADT) with enzalutamide versus placebo improved clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC). Understanding the benefits and tolerability of enzalutamide for men aged ≥75 yr may inform disease management. OBJECTIVE: To determine whether age is associated with clinical outcomes in mHSPC. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of the multinational, double-blind, randomized, placebo-controlled, phase 3 ARCHES trial in 1150 men with mHSPC (median follow-up [mo]: <75 yr, 44.6; ≥75 yr, 44.3) was performed. INTERVENTION: Randomization 1:1 to enzalutamide (160 mg/d) plus ADT or placebo plus ADT; stratification by disease volume and prior docetaxel use. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), radiographic progression-free survival (rPFS), safety, and other secondary endpoints were compared between age groups (<75 and ≥75 yr) and treatment arms (Cox proportional hazard models). RESULTS AND LIMITATIONS: Men aged <75 versus ≥75 yr had longer OS (enzalutamide plus ADT: hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.47-0.91; p = 0.02; placebo plus ADT: HR 0.81; 95% CI 0.60-1.09; p = 0.13) and rPFS (enzalutamide plus ADT: HR 0.78; 95% CI 0.58-1.04; p = 0.12; placebo plus ADT: HR 0.98; 95% CI 0.74-1.30; p = 0.007). Enzalutamide improved OS (<75 yr: HR 0.61; 95% CI 0.47-0.79; ≥75 yr: HR 0.76; 95% CI 0.54-1.09) and secondary efficacy endpoints without evidence of statistical heterogeneity, and was generally well tolerated in both age groups, with minimal quality-of-life impact. Older versus younger patients experienced more frequent dose interruptions (20.2% vs 10.9%) and treatment-emergent adverse events (95.2% vs 89.1%). Post hoc examination and small sample size preclude definitive conclusions. CONCLUSIONS: Enzalutamide plus ADT improved efficacy outcomes and was generally well tolerated despite shorter treatment exposure in older patients, indicating enzalutamide's utility in patients with mHSPC aged <75 and ≥75 yr. PATIENT SUMMARY: Enzalutamide is a drug approved to treat men with prostate cancer. In this report, we compared patients aged <75 and ≥75 yr treated with enzalutamide plus androgen deprivation therapy to determine whether age affected how long they lived without the cancer spreading to other parts of their body. We found that, although younger patients had more favorable survival outcomes, enzalutamide was associated with longer survival and reduced disease spread in both age groups.

The Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: A Post Hoc Analysis of ARCHES.

BACKGROUND: Few phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk of undertreatment. OBJECTIVE: To evaluate outcomes for patients with oligometastatic and polymetastatic HSPC treated with enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of data for 927 patients with nonvisceral metastatic HSPC in the ARCHES trial (NCT02677896). INTERVENTION: Patients were randomized 1:1 to enzalutamide (160 mg/d orally) plus ADT or placebo plus ADT with HSPC categorized as oligometastatic (1-5 metastases) or polymetastatic (≥6 metastases). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The treatment effect on radiographic progression-free survival (rPFS), overall survival (OS), and secondary efficacy endpoints was evaluated in terms of the number of metastases. Safety was assessed. Cox proportional hazards models were used to generate hazard ratios (HRs). The Brookmeyer and Crowley method was used to generate 95% confidence intervals (CIs) for Kaplan-Meier median values. RESULTS AND LIMITATIONS: Enzalutamide plus ADT improved rPFS (HR 0.27, 95% CI 0.16-0.46; p < 0.001), OS (HR 0.59, 95% CI 0.40-0.87; p < 0.005), and secondary endpoints in patients with oligometastatic or polymetastatic disease (rPFS: HR 0.33, 95% CI 0.23-0.46; p < 0.001; OS: HR 0.55, 95% CI 0.41-0.74; p < 0.001). Safety profiles were generally similar across subgroups. Limitations include the small numbers of patients with fewer than three metastases. CONCLUSIONS: This post hoc analysis demonstrated the utility of enzalutamide, irrespective of metastatic burden or type of oligometastatic disease, and suggests that earlier treatment intensification with systemic potent androgen receptor inhibition is advantageous. PATIENT SUMMARY: This study considered two treatment options for metastatic hormone-sensitive prostate cancer in patients with one to five metastases or six or more metastases. Treatment with enzalutamide plus ADT improved survival and other outcomes over ADT alone, whether patients had few or many metastases.

Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.

BACKGROUND: The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. METHODS: We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392. FINDINGS: A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544-0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm. INTERPRETATION: Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma. FUNDING: Pfizer Inc.

Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In primary analysis, enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC); however, overall survival data were immature. In the phase III, double-blind, global ARCHES trial (ClinicalTrials.gov identifier: NCT02677896), 1,150 patients with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg once daily) plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. Here, we report the final prespecified analysis of overall survival (key secondary end point) and an update on rPFS, other secondary end points, and safety. After unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. As of May 28, 2021 (median follow-up, 44.6 months), 154 of 574 patients randomly assigned to enzalutamide plus ADT and 202 of 576 patients randomly assigned to placebo plus ADT had died. Enzalutamide plus ADT reduced risk of death by 34% versus placebo plus ADT (median not reached in either group; hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P < .001). Enzalutamide plus ADT continued to improve rPFS and other secondary end points. Adverse events were generally consistent with previous reports of long-term enzalutamide use. In conclusion, enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in patients with mHSPC.

Efficacy of enzalutamide in subgroups of men with metastatic hormone-sensitive prostate cancer based on prior therapy, disease volume, and risk.

BACKGROUND: While enzalutamide plus androgen deprivation therapy (ADT) significantly reduces the risk of radiographic progression-free survival (rPFS) and improves overall survival in metastatic hormone-sensitive prostate cancer (mHSPC), the efficacy in clinically relevant subgroups of patients based on prior local and systemic therapy, disease volume, and risk has not been analyzed to date. These post hoc analyses of the phase 3 ARCHES trial (NCT02677896) evaluated the efficacy of enzalutamide plus ADT according to prior local and systemic treatment, disease volume, and risk, assessed at trial baseline. METHODS: In ARCHES, a global, double-blind, placebo-controlled, phase 3 study, 1150 patients with mHSPC were randomized 1:1 to receive enzalutamide (160 mg/day) plus ADT or placebo plus ADT, stratified by prior docetaxel therapy and disease volume. Primary endpoint was rPFS. Secondary endpoints included time to prostate-specific antigen progression, symptomatic skeletal events, and prostate-specific antigen and radiographic responses. Analyses of clinical endpoints were completed by prior local therapy, prior docetaxel exposure, CHAARTED (NCT00309985)-defined disease volume, and LATITUDE (NCT01715285)-defined risk groups. RESULTS: Patients were randomized to enzalutamide plus ADT (n = 574) and placebo plus ADT (n = 576). Enzalutamide plus ADT significantly improved rPFS (hazard ratio: 0.39; p < 0.0001), with similar improvements reported in all subgroups based on prior local and docetaxel treatment, disease volume, and risk. Treatment benefits were observed with enzalutamide plus ADT in multiple secondary clinical endpoints in the overall population and all subgroups. CONCLUSIONS: Enzalutamide plus ADT demonstrated clinical benefit across all patients with mHSPC, irrespective of prior local and systemic treatment, disease volume, and risk.

Updated Efficacy and Safety Outcomes for Patients with Well-Differentiated Pancreatic Neuroendocrine Tumors Treated with Sunitinib.

BACKGROUND: Sunitinib prolonged progression-free survival (PFS) versus placebo in patients with metastatic pancreatic neuroendocrine tumors (panNETs) in a phase III trial. The efficacy and safety of sunitinib in patients with panNETs were confirmed in an open-label phase IV trial. OBJECTIVE: To assess the clinical benefit with sunitinib using the combined data from these trials. PATIENTS AND METHODS: An updated overall survival (OS) in patients with panNETs for the phase IV trial was provided, and an analysis of results from the sunitinib-treated combined cohort from the phase III and IV trials (combined cohort) was conducted to assess PFS, OS, and objective response rate (ORR). RESULTS: The updated median OS for the phase IV trial was 54.1 months (95% CI 37.9-not reached). Investigator-assessed median PFS for the combined cohort (n = 102) was 12.9 months (95% CI 7.4-16.7) with a significant benefit versus placebo in the phase III trial (n = 35) (HR 0.429; 95% CI 0.245-0.752; p = 0.001). Median OS could not be calculated for the combined cohort or placebo group due to the high number of patients censored; however, the estimated HR of 0.303 (CI 0.100-0.921; p = 0.013) favored sunitinib. ORR for the combined cohort was 16.7% (95% CI 10.0-25.3). Sunitinib was well tolerated in both trials with a safety profile similar to previously seen in other studies. CONCLUSIONS: The combined analysis of these studies confirms the objective tumor responses and improvements in PFS observed in the initial phase III trial, providing further support for the clinical benefit of sunitinib in patients with advanced panNETs. CLINICALTRIALS. GOV IDENTIFIERS: NCT00428597 and NCT01525550.