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PURPOSE For patients with metastatic hormone-sensitive prostate cancer, metastatic burden affects outcome. We examined efficacy and safety from the ARASENS trial for subgroups by disease volume and risk. METHODS Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel. High-volume disease was defined as visceral metastases and/or ≥ 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis. High-risk disease was defined as ≥ 2 risk factors: Gleason score ≥ 8, ≥ 3 bone lesions, and presence of measurable visceral metastases. RESULTS Of 1,305 patients, 1,005 (77%) had high-volume disease and 912 (70%) had high-risk disease. Darolutamide increased overall survival (OS) versus placebo in patients with high-volume (hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.82), high-risk (HR, 0.71; 95% CI, 0.58 to 0.86), and low-risk disease (HR, 0.62; 95% CI, 0.42 to 0.90), and in the smaller low-volume subgroup, the results were also suggestive of survival benefit (HR, 0.68; 95% CI, 0.41 to 1.13). Darolutamide improved clinically relevant secondary end points of time to castration-resistant prostate cancer and subsequent systemic antineoplastic therapy versus placebo in all disease volume and risk subgroups. Adverse events (AEs) were similar between treatment groups across subgroups. Grade 3 or 4 AEs occurred in 64.9% of darolutamide patients versus 64.2% of placebo patients in the high-volume subgroup and 70.1% versus 61.1% in the low-volume subgroup. Among the most common AEs, many were known toxicities related to docetaxel. CONCLUSION In patients with high-volume and high-risk/low-risk metastatic hormone-sensitive prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel increased OS with a similar AE profile in the subgroups, consistent with the overall population. [Media: see text]

15 Background: In ARASENS (NCT02799602), DARO plus ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI: 0.57–0.80; P

148 Background: In ARASENS (NCT02799602), DARO in combination with ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P2 q21d for 6 cycles). The effect of DARO on DOC PK was assessed by noncompartmental analysis from the first 25 patients with dense PK data and by population PK (PopPK) for all patients. DARO PK from ARASENS were compared with PK data from ARAMIS (NCT02200614; without DOC) to evaluate the impact of DOC on DARO PK. Results: Of 1306 randomized patients, 1305 were included in the full analysis set (DARO, n=651; PBO, n=654). The median treatment duration was longer with DARO vs PBO (41.0 vs 16.7 months) and more DARO-treated patients (45.9% vs 19.1%) were still receiving treatment at primary analysis cutoff (Oct 25, 2021). Almost all patients completed 6 cycles of DOC in both groups (DARO, 87.6%; PBO, 85.5%). The proportion of patients requiring DOC dose modification (interrupted/delayed or reduced) was similar between groups (DARO, 60.0%; PBO, 62.9%). TEAEs led to discontinuation/reduction of DOC in 8.0%/19.9% of DARO patients and 10.3%/19.5% of PBO patients. PopPK analysis indicated that DOC PK in ARASENS was generally consistent with that in the literature. A slight numeric increase in DOC exposure was observed in the DARO + DOC + ADT arm, with 15% higher maximum plasma concentration (geometric mean, 1.93 vs 1.68 µg/mL) and 6% higher area under the concentration-time curve (AUC0-tlast within an 8-hour sampling interval, 2.10 vs 1.99 µg·h/mL) vs PBO + DOC + ADT. This small numeric increase is likely not clinically relevant given the variability in DOC exposure (coefficient of variation, 23%–54%). PK meta-analysis of ARASENS and, which considered patients’ intrinsic characteristics as covariates (eg, age, body weight, region), indicated a 10% lower AUC0-12ss of DARO in patients receiving DOC vs those not receiving DOC, which is not considered clinically relevant. Conclusions: The combination of DARO + DOC + ADT increases overall survival with similar overall incidence of TEAEs and no observed drug-drug interactions between DARO and DOC. DARO can be effectively and safely administered with DOC in patients with mHSPC without clinically relevant changes in PK of DARO or DOC. Clinical trial information: NCT02799602 .

Darolutamide is a structurally distinct androgen-receptor inhibitor that is approved for the treatment of nonmetastatic, castration-resistant prostate cancer. In the planned primary analysis of a phase 3 trial, the median metastasis-free survival was significantly longer with darolutamide (40.4 months) than with placebo (18.4 months). The data for the analysis of overall survival were immature at the time of the primary analysis.In this double-blind, placebo-controlled trial, we randomly assigned 1509 men, in a 2:1 ratio, to receive darolutamide (955 patients) or placebo (554 patients) while they continued to receive androgen-deprivation therapy. After the results of the primary end-point analysis were found to be positive, unblinding of the treatment assignments occurred, and patients in the placebo group were permitted to cross over to receive open-label darolutamide treatment. At the time of this prespecified final analysis, which had been planned to be performed after approximately 240 deaths had occurred, overall survival and all other secondary end points were evaluated.The median follow-up time was 29.0 months. At the time of unblinding of the data, all 170 patients who were still receiving placebo crossed over to receive darolutamide; 137 patients who had discontinued placebo before unblinding had occurred received at least one other life-prolonging therapy. Overall survival at 3 years was 83% (95% confidence interval [CI], 80 to 86) in the darolutamide group and 77% (95% CI, 72 to 81) in the placebo group. The risk of death was significantly lower, by 31%, in the darolutamide group than in the placebo group (hazard ratio for death, 0.69; 95% CI, 0.53 to 0.88; P = 0.003). Darolutamide was also associated with a significant benefit with respect to all other secondary end points, including the time to first symptomatic skeletal event and the time to first use of cytotoxic chemotherapy. The incidence of adverse events after the start of treatment was similar in the two groups; no new safety signals were observed.Among men with nonmetastatic, castration-resistant prostate cancer, the percentage of patients who were alive at 3 years was significantly higher among those who received darolutamide than among those who received placebo. The incidence of adverse events was similar in the two groups. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).

Background In the phase 3 GRID trial, regorafenib improved progression-free survival (PFS) independent of KIT mutations in exons 9 and 11. In this retrospective, exploratory analysis of the GRID trial, we investigated whether a more comprehensive KIT mutation analysis could identify mutations that impact treatment outcome with regorafenib and a regorafenib-induced mutation pattern. Methods Archived tumor samples, collected at any time prior to enrollment in GRID, were analyzed by Sanger sequencing (n = 102) and next-generation sequencing (FoundationONE; n = 47). Plasma samples collected at baseline were analyzed by BEAMing (n = 163) and SafeSEQ (n = 96). Results In archived tumor samples, 67% (68/102) had a KIT mutation; 61% (62/102) had primary KIT mutations (exons 9 and 11) and 12% (12/102) had secondary mutations (exons 13, 14, 17, and 18). At baseline, 81% of samples (78/96) had KIT mutations by SafeSEQ, including the M541L polymorphism (sole event in 6 patients). Coexisting mutations in other oncogenes were rare, as were mutations in PDGFR, KRAS, and BRAF. Regorafenib showed PFS benefit across all primary and secondary KIT mutational subgroups examined. Available patient-matched samples taken at baseline and end of treatment (n = 41; SafeSEQ), revealed heterogeneous KIT mutational changes with no specific mutation pattern emerging upon regorafenib treatment. Conclusion These data support the results of the GRID trial, and suggest that patients may benefit from regorafenib in the presence of KIT mutations and without the selection of particular mutation patterns that confer resistance. The study was not powered to address biomarker-related questions, and the results are exploratory and hypothesis-generating.

Darolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis and death in men with nonmetastatic, castration-resistant prostate cancer.We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg [two 300-mg tablets] twice daily) or placebo while continuing androgen-deprivation therapy. The primary end point was metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks.In total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end-point events had occurred, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence interval, 0.34 to 0.50; P0.001). Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. The incidence of adverse events that occurred or worsened during the treatment period and had a frequency of 5% or more or were of grade 3 or higher was similar in the two groups; all such events except fatigue occurred in less than 10% of patients in either group. The percentage of patients who discontinued the assigned regimen because of adverse events was 8.9% in the darolutamide group and 8.7% in the placebo group. Darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension than placebo.Among men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo. The incidence of adverse events was similar for darolutamide and placebo. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).

5078 Background: Reductions in PSA level have been associated with improved OS in patients (pts) with mHSPC. In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) in combination with docetaxel significantly reduced the risk of death by 32.5% (hazard ratio [HR] 0.675; 95% confidence interval [CI] 0.568–0.801; P< 0.0001) vs ADT + docetaxel in pts with mHSPC. We report the association between PSA response and OS from ARASENS. Methods: Pts with mHSPC were randomized 1:1 to DARO 600 mg twice daily or matching PBO + ADT and docetaxel. Serum PSA was measured at screening and every 12 weeks. Exploratory analyses included time to PSA progression (≥25% increase from PSA nadir [lowest or at study entry] and PSA increase ≥2 ng/mL ≥12 weeks from nadir [both confirmed by a second value ≥3 weeks later]) and undetectable PSA (< 0.2 ng/mL for 2 samples ≥3 weeks apart) at 24, 36, and 52 weeks and any time during treatment. Comparisons between treatment groups were performed using the Cochran-Mantel Haenszel test stratified by randomization stratification factors (metastatic spread according to TNM classification and alkaline phosphatase levels at study entry). Post hoc landmark analyses evaluated the association between undetectable PSA at weeks 24 and 36 and OS for the overall population. Results: Of 1306 randomized pts, 1305 were included in the full analysis set (DARO 651; PBO 654), both with ADT and docetaxel. Median (range) PSA levels at study entry were 30.3 (0.0–9219.0) and 24.2 (0.0–11,947.0) ng/mL, respectively. DARO significantly prolonged time to PSA progression (HR 0.255; 95% CI 0.208–0.313; P< 0.0001). Undetectable PSA was achieved in more pts receiving DARO (48.7%) vs PBO (23.9%) at 24 weeks, and the rate continued to increase at 36 and 52 weeks in the DARO group to 57.1% and 60.2%, respectively, vs minimal change in the PBO group (25.1% and 26.1%). Undetectable PSA levels at any time were achieved in 67.3% in the DARO group and 28.6% in the PBO group. A treatment difference in undetectable PSA based on non-overlapping 95% CIs was observed at all time points. For the overall population, OS was improved for pts who achieved undetectable PSA levels vs those who did not at 24 weeks (HR 0.398; 95% CI 0.321–0.493) and 36 weeks (HR 0.351; 95% CI 0.284–0.434). Additional baseline and safety data by PSA level will be reported. Conclusions: The combination of DARO + ADT and docetaxel significantly prolonged the time to PSA progression and more pts receiving DARO vs PBO achieved undetectable PSA levels, reflecting strong PSA response over time. In pts with mHSPC, achievement of undetectable PSA at 24 and 36 weeks was associated with improved OS, with risk of death reduced by 60% and 65%, respectively, vs those who did not achieve undetectable PSA at 24 and 36 weeks. Clinical trial information: NCT02799602.

Background: In the ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT significantly improved metastasis-free survival (MFS), overall survival (OS) and time to pain progression in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Herein, we present analyses of patient-reported health-related quality of life (HRQoL) outcomes. Patients and methods: This double-blind, placebo-controlled, phase III trial randomised patients with nmCRPC and prostate-specific antigen doubling time ≤10 months to darolutamide 600 mg (n = 955) twice daily or matched placebo (n = 554) while continuing ADT. The primary end-point was MFS; the secondary end-points included OS and time to pain progression. In this analysis, HRQoL was assessed by the time to deterioration using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) prostate cancer subscale (PCS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer Module (EORTC QLQ-PR25) subscales. Results: Darolutamide significantly prolonged time to deterioration of FACT-P PCS versus placebo (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.70–0.91; P = 0.0005) at the primary analysis (cut-off date: 3rd September 2018). Time to deterioration of EORTC QLQ-PR25 outcomes showed statistically significant delays with darolutamide versus placebo for urinary (HR 0.64, 95% CI 0.54–0.76; P < 0.0001) and bowel (HR 0.78, 95% CI 0.66–0.92; P = 0.0027) symptoms. Time to worsening of hormonal treatment–related symptoms was similar between the two groups. Conclusion: In patients with nmCRPC who are generally asymptomatic, darolutamide maintained HRQoL by significantly delaying time to deterioration of prostate cancer–specific quality of life and disease-related symptoms versus placebo. publishedVersion

Background Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. Methods In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. Results In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11–0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. Conclusions Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

13 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor that demonstrated improved overall survival (OS) and metastasis-free survival vs placebo (PBO) and a low incidence of treatment-emergent adverse events (TEAEs) in patients (pts) with nonmetastatic castration-resistant prostate cancer (CRPC). We investigated whether DARO in combination with standard androgen-deprivation therapy (ADT) + docetaxel would increase OS in pts with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS study (NCT02799602). Methods: This international, double-blind, phase 3 study enrolled pts with mHSPC and ECOG PS 0/1 who were randomized 1:1 to DARO 600 mg twice daily or matching PBO in addition to ADT + docetaxel. Randomization was stratified by extent of disease according to TNM (M1a vs M1b vs M1c) and alkaline phosphatase levels ( < vs ≥ upper limit of normal). The primary endpoint was OS. Secondary efficacy endpoints included time to CRPC, time to pain progression, time to first symptomatic skeletal event (SSE), and time to initiation of subsequent systemic antineoplastic therapies. Safety was also assessed. Results: From Nov 2016 to June 2018, 1306 pts were randomized, 651 to DARO and 655 to PBO, in combination with ADT + docetaxel. Median age was 67 y in both arms. At the primary data cutoff (Oct 25, 2021), DARO significantly decreased the risk of death by 32.5% vs PBO (HR 0.675, 95% CI 0.568–0.801; P < 0.0001). The significant improvement in OS was observed even though substantially more pts received subsequent life-prolonging systemic antineoplastic therapy in the PBO arm (75.6%) vs the DARO arm (56.8%). The significant OS benefit was consistent across prespecified subgroups. In addition, DARO significantly delayed time to CRPC versus PBO (HR 0.357, 95% CI 0.302–0.421; P < 0.0001). Time to pain progression was also significantly longer with DARO vs PBO (HR, 0.792, 95% CI 0.660–0.950; P= 0.0058), as were time to first SSE and time to initiation of subsequent systemic antineoplastic therapy. TEAEs were similar between treatment arms, and the incidences of the most common TEAEs (≥10%) were highest during the overlapping docetaxel treatment period for both arms, with grade 3/4 TEAEs of 66.1% for DARO and 63.5%for PBO, mainly due to neutropenia (33.7% vs 34.2%, respectively). TEAEs led to treatment discontinuation in 13.5% of pts in the DARO arm and 10.6% of pts in the PBO arm. Conclusions: In pts with mHSPC, early treatment combining DARO with ADT + docetaxel significantly increased OS and improved key secondary endpoints vs ADT + docetaxel alone. The incidence of TEAEs was similar in the two treatment arms. Clinical trial information: NCT02799602.

TPS200 Background: Previous randomized, phase 3 trials have shown the efficacy of adding docetaxel, abiraterone acetate, enzalutamide, or apalutamide to ADT in improving overall survival and/or radiologic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, these combinations are associated with an increased risk of adverse events (eg, fatigue, rash, and cardiovascular events). Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor. In the ARAMIS study, darolutamide has been shown to significantly reduce the risk of death by 31% and have a favorable safety profile in men with nonmetastatic castration-resistant prostate cancer. It has a low incidence of central nervous system−related adverse events, which may be explained by its distinct low blood−brain barrier penetration. Darolutamide has also been shown to have a low potential for drug−drug interactions, allowing flexibility with concomitant medications. ARANOTE will evaluate the efficacy and safety of darolutamide plus ADT in patients with mHSPC (NCT04736199). Methods: ARANOTE is an international, multicenter (ex-US), randomized, double-blind, placebo-controlled, phase 3 study in patients with histologically or cytologically confirmed adenocarcinoma of the prostate and documented metastatic disease by conventional imaging (eg, computed tomography or magnetic resonance imaging) who started ADT ≤12 weeks before randomization. In total, 555 patients will be randomized 2:1 to darolutamide 600 mg twice daily or placebo, plus ADT. Patients will be stratified by the presence of visceral metastases, assessed by central review, and prior local therapy. Patients will be evaluated every 12 weeks for efficacy, safety, and quality of life (using the FACT-P questionnaire) during treatment and active follow-up post treatment. For long-term follow-up, patients will be contacted by telephone every 12 weeks. The primary endpoint is rPFS; secondary endpoints include overall survival, time to castration-resistant prostate cancer, time to prostate-specific antigen progression, and safety. Recruitment is ongoing, and the first patient first visit was on February 23, 2021. The estimated study completion date is September 2025. Clinical trial information: NCT04736199.

90 Background: Darolutamide, a structurally distinct and highly potent androgen receptor inhibitor, had a consistently favorable safety and tolerability profile in patients with nonmetastatic castration-resistant prostate cancer in ARAMIS, and discontinuation rates due to adverse events (AEs) remained consistently low after longer follow-up. In previously reported phase 1/2 studies in patients with metastatic castration-resistant prostate cancer (mCRPC), darolutamide was well tolerated for up to 25 months. We report the safety and tolerability of extended treatment with darolutamide in these mCRPC studies. Methods: Data from three phase 1/2 studies (NCT02363855, NCT01317641/NCT01429064, and NCT01784757) in patients with mCRPC were pooled for analysis of long-term safety. Results are summarized descriptively. Results: Of 173 patients with mCRPC evaluable for safety in the 3 studies, 13 patients received > 2 years of darolutamide treatment; median duration of treatment was 38 months (range 24–90). Six patients received > 4 years of darolutamide treatment. Nine of 13 patients with > 2 years of darolutamide therapy initially received 600 mg BID; others received 200 mg (n = 1), 300 mg (n = 1), or 700 mg (n = 2) BID. Median age was 68 years in the > 2-years group, and most patients were white. Patients were enrolled from France (n = 4), Latvia (n = 3), United Kingdom (n = 3), Finland (n = 2), and Japan (n = 1). Most patients had normal renal function (n = 10) and hepatic function (n = 10), 12 patients had Eastern Cooperative Oncology Group performance status of 0, and 9 patients had a Gleason score ≥7. Prior systemic anticancer treatments taken by more than 1 patient were bicalutamide (n = 10); cyproterone (n = 3); and triptorelin and leuprorelin (n = 2 each). No patient received prior chemotherapy. All 13 patients reported AEs, most grade 1 or 2; 6 reported grade 3 AEs. Treatment-related AEs were reported in 5 patients, and all were grade 1 in severity. Serious AEs were reported in 6 patients, and all were judged not related to darolutamide. One patient treated with darolutamide for > 2 years had an AE (new neoplasm; not related to darolutamide) that led to treatment discontinuation. Conclusions: Extended darolutamide treatment > 2 years in this small group of patients with mCRPC was generally well tolerated, with safety and tolerability consistent with that previously reported. Clinical trial information: NCT02363855, NCT01317641/NCT01429064, and NCT01784757.

Background Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metastasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug–drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential—other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected. Objective Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC. Patients and Methods Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted. Results Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one comedication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of comedications with DDI potential, no significant effects on darolutamide pharmacokinetics were identified. Comedications included lipid-modifying agents (34.5%), β-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses. Conclusions These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614. Electronic supplementary material The online version of this article (10.1007/s11523-019-00674-0) contains supplementary material, which is available to authorized users., Plain Language Summary Background Darolutamide is a medicine used to treat men with prostate cancer that has not spread to other parts of the body (nonmetastatic). Often, these patients are taking other medicines for common age-related illnesses. Taking more than one medicine at the same time increases the chances of what is known as drug–drug interactions. Drug–drug interactions can decrease how well the medicines work or may sometimes increase side effects. Study Aim To test for possible drug–drug interactions in men with prostate cancer who take darolutamide alongside other medicines. Study Participants Men with nonmetastatic prostate cancer who were being treated with a medicine that lowers testosterone, a chemical in the body that causes prostate cancer tumors to grow. Participants took two darolutamide 300 mg tablets, or an inactive placebo, twice a day. What Did the Researchers Measure? The researchers documented the number of medicines taken by each participant and the number of other medical conditions that they had. Tests were done to find out whether other medicines affected the way that darolutamide works in the body and whether patients taking darolutamide alongside other medicines experienced more side effects. Results As would be expected, based on the typical age of patients with prostate cancer, more than 90% of participants in this study used medicines other than darolutamide to manage common age-related illnesses or medical conditions. Taking medicines alongside darolutamide did not impact how darolutamide worked in the body and did not increase the number of side effects experienced by patients. Darolutamide is known to interact with rosuvastatin, a cholesterol-lowering drug. However, in this study, there was no overall increase in side effects among darolutamide-treated patients who took this type of drug compared with in those who did not. Conclusion In this study of patients with nonmetastatic prostate cancer, limited drug–drug interactions were seen when taking darolutamide alongside other medicines given to these patients to manage age-related medical conditions. Electronic supplementary material The online version of this article (10.1007/s11523-019-00674-0) contains supplementary material, which is available to authorized users.

5079 Background: Patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) need therapy that prolongs survival with little added toxicity, thus preserving quality of life. The second-generation androgen receptor inhibitors (ARIs) including DARO, apalutamide, and enzalutamide offer durable survival in nmCRPC but differences exist in AE profiles (eg, fatigue, falls, fractures, rash, mental impairment, and hypertension) that can limit daily activities. These AEs may require dose modifications and limit pts’ willingness to continue treatment, with an adverse impact on efficacy. DARO is a structurally distinct ARI that significantly extended metastasis-free survival and overall survival (OS) vs placebo (PBO) in ARAMIS (NCT02200614), with minimal AE risk. We report tolerability from extended follow-up and treatment response analyses from ARAMIS. Methods: Pts with nmCRPC (N=1509) were randomized 2:1 to DARO or PBO with androgen deprivation therapy. The ARAMIS trial was unblinded at the primary analysis, after which all pts could receive open-label (OL) DARO. Tolerability was assessed every 16 weeks. Pharmacodynamic modeling investigated the association between treatment response (maximum prostate-specific antigen [PSA] decline from baseline) and OS at 2 years using a Cox proportional hazards model. Results: As shown in the table, DARO remained well tolerated over the double-blind (DB) and OL periods: 98.8% of pts on DARO received the full planned dose and almost all pts with dose modifications were able to resume and re-establish the planned dose (DARO 89.6% vs PBO 89.7%). Discontinuation of DARO due to AEs increased slightly from the DB period (9.0%) to the DB+OL period (10.5%). Pharmacodynamic modeling showed that longer OS was positively associated with maximum PSA decline in DARO-treated pts. Conclusions: DARO remained well tolerated with extended treatment at the recommended dose of 600 mg twice daily. Almost all pts with nmCRPC were able to receive the full planned dose, increasing the likelihood of clinical benefit from effective disease control (PSA decline) and prolonged survival. Tolerability of different ARIs in the real world should be assessed. Clinical trial information: NCT02200614. [Table: see text]

INTRODUCTION AND OBJECTIVES:Asymptomatic nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients (pts) would benefit from treatments (Tx) that delay disease progression with minimal Tx-r...

239 Background: DARO is a structurally distinct androgen receptor inhibitor (ARI) approved for treating nmCRPC. In ARAMIS, DARO significantly reduced the risk of death by 31% (HR = 0.69; 95% CI: 0.53-0.88; p = 0.003) and prolonged median metastasis-free survival vs placebo (PBO; 40.4 months vs 18.4 months; HR = 0.41; 95% CI: 0.34-0.50; p < 0.001). Adverse events (AEs) of interest commonly associated with ARI therapy, such as fatigue, falls, fractures, rash, mental impairment, and hypertension, as well as interactions between ARIs and concomitantly administered drugs, can impact patient daily life. In the final analysis of the double-blind (DB) period of the ARAMIS trial, DARO had a favorable safety profile, showing ≤2% difference vs PBO for most AEs of interest. Fatigue was the only AE with > 10% incidence with DARO. The incidence of permanent discontinuation due to AEs was also similar between DARO and PBO (8.9% vs 8.7%). Here we present safety data for prolonged treatment with DARO from the final analysis of the DB + open-label (OL) period of ARAMIS. Methods: Patients (pts) with nmCRPC (N = 1509) were randomized 2:1 to DARO or matched PBO while continuing androgen deprivation therapy. The data cut-off for the primary analysis of the DB period was September 3, 2018. Study unblinding occurred on November 30, 2018, after which pts in the DARO arm still receiving study treatment continued with OL DARO. The data cut-off for final analysis of the DB+OL period was November 15, 2019. Results: At the final analysis, the median treatment duration for pts randomized to DARO was 18.5 months for the DB period and 25.8 months for the DB+OL period. At the final cut-off date, 48.8% of patients in the DARO DB+OL group were still receiving DARO treatment. The increase in the incidence of any-grade AEs (85.7% vs 89.8%) and serious AEs (26.1% vs 32.1%) between the DB and DB+OL period was small. Between the DB and DB+OL periods, only minor numerical changes for ARI-associated AEs were observed. When the incidences were corrected for exposure, there were minimal differences between the DB and DB+OL period, e.g., the fracture rate was 3.4 vs 4.0 per 100 patient-years for the DB vs DB+OL periods, respectively. Fatigue was the only ARI-associated AE of interest that exhibited > 10% incidence in the DARO arm during the DB+OL period. The incidence of permanent discontinuation of DARO due to AEs increased slightly from 8.9% during the DB period to 10.5% during the DB+OL period; the incidence of discontinuation of PBO due to AEs during the DB period was 8.7%. Conclusions: With longer treatment exposure, DARO remained well-tolerated. In the DB+OL period, no new safety signals were observed. The expected increases in incidence of AEs between the DB and DB+OL periods largely disappeared when adjusted for the longer exposure, confirming the favorable safety profile of DARO with prolonged treatment. Clinical trial information: NCT02200614.

5514 Background: DARO is a structurally distinct androgen receptor inhibitor with a favorable safety profile, approved for treating men with nmCRPC after demonstrating significantly prolonged metastasis-free survival, compared with placebo (PBO), in the phase III ARAMIS trial: median 40.4 vs 18.4 months, respectively (HR 0.41; 95% CI 0.34–0.50; P

326 Background: DARO is an oral androgen receptor antagonist with a unique structure and a low blood–brain barrier penetrance noted in rodents. Here we compare CBF following administration of DARO, ENZA, and PBO using arterial spin labelled magnetic resonance imaging (ASL-MRI) in humans. Methods: This phase I, randomized, PBO-controlled, 3-period crossover study investigated drug-induced changes in CBF for brain grey matter and for specific regions related to cognitive function in healthy males (age 19–44). Twenty-three participants received a single oral dose of DARO, ENZA, or PBO at 6-week intervals at similar unbound concentrations . An ASL-MRI scan was performed ~4 hours after each dose. Blood samples for drug analysis and physiological measures were collected prior to drug administration and immediately post-scan. ASL data were preprocessed and statistical parametric modelling was used for treatment comparisons (paired t-tests). Whole-brain results were considered significant after correction for multiple comparisons. A linear mixed effects model was used for predetermined region of interest (ROI) analysis, with physiological parameters as nuisance regressors. Results: Drug-concentration data confirmed similar unbound exposure during MRI scans and a complete washout between treatments. No unexpected safety concerns were noted in the study. Whole-brain analysis showed a significant localized 5.2% reduction in CBF for ENZA in temporo-occipital cortices but no significant CBF reduction with DARO compared to PBO. A significant 5.9% localized reduction in CBF was measured for ENZA vs DARO. ROI analysis showed a significant reduction in CBF for ENZA vs PBO (p = 0.045) and for ENZA vs DARO (p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. A significant reduction was noted in CBF for ENZA vs PBO in right amygdala (p = 0.047). Conclusions: Compared to PBO and DARO, significant localized reductions in CBF were noted for ENZA. These results may be relevant to cognitive function (executive function, memory, and anxiety) with extended treatment and warrant further investigation. Clinical trial information: NCT03704519.

Background Asymptomatic nmCRPC patients (pts) would benefit from treatments (Tx) that delay disease progression and maintain quality of life (QoL), with minimal Tx-related adverse events (AEs). In ARAMIS, darolutamide (DARO) prolonged metastasis-free survival vs placebo (PBO) (40 vs 18 months; HR 0.41; 95% CI 0.34–0.50; P Methods Pts were randomized to DARO 600 mg twice daily (n = 955) or PBO (n = 554), while androgen deprivation therapy continued in both arms. Secondary/exploratory endpoints included safety, time to cytotoxic chemotherapy, time to antineoplastic therapy, time to PSA progression, and QoL. Results DARO substantially delayed times to PSA progression (33 vs 7 months; HR 0.13; 95% CI 0.11–0.16; P 10% of pts. Discontinuation rates due to AEs were 8.9% with DARO and 8.7% with PBO. AEs noted with other androgen receptor inhibitors (including fracture, falls, seizures, hypertension and cognitive disorder) showed minimal or no difference in incidence between groups. DARO maintained QoL, and delayed the onset of pain and disease-related urinary symptoms compared with PBO. Conclusions DARO delays disease progression and subsequent Tx for metastatic castration-resistant prostate cancer vs PBO, maintaining QoL without increasing incidence of key AEs. Clinical trial identification NCT02200614. Editorial acknowledgement Medical writing support for the development of this abstract was provided by Lucy Smithers, PhD, and editorial support, including formatting, proofreading, and submission was provided by Beth King, both of Scion Medica, London, supported by Bayer according to Good Publication Practice guidelines. Legal entity responsible for the study Orion Corporation, Orion Pharma and Bayer AG. Funding Orion Corporation and Bayer AG. Disclosure J.S-T. Pang: Non-remunerated activity/ies, Writing support: Bayer. N. Shore: Advisory / Consultancy, Research grant / Funding (self): Ferring; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Research grant / Funding (self): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Dendreon; Advisory / Consultancy, Research grant / Funding (self): Tolmar; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self): Myovant Sciences; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): Nymox. M.R. Smith: Honoraria (self): Amgen; Honoraria (self): Astellas; Honoraria (self): Bayer; Honoraria (self): Clovis; Honoraria (self): Gilead; Honoraria (self): Janssen; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer. T.L. Tammela: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (self): Lidds AB; Advisory / Consultancy, Research grant / Funding (self): Astellas. E. Vjaters: Research grant / Funding (self): Ipsen; Research grant / Funding (self): Bayer; Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Orion. M. Jievaltas: Honoraria (self): Bayer; Honoraria (self): Ipsen; Honoraria (self): Janssen. M. Luz: Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Research grant / Funding (self): Janssen; Research grant / Funding (self): AstraZeneca; Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (self): Ferring; Speaker Bureau / Expert testimony: Sanofi. B. Alekseev: Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Bayer; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Astellas; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Ferring; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Janssen; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: MSD; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), Non-remunerated activity/ies: Sanofi. I. Kuss: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bayer. M-A. Le Berre: Full / Part-time employment: Bayer Healthcare. A. Snapir: Full / Part-time employment: Orion Pharma. T. Sarapohja: Full / Part-time employment: Orion Corporation. K. Fizazi: Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self): Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Sanofi; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Curevac; Advisory / Consultancy: ESSA; Advisory / Consultancy: Orion Pharma; Advisory / Consultancy: Roche/Genentech. All other authors have declared no conflicts of interest.

The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19–0.39; p

5000 Background: DARO is a structurally distinct androgen receptor antagonist for which in vitro and phase 1/2 studies suggest low risk of adverse events (AEs) and drug–drug interaction. In the ARAMIS study of DARO in nmCRPC, metastasis-free survival (MFS) was significantly prolonged vs placebo (PBO) (40.4 vs 18.4 mo; hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; P < 0.001) and interim overall survival (OS) favored DARO (HR 0.71; 95% CI 0.50–0.99; P = 0.045). Methods: 1509 pts were randomized 2:1 to DARO 600 mg (two 300 mg tablets) twice daily (n = 955) or PBO (n = 554) while continuing androgen deprivation therapy (ADT). Primary endpoint was MFS. Secondary endpoints included OS and time to pain progression (assessed by Brief Pain Inventory Short Form). QoL was assessed by European Organisation for Research and Treatment of Cancer QoL Prostate Cancer module (EORTC-QLQ-PR25) at baseline (BL) and every 16 wks until end of treatment. Analysis of time to deterioration in EORTC-QLQ-PR25 subscales, defined as first occurrence of a minimally important difference (half the standard deviation of BL value), used Kaplan–Meier estimators and stratified Cox proportional hazard models. Results: DARO significantly delayed pain progression vs PBO (40.3 vs 25.4 mo; HR 0.65; 95% CI 0.53–0.79; P < 0.001); this was maintained beyond end of study treatment. Time to deterioration of EORTC-QLQ-PR25 outcomes showed statistically and clinically significant delays with DARO vs PBO for urinary symptoms (25.8 vs 14.8 mo; HR 0.64; 95% CI 0.54–0.76; P < 0.01). Time to deterioration of hormonal treatment-related symptoms was comparable with DARO vs PBO (18.9 vs 18.4 mo; HR 1.06; 95% CI 0.88–1.27; P = 0.52). DARO was well tolerated. Exposure-adjusted incidences (pts per 100 years’ exposure) of AEs of interest were similar/lower with DARO vs PBO (fatigue/asthenic conditions [11.3 vs 11.1], hypertension [4.7 vs 5.1], hot flush [3.7 vs 4.1], fracture [3.0 vs 3.5], falls [2.7 vs 4.1], cognitive disorder [0.3 vs 0.2], and seizure [0.2 vs 0.2]). Conclusions: For nmCRPC pts, DARO prolongs MFS, is well tolerated, maintains QoL, and delays worsening of pain and disease-related symptoms compared with PBO. Clinical trial information: NCT02200614.

140 Background: Delaying metastases for nmCRPC patients, while minimizing the risk of adverse events, is an important treatment goal. Darolutamide, a structurally unique androgen receptor (AR) antagonist, is being evaluated for the treatment of advanced prostate cancer. The ARAMIS trial studied the efficacy and safety of darolutamide in nmCRPC patients. Methods: This double-blind, placebo-controlled phase III trial randomized nmCRPC patients in a 2:1 ratio to receive darolutamide 600 mg (two 300 mg tablets) twice-daily or placebo, while continuing androgen deprivation therapy. Patients were stratified by prostate-specific antigen doubling time (≤6 months or >6 months) and use of osteoclast-targeted therapy. The primary endpoint was metastasis-free survival (MFS), with independent central review of radiographic imaging every 16 weeks. Secondary endpoints include overall survival (OS), times to pain progression (assessed by Brief Pain Inventory), first cytotoxic chemotherapy and first symptomatic skeletal event, as well as safety profile. Results: In total, 1,509 patients were randomized (955 to darolutamide, 554 to placebo). Median MFS was 40.4 months with darolutamide vs 18.4 months with placebo (hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; 2-sided p10%. Discontinuation rates due to AEs were 8.9% with darolutamide and 8.7% with placebo. Grouped terms for AEs noted with other AR inhibitors (including fracture, falls, seizures, weight decrease, hypertension, and cognitive disorder) showed minimal or no difference in incidence between study arms. Conclusion: Among men with nmCRPC, MFS was significantly longer with darolutamide than with placebo with a low incidence of treatment-related AEs in this asymptomatic patient population. Clinical trial information: NCT02200614.

TPS383 Background: The addition of either docetaxel or abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) improves overall survival (OS) compared with ADT alone in men with mHSPC. It is hypothesized that other androgen receptor (AR)-targeted therapies could be combined with docetaxel for mHSPC. Darolutamide (ODM-201) is an investigational oral AR antagonist with a unique chemical structure and negligible blood-brain barrier penetration that inhibits tumor growth by binding to AR and AR mutants (eg, W742L and F877L) with high affinity and specificity. In phase 1/2 ARADES and phase 1 ARAFOR trials, darolutamide demonstrated antitumor activity and was well tolerated in men with metastatic castration-resistant prostate cancer (mCRPC). ARASENS will evaluate the addition of darolutamide to standard ADT and docetaxel in men with mHSPC. Methods: This international, randomized, double-blind, placebo-controlled phase 3 trial (NCT02799602) is being conducted at > 300 sites in 23 countries. ~1300 men with newly diagnosed mHSPC will be randomized 1:1 to darolutamide (600 mg orally twice daily) or matching placebo. All patients will receive standard ADT + docetaxel (6 cycles). Patients will be stratified by disease extent and alkaline phosphatase level. Key inclusion criteria: histologically or cytologically confirmed PC with documented metastases, started ADT ± first-generation antiandrogen therapy ≤12 weeks before randomization, and ECOG performance status 0-1. The primary end point is OS. Secondary end points include time to mCRPC, initiation of subsequent anticancer therapy, symptomatic skeletal event (SSE)-free survival, time to first SSE, first opioid use, pain progression, and worsening of physical symptoms. Safety will be assessed. ARASENS is actively enrolling at > 280 sites across 23 countries. Clinical trial information: NCT02799602.

A subset of circulating T cells (CD8(+)CD45RO(-)CD27(-)) with a naïve phenotype, but mediating effector function, is considered to play an important role in host antitumour defence. To investigate the attributes of these effector T cells in patients with squamous cell carcinoma (SCC) of the head and neck cancer, venous blood was obtained from 39 individuals with cancer and 45 normal controls (NC). Peripheral blood mononuclear cells were isolated, stained with labelled monoclonal antibodies specific for CD8, CD45RO, CD45RA, CD62L, CD27, TCR-zeta as well as isotype controls and examined by multicolour flow cytometry. Annexin V binding to CD8(+) T cells and PMA/ionomycin-induced IFN-gamma expression were also evaluated in patients and NC. The proportions of CD45RA(+)CD45RO(-) (naïve) and CD45RA(-)CD45RO(+) (memory) cells were found to be comparable within the CD8(+) T-cell subset. However, relative to NC, the frequency of effector CD8(+)CD45RO(-)CD27(-) cells was strikingly increased in all SCC patients regardless of the disease status (P=0.0003). The proportion of these cells was found to increase with age in both patients and NC. In NC, stimulated IFN-gamma expression was largely restricted to CD8(+)CD45RO(-)CD27(+) cells, while in patients CD8(+)CD45RO(-)CD27(-) expressed IFN-gamma after ex vivo stimulation. Expression of the TCR-associated zeta chain was decreased or absent in freshly isolated CD8(+)CD45RO(-)CD27(-) T cells in patients (P0.0001). Annexin V was found to bind to a higher proportion of circulating CD8(+) T cells in patients than NC (P0.006), and significantly more Annexin V(+) T cells were present in the effector (P0.0059) than the naïve subset within the CD8(+)CD45RO(-) compartment. The data indicate that the expanded CD8(+)CD45RO(-)CD27(-) T cells, which contain precursors of IFN-gamma-producing T cells, are zeta-negative and sensitive to apoptosis in the circulation of patients with HNC.

Expression levels of T-cell receptor (TcR)-associated zeta chain were reported to reflect functional competence of T lymphocytes in patients with cancer. This retrospective study was performed to evaluate zeta chain expression in circulating T cells obtained from clinical responders and nonresponders among 19 patients with advanced ovarian carcinoma treated with intraperitoneal interleukin-2 (IL-2) biotherapy. Banked lymphocytes, which were collected from the patients who participated in a phase I clinical trial performed between 1987 and 1990, were used for quantitative flow cytometry to measure zeta-chain expression in T lymphocytes prior to and at the end of therapy. The data were correlated with 7-year survival. The patients (9 responders and 10 nonresponders) were stratified into two groups based on zeta chain expression in CD3+ T cells above or below the mean. Patients with lower zeta expression in circulating T cells had shorter survival compared to patients whose T cells expressed high zeta. Pretherapy zeta expression was significantly lower (p = 0.03) in CD8+T cells of nonresponders than in CD8+T cells of normal controls. In patients with advanced ovarian carcinoma, low expression of the zeta chain in peripheral blood T cells prior to biotherapy might both reflect a large tumor burden and predict a poor of response to IL-2 bio-therapy.

TPS5092 Background: Androgen deprivation therapy (ADT) ± docetaxel is recommended first-line therapy for mHSPC, but most patients progress to castration-resistant PC (CRPC). BAY-1841788 (ODM-201) is an investigational oral androgen receptor (AR) antagonist that has a unique chemical structure designed to block the growth of cancer cells through binding to the AR with high affinity and inhibiting the receptor function. In preclinical studies, ODM-201 and its main circulating metabolite are active also in known AR mutants (eg, W742L, F877L), and have been found to have negligible blood-brain barrier penetration. In the phase 1 ARAFOR and phase 1/2 ARADES trials, ODM-201 had antitumor activity and was well tolerated in men with mCRPC (Massard et al. Eur Urol. 2016;69:834‒840; Fizazi et al. Lancet Oncol. 2014;15:975‒985). Given this promising activity in mCRPC, the ARASENS trial is evaluating ODM-201 plus standard ADT + docetaxel in men with metastatic disease (mHSPC). Methods: This international, randomized, double-blind, placebo-controlled, phase 3 trial (NCT02799602) is being conducted in 23 countries. ~1300 men with newly diagnosed mHSPC will be randomized 1:1 to either ODM-201 600 mg twice daily (2×300 mg tablets) orally with food or placebo, both with ADT + docetaxel (6 cycles after randomization), and stratified by extent of disease and alkaline phosphatase levels. Key inclusion criteria are histologically or cytologically confirmed PC with documented metastases, started ADT ± first-generation anti-androgen therapy ≤12 weeks before randomization, and Eastern Cooperative Oncology Group performance status 0 or 1. The primary objective is to show superior overall survival with ODM-201 vs placebo, both with ADT + docetaxel. Secondary end points include time to CRPC, initiation of subsequent anticancer therapy, symptomatic skeletal event-free survival (SSE-FS), time to first SSE, initiation of opioid use, pain progression, and worsening of physical symptoms, all measured at 12-week intervals. Safety will be assessed by adverse events. The trial is open for enrollment; first patient first visit was in November 2016 and > 10 sites are open for recruitment and enrolling patients. Clinical trial information: NCT02799602.

10551 Background: REG, an oral receptor kinase inhibitor with activity against KIT, PDGFR, VEGFR, FGFRs, and other oncologic targets, demonstrated significant improvement in progression-free survival (PFS) over placebo (PL) in a phase III study (GRID) of patients (pts) with advanced GIST following failure of at least imatinib (IM) and sunitinib (SU). To understand the impact of pts’ baseline characteristics on outcome, we performed an exploratory analysis of REG effects across pt subgroups based on sex, age, and mitotic index of primary GIST tissue, as well as duration and number of lines of previous therapies. Methods: Adult pts with metastatic GIST (n=199) progressing after at least IM and SU were randomized 2:1 to receive oral REG 160 mg or PL once daily for the first 3 weeks of each 4-week cycle. Subgroup analysis of centrally assessed PFS was performed, based on sex, age (

Background: The progesterone-receptor (PR) antagonists onapristone (type I) and mifepristone (type II) showed modest activity in hormone-receptor-positive breast cancer; however, onapristone in particular was associated with hepatotoxicity. Lonaprisan is a novel, type III PR antagonist that was well tolerated in phase I studies. Patients and methods: This randomized, open-label, phase II study evaluated the efficacy and tolerability of lonaprisan as second-line endocrine therapy in postmenopausal women with stage IV, PR-positive, HER2-negative, metastatic breast cancer. Results: Patients received once-daily lonaprisan 25 mg (n= 34) or 100 mg (n= 34). The primary objective was not met (≥35% clinical benefit rate: complete/partial responses at any time until month 6 or stable disease [SD] for ≥6 months from start of treatment). There were no complete/partial responses. In the 25 mg and 100 mg groups, 6 of 29 patients (21%) and 2 of 29 patients (7%), respectively, had SD ≥6 months. Overall, 61 of 68 patients (90%) had ≥1 adverse event (AE), the most frequent (≥10% overall) being fatigue, hot flush, dyspnoea, nausea, asthenia, headache, constipation, vomiting, and decreased appetite; 33 patients had serious AEs. Conclusion: Lonaprisan showed limited efficacy as second-line endocrine therapy in postmenopausal women with PR-positive metastatic breast cancer.

TPS5094Background: Treatment for nonmetastatic castration-resistant prostate cancer (nmCRPC) other than continuing androgen deprivation therapy (ADT) remains an unmet need. There are no approved therapies for preventing metastatic disease in nmCRPC. Pts with nmCRPC who have shorter prostate-specific antigen doubling time (PSADT) are at higher risk for metastatic disease or death. ODM-201, a novel second-generation oral androgen receptor inhibitor, has demonstrated a tolerable safety profile and antineoplastic activity in progressive CRPC. The ARAMIS trial will evaluate the efficacy and safety of ODM-201 in high-risk nmCRPC pts. Methods: This randomized, double-blind, placebo-controlled phase 3 trial (NCT02200614) involves > 450 sites in > 33 countries. 1500 pts on ADT will be randomized 2:1 to ODM-201 600 mg or placebo BID. Pts will be stratified by PSADT and baseline bone-targeting agent use. Eligibility criteria include nmCRPC, PSADT ≤ 10 months, and screening PSA ≥ 2 ng/mL. 90% power to detect a target...

Background Regorafenib (REG) therapy significantly improved progression-free survival (PFS) in patients (pts) with GIST after failure of both IM and SU (J Clin Oncol 2012; 30: suppl; abstr LBA10008). Results of subgroup and post-progression analyses are presented here. Methods Pts were randomized (2:1) to receive best supportive care plus either REG 160 mg or placebo (PL) po once daily (3 wks on/1 wk off). The primary endpoint was PFS. Upon progression in either arm, unblinding could occur. Pts on PL were eligible for crossover to open-label (OL) REG and progressive pts on REG were allowed to continue REG upon local physician's choice. Results GRID screened 234 pts and randomized 199 (REG: 133, PL: 66), well balanced for baseline characteristics. The PFS primary endpoint (according to RECIST) was met both per central review (median PFS 4.8 mo for REG vs. 0.9 mo for PL), and by investigator assessment (median PFS 7.4 mo for REG vs. 1.7 mo for PL). Exploratory sensitivity analyses demonstrate similar positive impact on PFS across pre-specified subgroups by number of prior systemic therapy, geographical region, age, baseline ECOG score, duration of prior treatment with imatinib, or KIT/PDGFRA mutation. Median overall survival has not been reached in either arm. Taking the double-blind and OL periods together, 188 pts received REG. Post-progression PFS per investigator assessment was 5.0 mo for pts in the PL arm who crossed over to REG (n = 56), and 4.5 mo for pts in the REG arm who continued to receive REG after unblinding (n = 41). Conclusion REG induced significant PFS benefit in GIST pts following resistance to both IM and SU across all pre-specified subgroups. Interestingly, 41 pts on REG (out of 133) whose physicians decided to continue REG after RECIST progression had an additional PFS benefit which was in the same range. This suggests that continuous kinase inhibition after progression may benefit pts by slowing tumor progression and/or that RECIST criteria for progression applied by blind central review have clinical shortcomings. Disclosure P.G. Casali: Consultant/advisory: Bayer, MSD, GSK, Infinity, Novartis, Pfizer, PharmaMar, Sanofi Honoraria: Novartis, Pfizer, PharmaMar Research funds: Amgen Dompe, Bayer, MSD, GSK, Imclone, Infinity, Lilly, Molmed, Novartis, Pfizer, PharmaMar, Sanofi. P. Reichardt: Consultant/advisory: Bayer. Y. Kang: Consultant/advisory: Bayer Research funding: Bayer. J. Blay: Honoraria: Pharmama, Novartis, Pfizer, Roche, GSK Research funding: Pharmama, Novartis, Pfizer, Roche, GSK. P. Rutkowski: Consultant/advisory: Novartis, MSD, BMS Honoraria: Novartis, Pfizer, BMS, MSD, Roche. M. Leahy: Research funding as PI for GRID study at Christie Hospital, Manchester, UK. M. von Mehren Consultant/advisory: Novartis, Pfizer, Astex; Honoraria: Novartis, Pfizer. H. Joensuu Consultant/advisory: Novartis, Boehringer-Ingelheim. A. Le Cesne Honoraria: Novartis, Pfizer, Pharmamar. P. Schoffski: Research funding: Bayer. R. Maki: Consultant/advisory: Bayer, Pfizer, Novartis; Honoraria: Bayer, Pfizer, Novartis; Research funding: Pfizer; Expert testimony: Pfizer. I. Kuss: Employment: Bayer. D. Laurent: Employment: Bayer Stock ownership: Bayer. G.D. Demetri: Consultant/advisory: Novartis, Pfizer, GSK, Roche, Deciphra (uncompensated), Infinity Research funding: Novartis, Pfizer, GSK, Infinity Expert testimony (uncompensated): Infinity, Pfizer, Novartis, Bayer. All other authors have declared no conflicts of interest.

110 Background: The GRID study showed that regorafenib improves progression-free survival compared with placebo in patients with advanced GIST after failure of at least imatinib and sunitinib (HR 0.27; 1-sided p

Twenty-five patients with advanced breast cancer (ABC) who had failed from first-line chemotherapy entered into a phase II study employing weekly 5-fluorouracil (FU) 350 mg/m2, folinic acid (FA) 500 mg/m2, and epirubicin (EPI) 35 mg/m2, for a maximum of 18 cycles. Twenty-three patients were evaluable for response. One achieved a complete response and 7 showed a partial response, for an objective response rate of 35%; 7 (31%) patients achieved a stabilization of the disease, while 8 (35%) patients progressed under treatment. The median duration of response was 6 months and median survival amounted to 10.6 months. Side effects were in general mild with grade III leukopenia in 5 patients and grade IV leukopenia in 1 patient. Other toxicity included nausea and vomiting (88%), diarrhea (26%), stomatitis (40%) and alopecia (84%), but all of them mainly restricted to WHO grade I and II. Our results suggest that the combination of high-dose FA, FU, and EPI can be safely administered in the investigated schedule and represents an attractive alternative in the search for second-line therapies that combine effectiveness with acceptable toxicity in the treatment of refractory ABC.

Background: The GRID study demonstrated that regorafenib provides a significant improvement in progression-free survival (HR 0.27; p Methods: 91 plasma samples from patients enrolled in the Ph 3 study (GRID) for which BEAMing data (Jeffers et al 2013 JCO 31:10503) were subjected to Safe-SeqS covering cKit Exon 8 to Exon 18. Results: In 6 of 32 samples reported to be cKIT wildtype by BEAMing, mutations were identified by SafeSeqS. The detection of primary KIT exon 9 mutations showed a high degree of concordance among the two mutation-detection methods evaluated. Secondary / resistance hotspot mutations were also readily detected by both methods, although a greater number of such mutations were detected by Safe-SeqS than by BEAMing. The localization of the additional mutations detected by Safe-SeqS in known mutational hotspots supports their legitimacy. Safe-SeqS also detected KIT mutations for which BEAMing assays had not been developed, whereas in 17 samples a mutation for which a BEAMing assay was available was not detectable by Safe SeqS. In 58% (10/17) of samples, the mutant allele frequency found by BEAMing was close to the detection limit of this platform ( Conclusion: Our data support the use of Safe-SeqS as a sensitive and specific “liquid biopsy” method for non-invasive tumor genotyping of patients with GIST, enabling the identification of known and novel tumor-associated mutations using circulating DNA. These results confirm and extend the genotypic heterogeneity that had previously been identified in GRID circulating DNA samples by BEAMing. The comprehensive tumor mutational profiles generated by Safe-SeqS will be used to evaluate potential correlations between tumor genotype and clinical outcome. Citation Format: Michael Jeffers, Henrik Seidel, Susanne Schwenke, Joachim Reischl, Mark Rutstein, Christian Kappeler, Iris Kuss, Michael Teufel. Tumor genotyping in the phase III GRID study of regorafenib vs placebo in tyrosine kinase inhibitor (TKI)-refractory GIST: Detection of KIT mutations in circulating tumor DNA comparing digital PCR and massive parallel sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 929. doi:10.1158/1538-7445.AM2015-929

TPS5080 Background: There is no standard treatment for nmCRPC besides continuing androgen deprivation therapy (ADT). Preventing metastatic disease in nmCRPC is a major unmet need. Patients with nmC...

Purpose: Apoptosis of circulating CD8+ T cells seen in patients with squamous cell carcinoma of the head and neck [SCCHN (Hoffmann T, et al. Clin Cancer Res 2002;8:2553–62)] suggested a possibility of lymphocyte imbalance. Therefore, absolute numbers and percentages of lymphocyte subsets were examined in the peripheral blood of SCCHN patients and controls. Experimental Design: Venous blood was obtained from 146 patients with SCCHN and 54 normal volunteers. Absolute numbers of CD3+, CD4+, and CD8+ T lymphocytes were determined using fluorobeads in a flow cytometry-based technique. Percentages of T lymphocyte subsets were also evaluated by flow cytometry. The patients were grouped at the time of blood draw [active versus no evidence of disease (NED), type of therapy administered, and the length of follow-up]. Results: Patients with SCCHN had significantly lower absolute numbers of CD3+ CD4+, and CD8+ T cells than normal controls. However, no differences in the percentages of T-cell subsets between patients and normal controls were observed. Patients with active disease had significantly lower CD3+ and CD4+ T-cell counts than those with NED. Patients who had NED after surgery and radiotherapy had the lowest T-cell counts among the NED cohort. Patients who had NED for >2 years did not recover their T-cell counts, and the T-cell imbalance was evident many years after curative surgery. The tumor-node-metastasis (TNM) stage or site of the disease was not related to the absolute T-cell count. Patients with recurrent disease at the time of blood draw tended to have the lowest CD4+ T-cell counts. Conclusions: Patients with SCCHN have altered lymphocyte homeostasis, which persists for months or years after curative therapies.

Prolactin (PRL) has been reported to inhibit apoptosis in various cell types and to serve as a cofactor in the upregulation of CD25 on T cells during activation. We investigated a possible relation between prolactin receptor (PRL-R) or IL-2 receptor alpha (IL-2Ralpha, CD25) expression on circulating T lymphocytes and their apoptosis in patients with breast cancer. Peripheral blood mononuclear cells obtained from 25 patients, 25 normal controls (NC) and three cord blood samples were evaluated for Annexin V binding and expression of CD95, CD25, and PRL-R on CD3(+) T cells by multicolour flow cytometry. Plasma levels of PRL, sCD95L, and sIL-2R were determined in patients and controls and related to T-cell apoptosis. The ability of PRL to protect T cells from apoptosis induced by various agents was also studied. Expression of PRL-R on the surface of T cells was comparable in patients with breast cancer and NC, but PRL plasma levels in patients were significantly lower (P0.05). In patients, 18+/-11% (mean+/-s.d.) of CD3(+) cells bound Annexin V, compared to 9+/-6% in NC (P0.0004). Percentages of CD3(+)Fas(+) and CD3(+)CD25(+) cells were higher in the peripheral circulation of patients than NC (P0.0001 and0.04, respectively). Levels of sFasL were lowest in plasma of the patients with the highest proportions of CD3(+)Fas(+) T cells. Most T cells undergoing apoptosis were CD3(+)CD25(-) in patients, and the proportion of CD3(+)CD25(-) Annexin V(+) cells was significantly increased in patients compared to NC (P0.006). Ex vivo PRL protected T cells from starvation-induced or anti-CD3Ab-induced but not from Fas/FasL-dependent apoptosis. These results indicate that expression of CD25 but not of PRL-R on the surface of activated T lymphocytes appears to be involved in modulating Fas/Fas - ligand interactions, which are, in part, responsible for apoptosis of T lymphocytes and excessive turnover of immune cells in the circulation of patients with breast cancer.

Natural killer (NK) cells (CD56(+)/CD3(-)) in the circulation of cancer patients were reported to have low NK activity and undergo spontaneous apoptosis. A possible relationship between apoptosis and impaired NK activity was studied by Annexin V-binding and NK-cell assays performed with peripheral blood mononuclear cells of patients with head and neck cancer (HNC), breast cancer (BC) and normal controls (NC). Cells stained with Annexin V (Anx) and antibodies to CD56, CD3, CD95, CD25, CD122 or CD132 were examined by flow cytometry. NK activity was tested against K562 targets in 4-h (51)Cr-release assays. The ratio of CD56(dim)/CD56(bright) NK cells was significantly different in patients vs. controls (10 vs. 16; p

We report on a 28-year-old male with a single metastasis of an osteosarcoma in the twelfth thoracic vertebra occurring 9 years after initial diagnosis of the primary tumour in the left distal femur and neoadjuvant treatment according to a modified T-10 protocol. After pre-operative second-line combination chemotherapy with doxorubicin, carboplatin and etoposide leading to regression of the primarily inoperable metastasis wide resection of the tumour employing total spondylectomy was done. The duration of response had been 65 months since the end of subsequent postoperative chemotherapy with the same regimen.