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Germline genetic testing is now routinely recommended for patients with prostate cancer (PCa) because of expanded guidelines and options for targeted treatments. However, integrating genetic testing into oncology and urology clinical workflows remains a challenge because of the increased number of patients with PCa requiring testing and the limited access to genetics providers. This suggests a critical unmet need for genetic services outside of historical models. This review addresses current guidelines, considerations, and challenges for PCa genetic testing and offers a practical guide for genetic counseling and testing delivery, with solutions to help address potential barriers and challenges for both providers and patients. As genetic and genomic testing become integral to PCa care, developing standardized systems for implementation in the clinic is essential for delivering precision oncology to patients with PCa and realizing the full scope and impact of genetic testing.

PURPOSE Intrapatient treatment response heterogeneity is under-recognized. Quantitative total bone imaging (QTBI) using 18F-NaF positron emission tomography/computed tomography (PET/CT) scans is a tool that allows characterization of interlesional treatment response heterogeneity in bone. Understanding spatial-temporal response is important to identify individuals who may benefit from treatment beyond progression. PATIENTS AND METHODS Men with progressive metastatic castration-resistant prostate cancer (mCRPC) with at least two lesions on bone scintigraphy were enrolled and treated with enzalutamide 160 mg daily (ClinicalTrials.gov identifier: NCT02384382 ). 18F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of prostate-specific antigen (PSA) progression, standard radiographic or clinical progression, or at 2 years without progression (PET3). QTBI was used to determine lesion-level response. The primary end point was the proportion of men with at least one responding bone lesion on PET3 using QTBI. RESULTS Twenty-three men were enrolled. Duration on treatment ranged from 1.4 to 34.1 months. In general, global standardized uptake value (SUV) metrics decreased while on enzalutamide (PET2) and increased at the time of progression (PET3). The most robust predictor of PSA progression was change in SUVhetero (PET1 to PET3; hazard ratio, 3.88; 95% CI, 1.24 to 12.1). Although overall functional disease burden improved during enzalutamide treatment, an increase in total burden (SUVtotal) was seen at the time of progression, as measured by 18F-NaF PET/CT. All (22/22) evaluable men had at least one responding bone lesion at PET3 using QTBI. CONCLUSION We found that the proportion of progressing lesions was low, indicating that a substantial number of lesions appear to continue to benefit from enzalutamide beyond progression. Selective targeting of nonresponding lesions may be a reasonable approach to extend benefit.

BackgroundWe previously reported a pilot clinical trial using a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP), given over 12 weeks either concurrently or in sequence with pembrolizumab, in patients with mCRPC. We report here the final analysis of this trial following two additional treatment arms in which patients with mCRPC were treated beyond 12 weeks until progression.MethodsPatients with mCRPC were treated with pTVG-HP and pembrolizumab every 3 weeks (Arm 3, n=20), or pTVG-HP every 2 weeks and pembrolizumab every 4 weeks (Arm 4, n=20). The primary objectives were safety, 6-month PFS, median time to radiographic progression, and objective response rates. Secondary objectives included immunological evaluations.ResultsTreatment was without unexpected toxicity, and only 1 grade 4 event (hyperglycemia) was observed. Immune related adverse events (irAE) > grade 1 included adrenal insufficiency, hepatitis, colitis, thyroid dysfunction, pancreatitis, pneumonitis, and rash, occurring in 42% of patients overall. 10/25 patients with measurable disease experienced any decrease in tumor volume from baseline, with 1 confirmed PR and no CR. 23/66 (35%) experienced any PSA decline from baseline. Overall median TTP was 5.4 months (95% CI; 5.3–8.1 months); median TTP for Arm 3 was 5.3 months compared to 8.0 months for Arm 4. Overall, 41.7% of patients had no radiographic progression at 6 months (29.9% Arm 3, 57.9% Arm 4). Median overall survival was 22.9 months. IFNγ and/or granzyme B immune response to PAP was detected in 2/20 patients in Arm 3 and 6/20 patients in Arm 4. Cytokines associated with immune activation and CD8+ T cell recruitment were augmented in the plasma of patients at weeks 6 and 12. Increased IFNγ in the sera at week 6 trended with prolonged TTP (p=0.010) and overall survival (p=0.025). The development of irAE was associated with a prolonged TTP (HR=0.25, p=0.003).ConclusionsPD-1 pathway inhibitors have demonstrated little clinical activity to date as monotherapies for mCRPC. Our findings demonstrate that combining PD-1 blockade with tumor-targeted T-cell activation using pTVG-HP is safe, can augment tumor-specific T cells, and result in objective changes with longer time to progression than what has been observed in previous trials. The association of progression or survival with increased IFNγ, irAE, and vaccine schedule suggests T cell activation by vaccination is critical to the mechanism of action of this combination. This study suggests this approach should be further evaluated in randomized clinical trials for patients with advanced mCRPC.AcknowledgementsFunding for this trial was from a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines, Inc.Trial RegistrationNCT02499835Ethics ApprovalThis trial was reviewed and approved by the University of Wisconsin Human Subjects’ Review Committee (IRB), protocol 2015–0453. All participants provided IRB-approved written informed consent before taking part.

Background The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. Patients and methods Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. Results The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). Conclusion This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

Bone flare has been observed on 99mTc-MDP bone scans of patients with metastatic castration-resistant prostate cancer (mCRPC). This exploratory study investigates bone flare in mCRPC patients receiving androgen receptor (AR) inhibitors using 18F-NaF PET/CT. Twenty-nine mCRPC patients undergoing AR-inhibiting therapy (abiraterone, orteronel, enzalutamide) received NaF PET/CT scans at baseline, week 6, and week 12 of treatment. SUV metrics were extracted globally for each patient (SUV) and for each individual lesion (iSUV). Bone flare was defined as increasing SUV metrics or lesion number at week 6 followed by subsequent week 12 decrease. Differences in metrics across timepoints were compared using Wilcoxon tests. Cox proportional hazard regression was conducted between global metrics and progression-free survival (PFS). Total SUV was most sensitive for flare detection and was identified in 14/23 (61%) patients receiving CYP17A1-inhibitors (abiraterone, orteronel), and not identified in any of six patients receiving enzalutamide. The appearance of new lesions did not account for initial increases in SUV metrics. iSUV metrics followed patient-level trends: bone flare positive patients showed a median of 72% (range: 0–100%) of lesions with total iSUV flare. Increasing mean SUV at week 6 correlated with extended PFS (HR = 0.58, p = 0.02). NaF PET bone flare was present on 61% of mCRPC patients in the first 6 weeks of treatment with CYP17A1-inhibitors. Characterization provided in this study suggests favorable PFS in patients showing bone flare. This characterization of NaF flare is important for guiding treatment assessment schedules to better distinguish between patients showing bone flare and those truly progressing, and should be performed for all emerging mCRPC treatments and imaging agents.

PURPOSE We previously reported the safety and immunologic effects of a DNA vaccine (pTVG-HP [MVI-816]) encoding prostatic acid phosphatase (PAP) in patients with recurrent, nonmetastatic prostate cancer. The current trial evaluated the effects of this vaccine on metastatic progression. PATIENTS AND METHODS Ninety-nine patients with castration-sensitive prostate cancer and prostate-specific antigen (PSA) doubling time (DT) of less than 12 months were randomly assigned to treatment with either pTVG-HP co-administered intradermally with 200 μg granulocyte-macrophage colony-stimulating factor (GM-CSF) adjuvant or 200 μg GM-CSF alone six times at 14-day intervals and then quarterly for 2 years. The primary end point was 2-year metastasis-free survival (MFS). Secondary and exploratory end points were median MFS, changes in PSA DT, immunologic effects, and changes in quantitative 18F-sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) imaging. RESULTS Two-year MFS was not different between study arms (41.8% vaccine v 42.3%; P = .97). Changes in PSA DT and median MFS were not different between study arms (18.9 v 18.3 months; hazard ratio [HR], 1.6; P = .13). Preplanned subset analysis identified longer MFS in vaccine-treated patients with rapid (< 3 months) pretreatment PSA DT (12.0 v 6.1 months; n = 21; HR, 4.4; P = .03). PAP-specific T cells were detected in both cohorts, including multifunctional PAP-specific T-helper 1–biased T cells. Changes in total activity (total standardized uptake value) on 18F-NaF PET/CT from months 3 to 6 increased 50% in patients treated with GM-CSF alone and decreased 23% in patients treated with pTVG-HP (n = 31; P = .07). CONCLUSION pTVG-HP treatment did not demonstrate an overall increase in 2-year MFS in patients with castration-sensitive prostate cancer, with the possible exception of a subgroup with rapidly progressive disease. Prespecified 18F-NaF PET/CT imaging conducted in a subset of patients suggests that vaccination had detectable effects on micrometastatic bone disease. Additional trials using pTVG-HP in combination with PD-1 blockade are under way.

Summary Background Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC.

Background Prostatic acid phosphatase (PAP) is a prostate tumor antigen, and the target of the only FDA-approved anti-tumor vaccine, sipuleucel-T. We have previously reported in two clinical trials that a DNA vaccine encoding PAP (pTVG-HP) could elicit PAP-specific, Th1-biased T cells in patients with PSA-recurrent prostate cancer. In the current pilot trial we sought to evaluate whether this vaccine could augment PAP-specific immunity when used as a booster to immunization with sipuleucel-T in patients with metastatic, castration-resistant prostate cancer (mCRPC). Methods Eigthteen patients with mCRPC were randomized to receive sipuleucel-T alone or followed by intradermal immunization with pTVG-HP DNA vaccine. Patients were followed for time to progression, and immune monitoring was conducted at defined intervals. Results Overall, patients were followed for a median of 24 months. 11/18 patients completed treatments as per protocol. No treatment-associated events > grade 2 were observed. Th1-biased PAP-specific T-cell responses were detected in 11/18 individuals, and were not statistically different between study arms. Higher titer antibody responses to PAP were detectable in patients who received pTVG-HP booster immunizations. Median time to progression was less than 6 months and not statistically different between study arms. The median overall survival for all patients was 28 months. Conclusions These findings suggest that prime-boost vaccination can augment and diversify the type of immunity elicited with anti-tumor vaccination in terms of T-cell and humoral immunity. Future studies will explore DNA as priming immunization rather than a booster immunization. Trial registration NCT01706458.

TPS5098 Background: Radiation therapy (RT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). Fluciclovine-PET/CT imaging is FDA-approved in this setting, with improved accuracy for detection of metastases not identified with conventional imaging (CIM). Given PET's greater sensitivity and specificity, its findings are increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for local or systemic treatment intensification of the otherwise non-tailored SOC approach. Improved systemic control and disease detection with molecular imaging have led to increasing use of focally ablative metastasis-directed RT, to delay or enhance systemic therapy through increased local control. There is also interest in earlier use of systemic therapy; apalutamide (Apa) is a nonsteroidal antiandrogen with established efficacy in improving overall and radiographic progression-free survival (PFS) for non-metastatic castration-resistant and metastatic castration-sensitive PC. This study will evaluate whether pts with PET-detected lesions benefit from such local or systemic treatment intensification approaches. Methods: PC pts with post-RP BCR (PSA>0.5ng/mL; >0.2ng/mL if within 12 mos of RP) and no metastases on CIM who are candidates for SOC ST (RT to prostate bed and pelvic nodes with STAD) are eligible. Prior to study registration, pts undergo SOC baseline PET (18F-fluciclovine but PSMA radiotracers permitted pending commercial availability). Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic metastases). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- metastasis-directed RT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of metastasis-directed RT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified log-rank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish 5-year PFS rate of 76.5% in the experimental arm from 61.5% in the control arm. Secondary endpoints include overall and event-free survival, toxicity, and PET progression. Clinical trial information: NCT04423211.

4507 Background: Cisplatin with gemcitabine (CG) remains the standard upfront chemotherapy regimen for metastatic urothelial cancer (mUC). Preclinical synergy was noted between cisplatin and berzosertib, a selective ATR inhibitor. The current study sought to determine if the combination of berzosertib and CG could improve clinical outcomes in mUC. Methods: An open-label, randomized study was conducted across 23 centers in the United States through the Experimental Therapeutics Clinical Trials Network of the National Cancer Institute. Key eligibility criteria included confirmed mUC, no prior cytotoxic therapy for metastatic disease, ≥ 12 months since perioperative therapy and eligibility for cisplatin based on standard criteria. Patients (pts) were randomized to receive either CG alone (control arm) or CG plus berzosertib (experimental arm). In the control arm, 70 mg/m2 of cisplatin was given on day 1 and gemcitabine at 1000 mg/m2 on days 1 and 8 of a 21-day cycle. In the experimental arm, 60 mg/m2 of cisplatin was given on day 1, gemcitabine at 875 mg/m2 on days 1 and 8 and berzosertib at 90 mg/m2 on days 2 and 9 of a 21-day cycle. The primary endpoint of the study was progression-free survival (PFS), with secondary endpoints including response rate (RR), overall survival (OS) and toxicity. Results: A total of 87 pts (median age 67; M:F 68:19) were randomized; 41 pts received CG alone while 46 received CG with berzosertib. Visceral metastases were present in 49% of pts and 52%, 45% and 3% of pts were Bajorin risk 0, 1 and 2, respectively. Median PFS was 8.0 months for both arms (Bajorin risk adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 0.72-2.08). RR was 54%(4 CR, 21 PR) in the CG with berzosertib arm and 63% (4 CR, 22 PR) in CG alone arm (P = 0.66). Median OS was shorter with CG with berzosertib as compared to CG alone (14.4 versus 19.8 months; Bajorin risk adjusted HR 1.42, 95%CI 0.76-2.68). Notably higher rates of grade 3/4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with CG plus berzosertib compared to CG alone. Higher rates of toxicity-related discontinuation were seen in the experimental arm (24% vs 15%), and the median cumulative cisplatin dose in the experimental arm was 250 mg/m2, as compared to 370 mg/m2 in the control arm (P < 0.001). Conclusions: No improvement in PFS was observed with the addition of berzosertib to CG, and a trend towards inferior survival was observed. These results suggest caution in reducing the starting dose of cytotoxic therapy to accommodate addition of a myelosuppressive agent, as in the experimental arm of this study. Clinical trial information: NCT02567409.

Purpose [18F]Sodium fluoride (NaF) positron emission tomography (PET)/computed tomography (CT) is a promising radiotracer for quantitative assessment of bone metastases. This study assesses changes in early NaF PET/CT response measures in metastatic prostate cancer for correlation to clinical outcomes. Patients and Methods Fifty-six patients with metastatic castration-resistant prostate cancer (mCRPC) with osseous metastases had NaF PET/CT scans performed at baseline and after three cycles of chemotherapy (n = 16) or androgen receptor pathway inhibitors (n = 40). A novel technology, Quantitative Total Bone Imaging, was used for analysis. Global imaging metrics, including maximum standardized uptake value (SUVmax) and total functional burden (SUVtotal), were extracted from composite lesion–level statistics for each patient and tracked throughout treatment. Progression-free survival (PFS) was calculated as a composite end point of progressive events using conventional imaging and/or physician discretion of clinical benefit; NaF imaging was not used for clinical evaluation. Cox proportional hazards regression analyses were conducted between imaging metrics and PFS. Results Functional burden (SUVtotal) assessed midtreatment was the strongest univariable PFS predictor (hazard ratio, 1.97; 95% CI, 1.44 to 2.71; P < .001). Classification of patients based on changes in functional burden showed stronger correlation to PFS than did the change in number of lesions. Various global imaging metrics outperformed baseline clinical markers in predicting outcome, including SUVtotal and SUVmean. No differences in imaging response or PFS correlates were found for different treatment cohorts. Conclusion Quantitative total bone imaging enables comprehensive disease quantification on NaF PET/CT imaging, showing strong correlation to clinical outcomes. Total functional burden assessed after three cycles of hormonal therapy or chemotherapy was predictive of PFS for men with mCRPC. This supports ongoing development of NaF PET/CT–based imaging biomarkers in mCRPC to bone.

Background/Aims Oral chemotherapy is increasingly utilized leaving the patient responsible for self-administering an often complex regimen where adverse effects are common. Non-adherence and reduced relative dose intensity are both associated with poorer outcomes in the community setting but are rarely reported in clinical trials. The purpose of this study is to quantify adherence and relative dose intensity in oncology clinical trials and to determine patient and study related factors that influence adherence and relative dose intensity. Methods Patients were identified from non-industry-funded clinical trials conducted between 1 January 2009 and 31 March 2013 at the University of Wisconsin Carbone Cancer Center. Data were extracted from primary research records. Descriptive statistics and linear regression modeling was performed using SAS 9.4. Results A total of 17 clinical trials and 266 subjects were included. Mean adherence was greater than 97% for the first eight cycles. Mean relative dose intensity was less than 90% for the first cycle and declined over time. Male gender, a performance status of 1 or 2, metastatic disease, and traveling more than 90 miles to reach the cancer center were associated with higher relative dose intensity. Conclusions Patients with cancer enrolled in clinical trials are highly adherent but unlikely to achieve protocol specified relative dose intensity. Given that determining the phase II dose is the primary endpoint of phase I trials, incorporating relative dose intensity into this determination should be considered.

Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and activated by DNA strand breaks. DNA damage from carboplatin is associated with activation of PARP. Preclinical data indicate that PARP inhibition potentiates the anti-tumor effect of platinum chemotherapy. Talazoparib (T) is an oral, selective PARP inhibitor with a single agent maximum tolerated dose (MTD) of 1mg orally qd. Primary dose-limiting toxicity (DLT) was thrombocytopenia. This phase I study combines T with the commonly used chemotherapy regimen of carboplatin (C) and paclitaxel (P). Methods: Two dosing schedules are being investigated. In both schedules, C is administered on day 1 and P on days 1, 8, and 15 of a 21-day cycle. T (100-1000mcg) is dosed once daily for days 1-7 (schedule A) or days 1-3 (schedule B) starting on day 1. A 3+3 design is used for dose escalation. Key eligibility criteria include age 318 with a measurable or evaluable solid incurable malignancy. Patients (pts) must have tumor type that is expected to respond to C + P or have BRCA germline or somatic mutation. Stable, treated brain metastases are allowed. No prior C for metastatic disease is allowed. Pts must have platelets>150 and no need for anticoagulation. After 4-6 cycles of combination therapy, pts may continue the combination, change to C and intermittent T without P or change to T alone with continuous daily dosing. Each schedule will have a 6 subject dose expansion at the MTD. The starting dose level for schedule B will be the MTD from schedule A. Results: Schedule A cohort results are reported: 11 pts (median age 59 [range 39-68]; 8 female; 3 male) have been enrolled. Pts had breast (6), ovarian (2), pancreatic (1), and SCC of oropharynx (1) and concurrent ovarian and pancreatic (1). Five pts are BRCA2+ and 3 pts are BRCA1+. Dose level 3 on schedule A (T 350mcg with C AUC 6 and P 80mg/m2) exceeded the MTD with 2 of 3 pts experiencing hematologic dose limiting toxicities (DLTs) including 1 pt with grade (gr) 3 neutropenic fever and gr 4 thrombocytopenia and another pt with grade 3/4 neutropenia lasting > 7 days. Most common AEs include neutropenia (grade 3-4: 7), anemia (grade 3-4: 3), and thrombocytopenia (grade 3-4: 4). Results from expansion of dose level 2 (T 250mcg with C AUC 6 and T 80mg/m2) will be presented. The 11 pts were on study a median of 9 weeks (range 9-36+). Four pts have discontinued study therapy: 1 due to need for anticoagulation for PE, 1 for prolonged cytopenias, and 2 for disease progression. Of the 8 pts with measurable disease evaluated for response to date, 4 had SD, 1 had a cPR, 1 had radiographic CR, and 2 with PD. A pt with BRCA 1+ triple negative breast cancer has maintained a prolonged PR (36+ weeks) even after dose reductions to T 100mcg with C AUC 3. One pt with ovarian cancer (BRCA WT) has radiographic CR (CA 125 remains mildly elevated) after 15+ weeks of therapy. Conclusion: PARP inhibition with talazoparib days 1-7 in combination with carboplatin and paclitaxel leads to DLT of myelosuppression. However, clinical responses are seen even with lower dose combinations. Citation Format: Turk A, Chan N, Leal T, O'Regan R, Tevaarwerk A, Rice L, Campbell T, Barroilhet L, Mehnert J, Eickhoff J, Kolesar J, Liu G, Wisinski K. NCI9782: A phase 1 study of talazoparib in combination with carboplatin and paclitaxel in patients with advanced solid tumors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-21.

Background: Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus. Methods: Patients with up to two prior regimens were eligible for treatment, consisting of vorinostat 200 mg orally two times daily × 2 weeks, and bevacizumab 15 mg kg−1 intravenously every 3 weeks. The primary end points were safety and tolerability, and the proportion of patients with 6 months of progression-free survival (PFS). Correlative studies included immunohistochemistry, FDG PET/CT scans, and serum analyses for chemokines and microRNAs. Results: Thirty-six patients were enrolled, with 33 evaluable for toxicity and efficacy. Eighteen patients had 1 prior treatment, 13 patients had 2 prior treatments, and 2 patients were treatment naïve. Two patients experienced grade 4 thrombocytopenia and three patients had grade 3 thromboembolic events during the course of exposure. We observed six objective responses (18%), including one complete response and five partial responses. The proportion of patients with PFS at 6 months was 48%. The median PFS and overall survival were 5.7 months (confidence interval (CI): 4.1–11.0) and 13.9 months (CI: 9.8–20.7), respectively. Correlative studies showed that modulation of specific chemokines and microRNAs were associated with clinical benefit. Conclusions: The combination of vorinostat with bevacizumab as described is relatively well tolerated. Response rate and median PFS suggest clinical activity for this combination strategy in previously treated ccRCC.

Purpose This study utilizes FLT PET/CT imaging to characterize changes in tumor cell proliferation and vasculature during intermittent treatment with VEGR-TKI axitinib.

Patients with metastatic castrate-resistant prostate cancer (mCRPC) can develop bone lesions throughout their skeleton. Previously the distribution of lesions and its impact on survival has been explored using (99m)Tc-methylene diphosphonate planar scintigraphy (bone scans), but not on the more sensitive (18)F-NaF PET/CT. We found that several regional SUV metrics were more prognostic of progression-free survival (PFS) than their whole-body counterparts. BACKGROUND: Background: Whole-body assessments of (18)F-NaF PET/CT provide promising quantitative imaging biomarkers of metastatic castrate-resistant prostate cancer (mCRPC). This study investigates whether the distribution of metastases across anatomic regions is prognostic of progression-free survival (PFS). METHODS: Fifty-four mCRPC patients with osseous metastases received baseline NaF PET/CTs. Patients received chemotherapy (N=16) or androgen-receptor (AR) pathway inhibitors (N=38). Semi-automated QTBI analysis extracted imaging metrics for the whole-, axial-, and appendicular-skeleton and 11 skeletal regions. Five PET metrics were extracted for each region: number of lesions (N(L)), maximum uptake (SUV(max)), average uptake (SUV(mean)), sum of uptake (SUV(total)), and diseased fraction of the skeleton (volume fraction, VF). Progression included clinical, biochemical, or radiographic. Univariate and multivariate Cox proportional-hazard regression analyses were performed between imaging metrics and PFS and were assessed according to their hazard ratios (HR) and concordance (C) indices. RESULTS: The strongest univariate models of PFS were pelvic N(L) and SUV(max) with HR=1.80 (N(L): false discovery rate adjusted p-value=0.003, SUV(max): adjusted p-value=0.005). Three other region-specific metrics (axial N(L): HR=1.59, adjusted p-value=0.02, axial SUV(max): HR=1.61, adjusted p-value=0.02, and skull SUV(max): HR=1.58, adjusted p-value=0.04) were found to be stronger prognosticators relative to their whole-body counterparts. Multivariate model including region-specific metrics (C-index=0.727) outperformed that of whole-body metrics (C-index=0.705). The best performance was obtained when region-specific and whole-body metrics were included (C-index=0.742). CONCLUSION: Quantitative characterization of metastatic spread by anatomic location on NaF PET/CT enhances potential prognostication. Further study is warranted to optimize the prognostic and predictive value of NaF PET/CT in mCRPC patients.

Background Immunotherapy has demonstrated remarkable success in treating different cancers. Nonetheless, a large number of patients do not respond, many respond without immediate changes detectable with conventional imaging, and many have unusual immune-related adverse events that cannot be predicted in advance. In this exploratory study, we investigate how 3′-Deoxy-3’-18F-fluorothymidine (FLT) positron emission tomography (PET) measurements of tumor and immune cell proliferation might be utilized as biomarkers in immunotherapy. Methods Seventeen patients with metastatic castrate resistant prostate cancer were treated with combination pTVG-HP DNA vaccine and pembrolizumab. Patients underwent baseline and 12-week FLT PET/CT scans. FLT PET standardized uptake values (SUVs) were extracted from tumors, non-metastatic lymph nodes, spleen, bone marrow, pancreas, and thyroid to quantify cell proliferation in these tissues. Regional immune cell responses to pTVG-HP DNA vaccine were assessed by comparing FLT uptake changes in vaccine draining and non-draining lymph nodes. Cox proportional hazards regression was utilized to relate FLT uptake and other clinical markers (PSA and tumor size) to progression-free survival. Area under receiver operating characteristic (AUC) curves and concordance indices were used to assess the predictive capabilities of FLT uptake. Results Changes in FLT uptake in vaccine draining lymph nodes were significantly greater than changes in non-draining lymph nodes (P = 0.02), suggesting a regional immune response to vaccination. However, the changes in FLT uptake in lymph nodes were not significantly predictive of progression-free survival. Increases in tumor FLT uptake were significantly predictive of shorter progression-free survival (concordance index = 0.83, P

TPS267 Background: Radiation therapy (RT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). Fluciclovine-PET/CT imaging is FDA-approved in this setting, with improved accuracy for detection of metastases (mets) not identified with conventional imaging (CIM). Given greater sensitivity and specificity of PET, its findings are being increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for local or systemic treatment intensification of otherwise non-tailored SOC. Earlier detection of mets with molecular imaging has led to increasing use of focally ablative met-directed RT, to delay or enhance systemic therapy through better local control. There is also interest in earlier use of advanced systemic therapy; apalutamide (Apa) is a nonsteroidal antiandrogen with established efficacy in improving overall and radiographic progression-free survival (PFS) for non-metastatic castrate-resistant and metastatic castration-sensitive PC, and potential activity for low-volume mets. This study will evaluate whether pts with PET-detected lesions benefit from such local or systemic treatment intensification approaches. Methods: PC pts with post-RP BCR (PSA>0.5ng/mL; >0.2 if RP within 12 mos), and negative CIM who are candidates for SOC ST (RT to prostate bed and pelvic nodes + STAD) and undergo SOC baseline PET are eligible. The study will initially use 18F-fluciclovine but permit additional radiotracers based on FDA approval and availability. Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic mets). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- met-directed RT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of met-directed RT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified logrank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish 5-year PFS rate of 76.5% in experimental arm from 61.5% in control arm. Secondary endpoints include overall and event-free survival, toxicity, and PET progression. Trial was activated on October 8, 2020; NCT04423211. Acknowledgement: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180868, U10CA180888, U10CA180821, UG1CA233196, UG1CA233253, UG1CA233277, UG1CA233328, and UG1CA233330. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government. Clinical trial information: NCT 04423211.

(18)F-NaF, a PET radiotracer of bone turnover, has shown potential as an imaging biomarker for assessing the response of bone metastases to therapy. This study aimed to evaluate the repeatability of (18)F-NaF PET–derived SUV imaging metrics in individual bone lesions from patients in a multicenter study. Methods: Thirty-five castration-resistant prostate cancer patients with multiple metastases underwent 2 whole-body (test–retest) (18)F-NaF PET/CT scans 3 ± 2 d apart from 1 of 3 imaging sites. A total of 411 bone lesions larger than 1.5 cm(3) were automatically segmented using an SUV threshold of 15 g/mL. Two levels of analysis were performed: lesion-level, in which measures were extracted from individual-lesion regions of interest (ROI), and patient-level, in which all lesions within a patient were grouped into a patient ROI for analysis. Uptake was quantified with SUV(max), SUV(mean), and SUV(total). Test–retest repeatability was assessed using Bland–Altman analysis, intraclass correlation coefficient (ICC), coefficient of variation, critical percentage difference, and repeatability coefficient. The 95% limit of agreement (LOA) of the ratio between test and retest measurements was calculated. Results: At the lesion level, the coefficient of variation for SUV(max), SUV(mean), and SUV(total) was 14.1%, 6.6%, and 25.5%, respectively. At the patient level, it was slightly smaller: 12.0%, 5.3%, and 18.5%, respectively. ICC was excellent (>0.95) for all SUV metrics. Lesion-level 95% LOA for SUV(max,) SUV(mean), and SUV(total) was (0.76, 1.32), (0.88, 1.14), and (0.63, 1.71), respectively. Patient-level 95% LOA was slightly narrower, at (0.79, 1.26), (0.89, 1.10), and (0.70, 1.44), respectively. We observed significant differences in the variance and sample mean of lesion-level and patient-level measurements between imaging sites. Conclusion: The repeatability of SUV(max), SUV(mean), and SUV(total) for (18)F-NaF PET/CT was similar between lesion- and patient-level ROIs. We found significant differences in lesion-level and patient-level distributions between sites. These results can be used to establish (18)F-NaF PET–based criteria for assessing treatment response at the lesion and patient levels. (18)F-NaF PET demonstrates repeatability levels useful for clinically quantifying the response of bone lesions to therapy.

Purpose: Preclinical data support combining AKT inhibitors with HER2-targeted therapies to overcome resistance to treatment. This phase I study combined the investigational AKT inhibitor, MK-2206, with lapatinib to determine the MTD. Experimental Design: The dose escalation cohort enrolled adults with advanced solid tumors, who received MK-2206 dosed 30 to 60 mg every other day and lapatinib 1,000 to 1,500 mg daily continuously, escalated using a 3+3 design. Cycles were 28 days except cycle 1 (35 days, including an initial 8 days of MK-2206 alone to evaluate pharmacokinetic interactions). The dose expansion cohort enrolled adults with advanced HER2+ breast cancer. Results: Twenty-three participants enrolled in the dose escalation cohort. Dose-limiting toxicities were hyponatremia, fatigue, rash, hypocalcemia, and mucositis. Common toxicities included diarrhea, nausea, and rash. The MTD was reached at MK-2206 45 mg orally every other day and lapatinib 1,500 mg orally daily. Two participants maintained stable disease for >4 months, including a colorectal cancer participant with substantial carcinoembryonic antigen decrease. Of 5 participants in the dose expansion cohort, 2 maintained stable disease for >6 months, including one with prior progression on single-agent lapatinib. Plasma MK-2206 concentrations decreased after addition of lapatinib, but in vitro studies indicate lapatinib increases the intracellular levels of MK-2206. Conclusions: MK-2206 combined with lapatinib can be tolerated with both drugs above biologically active single-agent doses. Overlapping toxicities result in significant diarrhea and rash, which can be managed medically. Antitumor activity was promising and supports evaluation of AKT inhibitors combined with HER2-targeted therapies. Clin Cancer Res; 22(11); 2659–67. ©2016 AACR.

Purpose Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups. Methods An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations. Results PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials. Conclusion PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

PURPOSE: PF-00337210 is an oral, highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We evaluated a composite of biomarkers in real time to identify the recommended phase 2 dose (RP2D) and preliminary anticancer activity of PF-00337210. PATIENTS AND METHODS: Patients (Pts) with advanced cancers were treated once (QD) or twice daily (BID) with escalating doses. Acute effects on tumor perfusion and vascularity were assessed using DCE-MRI, weekly BP readings, soluble VEGFR-2, and hemoglobin levels. RESULTS: Forty-six pts were treated with 0.67–9 mg QD and 4–6 mg BID of PF-00337210. Nineteen pts (41 %) previously received VEGF/VEGFR inhibitors. Two pts had dose-limiting toxicity (DLT) at 9 mg QD (troponin I increase and hypertension). The MTD at QD dose was 8 mg. Common drug-related adverse events were hypertension, fatigue, proteinuria, and nausea. Hypertension incidence and intensity corresponded with dose, but was well controlled with medication. Two confirmed partial responses and minor regressions (>10 to

Background KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. Methods A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. Results 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg PO BID and cetuximab 250 mg/m2 weekly following a 400 mg/m2 load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. Conclusions The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.

INTRODUCTION: Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In pre-clinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising pre-clinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. METHODS: Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m(2) on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. RESULTS: Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. CONCLUSIONS: Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC.

This study explores the imaging and therapeutic properties of a novel radiopharmaceutical, (131)I-CLR1404. Phase 1a data demonstrated safety and tumor localization by SPECT-CT. This 1b study assessed safety, imaging characteristics, and possible antineoplastic properties and provided further proof-of-concept of phospholipid ether analogues' retention within tumors. A total of 10 patients received (131)I-CLR1404 in an adaptive dose-escalation design. Imaging characteristics were consistent with prior studies, showing tumor uptake in primary tumors and metastases. At doses of 31.25 mCi/m(2) and greater, DLTs were thrombocytopenia and neutropenia. Disease-specific studies are underway to identify cancers most likely to benefit from (131)I-CLR1404 monotherapy.

149 Background: Patients with metastatic hormone-sensitive prostate cancer (mHSPC) have a variable response to ADT and some benefit from the addition of docetaxel or an androgen signaling pathway inhibitor. We found that loss of the epigenetic regulator KDM5D is associated with more aggressive prostate cancer (PC). We sought to determine whether MYBL2 which is regulated by KDM5D mediates this effect. MYBL2 is a transcription factor which controls key genes (e.g. FOXM1) and increases cell cycle progression and survival. Methods: AR expressing hormone-sensitive cell lines, LNCaP and LAPC4 were used. Motif analysis and CHiPseq of LNCaP with and without siKDM5D was performed and impact of modulation of KDM5D and MYBL2 in both cells on cell survival was assessed. Gene expression profiling (GEP) data assessed MYBL2’s association with KDM5D levels in localized disease (publicly available data) and mHSPC (Decipher whole Affymetrix platform on CHAARTED samples). Results: Silencing KDM5D increased H3K4me3 and increased MYBL2 expression. GEP showed a strong negative correlation between KDM5D and MYBL2 in patients with localized PC (-0.66; TCGA) but not from primary prostate cancer tissue with mHSPC (-0.03; CHAARTED). Cells with low KDM5D and high MYBL2 were androgen independent and more resistant to docetaxel. In TCGA, patients with high MYBL2 had a higher rate of relapse from localized disease. In patients with metastatic disease (CHAARTED) low MYBL2 was associated with a better overall survival (OS) on multivariable analysis when treated with ADT or ADT + docetaxel. Conclusions: Low MYBL2 is associated with a longer OS with ADT alone and ADT and docetaxel independent of clinical variables. Patients with high MYBL2 expression had better OS with ADT plus docetaxel compared with patients with high MYBL2 treated with ADT alone.[Table: see text]

TPS273 Background: Radical prostatectomy (RP) and radiation therapy (RT) are the gold standard, curative intent treatment for pts with presumed organ-confined PCa. However, about one third of these pts will have progressive or metastatic disease at 10 years (yr). Pts with PSA recurrence without radiographic evidence of metastatic (m) PCa (stage M0) will ultimately develop radiographically apparent mPCa within a median of 8 yr. Pts with rapid PSA doubling time (DT) have a markedly shorter time to mPCa and death. Utilizing an immunotherapeutic approach could utilize the sensitivity and specificity of the immune system to treat microscopic disease and potentially avoid or postpone androgen deprivation therapy (ADT) and its unwanted side effects. Methods: In this single arm, two-stage phase II trial, a total of 21-41 PCa pts with PSA only progression (4 rising PSA with final PSA ≥ 2 ng/mL) after initial RP for presumed organ-confined disease who have no radiographic evidence of mPCa in conventional imaging (CT and bone scan) will be enrolled. Pts with small cell or other variant PCa, or history of ADT other than concurrent with RT are excluded. All pts will be treated with pTVG-HP 100 μg intradermally (id) and Nivo 240 mg IV every (Q) 2 weeks (w) x6, and then pTVG-HP 100 μg id and Nivo 480 mg IV Q4w x9 beginning w12 on study. Pts with PSA on w4 > PSA on day 1 will additionally receive rhGM-CSF 208 μg id, as a vaccine adjuvant, Q2w x4 beginning w4 on study. Pts will be treated until progression or up to a total of 1 yr. Response will be monitored by CT and bone scan Q6 months or as clinically indicated. Primary endpoints are safety and tolerability of this combination and PSA complete response rate (PSA < 0.2 ng/mL). Key secondary endpoints are 2-yr metastasis-free survival, median radiographic progression-free survival, PSA response rate (≤50% of baseline), and changes in PSA DT. Elicited antigen-specific T-cell and/or IgG response and its correlation with PSA response will be explored. Bone mets not detected by conventional imaging and their association with response will be evaluated by Quantitative Total Bone Imaging (QTBI) by NaF PET/CT. Updated enrollment will be presented. Clinical trial information: NCT03600350.

162 Background: Through gene expression profiling (GEP), the PAM50 classifier demonstrates prognostic value in localized prostate cancer (PCa). Pre-clinical drug response models predict increased taxane sensitivity in luminal subtypes compared to basal subtype. Men with mHSPC and high-risk features have greatest benefit from androgen deprivation therapy (ADT) plus docetaxel (D) vs ADT alone. We therefore sought to test the prognostic and predictive value of PAM50 in pre-ADT specimens from E3805 CHAARTED. Methods: Whole transcriptomic profiling of formalin-fixed, paraffin-embedded primary PCa biopsies from pts enrolled in the E3805 CHAARTED trial of ADT vs ADT+D was performed using the Human Exon 1.0 ST microarray platform (Decipher Biosciences). Normalized gene expression was used to classify subjects as luminal A, luminal B or basal subtype. Multivariable analyses (MVA) adjusted for ECOG status, de novo metastasis vs prior local therapy and volume of disease. The primary endpoint was overall survival (OS). Secondary endpoint was time to castration resistant PCa (TTCRPC). Results: Successful GEP was completed in 160 of 198 pts with available specimens. Eighty (50%), 77 (48%) and 3 (2%) pts were classified as luminal B, basal and luminal A, respectively. High volume disease was similarly present in luminal B (79%) and basal (78%) subtypes. In the ADT arm, luminal B subtype was associated with shorter OS vs basal (HR 1.75, p=0.05); consistent in MVA. Pts with luminal B subtype treated with ADT+D showed significant improvement in TTCRPC and OS (Table). By contrast, basal subtype showed no OS benefit from ADT+D even in pts with high volume disease. Conclusions: We demonstrate that GEP identifies tumor subtypes associated with differential benefit from chemohormonal therapy for mHSPC. Luminal B subtype is associated with poorer OS with ADT alone and benefits from addition of D. Basal subtype shows a lack of OS benefit from upfront ADT+D. We plan to validate these findings in independent trial cohorts.[Table: see text]

Purpose In April 2017, the American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology released a joint evidence-based practice guideline on clinically localized prostate cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods The Clinically Localized Prostate Cancer guideline was reviewed for developmental rigor by methodologists. An ASCO Expert Panel then reviewed the content and the recommendations. Results The ASCO Expert Panel determined that the recommendations from the Clinically Localized Prostate Cancer guideline were clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the Clinically Localized Prostate Cancer guideline except for two recommendations on cryosurgery. The two recommendations covering cryosurgery were not endorsed because the panel found that there is insufficient evidence to support the use of cryotherapy in this setting. Recommendations The ASCO Expert Panel endorsed all but two of the original guideline recommendations as written and offered a series of discussion points to guide practice.

Background We report secondary and exploratory analysis with 18F-NaF PET/CT and CTCs to determine how tumour burden and RNA expression of androgen receptor (AR) splice variants and neuroendocrine (NE) features predict duration of treatment (DoTx) with ENZA. Methods Men with progressive mCRPC with ≥ 2 lesions on bone scintigraphy were enrolled and treated with ENZA 160 mg daily at 3 US sites. 18F-NaF PET/CT scans were obtained at baseline (BL) (PET1), week 13 (PET2), and at the time of PSA progression (per PCWG2 criteria), standard radiographic or clinical progression, or at 2 years without progression (PET3) using QTBI. CTCs were obtained at BL and at PET3. PSA decline and DoTx were compared with BL QTBI, CTC metrics, and change in QTBI. Results 23 men (median age, 72 years [range, 51-93]; median PSA, 20.5 ng/mL [range, 3.9-133.6]) were enrolled; 22 of which completed planned imaging. The mean number of bone lesions on PET1 was 58 (range 9-168), with a median total standardized uptake value (SUVtotal) of 3886.5 (range 506.7-22852.8). DoTx ranged from 1.4 to 31.8+ mo. In general, SUV metrics decreased while on ENZA (PET2) and increased by PET3. Change in lesion heterogeneity (PET1 to PET3) was the most significant predictor of time to PSA progression (hazard ratio, 3.88; 95% confidence interval, 1.24-12.1). ARV7/9 was found in CTCs in 3/20 men and NE features were found in 4/20 men at BL and in 4/19 and in 11/19 men, respectively, at PET3. Conclusions Although PSA response with ENZA is high, DoTx is variable. SUVtotal at BL did not correlate with DoTx; however, decrease in SUVtotal/mean was associated with increased DoTx, with less heterogeneity correlating with a longer time to PSA progression. ARV7/9 or NE expression in CTCs did not predict lack of benefit from ENZA; however, at the time of progression, the observed increase in ARV7/9 and NE expression are consistent with tumor evolution to more aggressive phenotypes. While BL heterogeneity may be prognostic, it may not predict response or DoTx. Assessing response heterogeneity may predict response duration, thus, should be explored as a possible surrogate of benefit in future studies. Clinical trial identification NCT02384382. Editorial acknowledgement Medical writing and editorial assistance funded by Pfizer Inc. and Astellas Pharma, Inc. was provided by Stephanie Vadasz, PhD, and Michele Salernitano from Ashfield Healthcare Communications. Legal entity responsible for the study Pfizer Inc. and Astellas Pharma, Inc. Funding Pfizer Inc. and Astellas Pharma, Inc. Disclosure G. Liu: Leadership role, Shareholder / Stockholder / Stock options, Employee: AIQ Solutions; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): TRACON Pharma; Research grant / Funding (self), Research grant / Funding (institution): Madison Vaccines Inc.; Research grant / Funding (self), Research grant / Funding (institution): Pfizer Inc. C.E. Kyriakopoulos: Advisory / Consultancy, Travel / Accommodation / Expenses: Exelixis; Speaker Bureau / Expert testimony: The France Foundation; Research grant / Funding (self), Research grant / Funding (institution): Sanofi. J.M. Lang: Shareholder / Stockholder / Stock options, Licensing / Royalties, I am listed on the patent on a technology for rare cell capture and analysis. This technology has been licensed by Salus Discovery, LLC though no commercial products are available: Salus Discovery; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Pfizer Inc.; Research grant / Funding (institution): Novartis. E.I. Heath: Advisory / Consultancy, Research grant / Funding (institution): Agensys; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Honoraria (self): Bayer; Honoraria (self), Research grant / Funding (institution): Dendreon; Honoraria (self), Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Tokai Pharmaceuticals; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Inovio Pharmaceuticals; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Zenith Epigenetics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Esanik; Research grant / Funding (institution): Oncolys BioPharma; Research grant / Funding (institution): CureMeta; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): eFFECTOR Therapeutics; Research grant / Funding (institution): Fortis. S. Perlman: Research grant / Funding (institution): GE Healthcare Progenics; Advisory / Consultancy: Pfizer Inc. T. Mayer: Advisory / Consultancy: Beacon Biosciences/ICON Medical; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Research grant / Funding (institution): Sotio; Research grant / Funding (institution): Merck; Research grant / Funding (self): Pfizer Inc. K. Modelska: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. A. Porcari: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. W. Duggan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. R. Jeraj: Licensing / Royalties, Patents: Wisconsin Alumni Research Foundation; Shareholder / Stockholder / Stock options: AIQ Solutions; Research grant / Funding (institution): GE Healthcare. All other authors have declared no conflicts of interest.

International audience; BACKGROUND:Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D.OBJECTIVE:To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT]).DESIGN, SETTING, AND PARTICIPANTS:Data were accessed from two independent phase III trials of ADT alone or ADT+D-GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The primary end point was OS.RESULTS AND LIMITATIONS:Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

Author(s): Armstrong, AJ; Antonarakis, ES; Taplin, M-E; Kelly, WK; Beltran, H; Fizazi, K; Dahut, WL; Shore, N; Slovin, S; George, D; Carducci, MA; Corn, P; Danila, D; Dreicer, R; Heath, E; Rathkopf, D; Liu, G; Nanus, D; Stein, M; Smith, MR; Sternberg, C; Wilding, G; Nelson, PS; Halabi, S; Kantoff, P; Clarke, NW; Evans, CP; Heidenreich, A; Mottet, N; Gleave, M; Morris, MJ; Scher, HI

Purpose Potential cytochrome P-450 (CYP) drug–drug interactions in adults with metastatic solid tumors and their effect on eligibility for Phase I clinical trials were characterized. Methods This study included adult patients with metastatic solid tumors seen by a medical oncologist from January 2008 through July 2011. The medications used by these patients were identified. Each medication’s potential for interacting with CYP isozymes was also characterized. Medication changes required to meet Phase I trial eligibility criteria were also reviewed. Results Data from 1773 patients were analyzed: 1489 were not enrolled in a Phase I trial and 284 were enrolled in a Phase I trial. Polypharmacy was significantly more prevalent in the group enrolled in a Phase I trial compared with those not enrolled (95% versus 80%, p < 0.001). The majority of patients not enrolled in a Phase I trial were taking at least one CYP isozyme inhibitor (87%) and at least one CYP isozyme inducer (45%). In a separate analysis, four Phase I trials were evaluated. Of 295 screened patients, 3.2% could not enroll due to concurrent medications. Charts from 74 enrolled patients revealed 655 concurrent medications—93 medications required further review for eligibility involving 51 (69%) of patients. Of the 93 medications, 38 (41%) were stopped and 41 (44%) were changed for the study. Conclusion Polypharmacy and the use of medications that interact with CYP isoyzmes were common in adult patients with metastatic solid tumors. Patients enrolling in Phase I studies often require medication changes to meet eligibility requirements.

Rapid disease progression associated with increased tumor proliferation has been observed during withdrawal of anti-angiogenic therapy. We characterize the dynamics of withdrawal flare for axitinib.Thirty patients with metastatic solid malignancies received axitinib for 2 weeks, followed by a 1-week drug holiday. Twenty patients suitable for PET imaging received scans with (18)F-3'deoxy-3'fluoro-L-thymidine (FLT), a marker of proliferation. Plasma VEGF and axitinib pharmacokinetic levels were also assessed at specified time points.During axitinib withdrawal, significant increases in both SUVmax (+22 %; p = 0.006) and SUVmean (+20 %; p = 0.001) were observed. Significant increases relative to peak axitinib concentration were observed at day 2 withdrawal for SUVmax and SUVmean, with no further significant increase from day 2 to day 7 of withdrawal. No significant change in SUVmax or SUVmean was observed during the treatment period, relative to baseline. VEGF concentration significantly increased when on drug (p 0.001) and decreased back to a level indistinguishable from baseline by day 7 of drug washout (p = 0.448). No correlation between change in VEGF and change in imaging metrics was observed.A significant increase in tumor proliferation was observed during withdrawal of axitinib therapy, and this flare occurred within 2 days of axitinib withdrawal. An exploratory analysis indicated that this flare may be associated with poor clinical outcome.

Background : AKT mediates signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. MK-2206 is an oral selective inhibitor of AKT. This study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), adverse events (AEs), clinical activity, pharmacokinetic (PK) parameters and explore potential biomarkers of the combination of MK-2206 with lapatinib. Methods : The dose escalation cohort included adult patients (pts) with solid tumors treated with MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. MK-2206 plasma concentrations were evaluated on day 1, 9 (steady state) and 15 (steady state in combination with lapatinib). Lapatinib plasma concentrations were evaluated on day 9 (first dose) and day 15 (steady state in combination with MK-2206). Both used a validated LC-MSMS assay. Pharmacokinetic parameters were calculated using non-compartmental methods with WinNonLin Phoenix version. The dose expansion cohort included women with advanced HER2+ breast cancer treated at the MTD. Peripheral blood mononuclear cells (PBMCs) and archived tumor samples were collected for all pts. Results : In the dose escalation cohort, 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. Cancers were colorectal (8 pts), lung (4 pts), breast (3 pts) and other (8 pts). 19 evaluable pts were treated a median of 8 weeks (range 3-35). At dose level four, 1 pt had grade 4 hyponatremia, grade 3 rash and hypocalcemia and 1 pt had intolerable grade 2 mucositis with delivery of Conclusions : Continuous dosing of MK-2206 in combination with lapatinib is well-tolerated. Preliminary results of pharmacokinetic analysis indicate a potential for a drug interaction. Clinical benefit was seen in patients with HER2+ breast cancer. Citation Format: Moniba Nazeef, Amye J Tevaarwerk, Jens Eickhoff, Mark E Burkard, Jennifer Heideman, Glenn Liu, Chris Flynn, Jill M Kolesar, Kari B Wisinski. A phase I study of MK-2206 in combination with lapatinib in patients with advanced solid tumors followed by dose-expansion in advanced HER2+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-20.

Background: Docetaxel–prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. Methods: Adult men with chemotherapy-naive mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone

Bevacizumab or temsirolimus regimens have clinical activity in the first-line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent.In the phase I portion, eligible patients were treated with temsirolimus (25 mg IV weekly) and escalating doses of IV bevacizumab (level 1 = 5 mg/kg; level 2 = 10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression-free rate. Secondary endpoints were response rate, toxicity evaluation, and PFS and OS.Maximum tolerated dose was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg IV every 2 weeks). The 6-month progression-free rate was 40 % (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5-23.7) months. Partial response, stable disease, and progressive disease were seen in 23, 63, and 14 % of patients, respectively. Most common grade 3-4 AEs included fatigue (17.8 %), hypertriglyceridemia (11.1 %), stomatitis (8.9 %), proteinuria (8.9 %), abdominal pain (6.7 %), and anemia (6.7 %). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively.Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population.

Background RO4929097 is an oral inhibitor of γ -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors. Methods Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m2 twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle. Results Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration. Conclusions The recommended phase 2 dose is capecitabine 1,000 mg/m2 orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1–3, 8–10 and 15–17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.

Background Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. Patients and methods Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months’ exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics’ GmbH). Results Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naive mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naive and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. Conclusions The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. ClinicalTrials.gov identifier NCT01171898.

Purpose: Several treatment response metrics, such as RECIST and PERCIST, have been established for assessing individual solid tumors. However, metastatic prostate cancer poses a unique challenge to these metrics because bone lesions are often numerous and non‐measureable. This study investigated the impact of using different imaging measures for treatment response assessment in patients with metastatic prostate cancer.Methods: Six patients with metastatic prostate cancer were treated with molecular targeted therapy and received whole body [18F]NaF PET/CT scans pre‐, mid‐, and post‐treatment. Lesions were segmented using a threshold of 20% the maximum SUV in bone and then manually adjusted with physician guidance. For each patient, SUVmax, SUVmean, SUVpeak, SUVtotal, number of lesions, and total volume of bone lesions were determined. For each measure, treatment response was calculated as the percent change relative to pre‐treatment. The range of the different responses was calculated for each patient at each response time point. The population average of the patient ranges was calculated. Results: The patient responses varied greatly for different imaging measures. The population‐averaged range for all response measures was 50%. In general, SUVmax, SUVmean, and SUVpeak responses were negative, indicating good response to treatment, but the number of lesions, volume, and SUVtotal responses were positive, indicating disease progression. When the measures were separated into these two groups, the population‐averaged range was only 25% among the number of lesions, volume, and SUVtotal responses and 10% among the SUVmax, SUVmean, and SUVpeak responses. Conclusions: Several treatment response metrics, such as RECIST and PERCIST, have been established for assessing individual solid tumors. However, metastatic prostate cancer poses a unique challenge to these metrics because bone lesions are often numerous and non‐measureable. This study investigated the impact of using different imaging measures for treatment response assessment in patients with metastatic prostate cancer.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Ever since the critical role of androgen deprivation therapy for the treatment of metastatic prostate cancer was established, several trials aimed to show an improved outcome with the early introduction of chemotherapy in metastatic disease. Until recently, all these trials-including the GETUG-AFU 15 trial-failed to confirm an improvement in survival. The recently published CHAARTED and STAMPEDE trials showed a striking benefit and changed the standard of care for patients with newly diagnosed metastatic prostate cancer. We summarize the evidence that emerged from these trials that support the use of combined chemohormonal therapy in metastatic hormone-sensitive prostate cancer.

Lessons Learned The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC). The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. Background Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. Results The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). Conclusion Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

e16516 Background: Methods for molecular image-guided biopsies have been limited to targeting lesions with high radiotracer uptake. The purpose of this study is to determine the value of using molecular imaging response to select lesions for biopsy. Methods: 7 metastatic prostate cancer patients received 18F-NaF PET/CT scans at baseline and after 12 weeks of enzalutamide therapy. Lesion uptake was quantified semi-automatically. Lesions were classified as partially responding (PR, significantly decreased uptake), stable disease (SD, no significant change), and progressing disease (PD, significantly increased uptake) using test-retest limits of agreement for the relative change in SUVtotal. In the case that response was stable by SUVtotal, the relative change of SUVmax (and corresponding limits of agreement) were used to reclassify response. 3 candidate lesions from each response category (PR, PD) were selected, including SD lesions if needed. Interventional radiologists biopsied two lesions from different response categories per patient within 7 days of the week 12 scan. Up to 3 needle cores and aspirate were taken per biopsy. Core and aspirate samples were subjected to multiplexed PCR using custom Ampliseq panels targeted to common mutations (DNA) and alterations (RNA) in prostate cancer. The presence of androgen receptor splice variant 7 (AR-V7) was determined for each sample. Results: 8/13 lesions biopsied contained tumor, but one patient’s samples were not tracked (one lesion contained tumor). 7/11 tracked lesions contained tumor including 2/3 PR lesions, 1/4 SD lesions, and 4/4 PD lesions. The average tumor content in successful needle passes was 30.0% for PR (3/6 passes), 20.0% for SD (1/8 passes), and 35.7% for PD lesions (7/8 passes). Aspirate samples were acquired for 1 PR and 3 PD lesions; all 4 contained tumor. AR-V7 was identified in 0/2 PR, 0/1 SD, and 3/4 PD lesions. 3/7 patients had two biopsy lesions that contained tumor. Two patients had PR and PD biopsies and one patient had SD and PD biopsies). AR-V7 was identified in the PD lesions of one of the PR/PD patients and the SD/PD patient. Conclusions: Molecular imaging response has the potential to increase the success of difficult biopsy scenarios. Additional information about developing therapy resistance can be gathered by preferentially sampling PD lesions. Clinical trial information: NCT02677376.

5036 Background: 18F-NaF PET/CT provides spatial and quantitative information on osteoblastic activity in men with bone mCRPC; thus, it can be used to assess interlesional response heterogeneity, a critical clinical issue. Here we assess the proportion of men treated with ENZA with responding lesions by 18F-NaF PET/CT at the time of prostate-specific antigen (PSA), standard radiographic, or clinical progression. Methods: Men with progressive mCRPC with ≥ 2 lesions on bone scintigraphy were enrolled and treated with ENZA 160 mg daily at 3 US sites. 18F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of PSA progression (increase of ≥ 25% and ≥ 2.0 ng/mL above nadir), standard radiographic or clinical progression, or at 2 years without progression (PET3) using Quantitative Total Bone Imaging (QTBI). The primary endpoint was the proportion of men with ≥ 1 responding bone lesion (defined as a lesion with a total NaF standardized uptake value [SUV] less than baseline) on PET3. Evaluable men had scans at PET1 and PET3. Results: A total of 23 men (median age, 72 years [range, 51-93]; median PSA, 20.5 ng/mL [range, 3.9-133.6]) were enrolled. The study met its primary objective; 22 of 22 (100%) evaluable men had ≥ 1 responding bone lesion on QTBI at PET3. Total disease burden changed from a mean baseline SUV of 5700 (range, 507-22,850) to 5590 (range, 213-17,090) at PET2 and 6020 (range, 118-16,650) at PET3. The proportion of progressive lesions increased from a mean 7.8% (range, 0-29) at PET2 to 9.4% (range, 0-32) at PET3. Conclusions: Although PSA response with ENZA is high, many men experience a mixed response to treatment. While overall functional disease burden improves during treatment, an eventual increase in global burden is seen at the time of progression as measured by 18F-NaF PET/CT. At the primary endpoint analysis the proportion of progressing lesions is low, supporting both the hypothesis that a substantial number of lesions continue to benefit from treatment and the concept of treating beyond progression and selectively targeting nonresponding lesions while keeping patients on ENZA. Clinical trial information: NCT02384382.

5037 Background: Phase I/II studies of pTVG-HP showed safety and increases in prostatic acid phosphatase (PAP)-specific T cells. Based on these, we conducted a multi-center, randomized phase II trial using pTVG-HP with GM-CSF adjuvant vs GM-CSF alone in patients with PSA-recurrent, non-metastatic, non-castrate, prostate cancer (stage M0). Methods: 99 patients with M0 prostate cancer (negative CT and bone scan) with PSA doubling time (DT) of < 12m were randomly assigned to pTVG-HP + GM-CSF vs GM-CSF. Treatments were every 2 wk x 6, and then quarterly for up to 24m. Primary endpoint was 2-year MFS. Secondary endpoints included median MFS, changes in PSA DT, and immune response to PAP antigen. Additional analysis included quantitative changes in bone lesion activity by NaF PET/CT. Results: Few grade 3/4 events were observed and were not statistically different between arms. 2-year MFS between control and pTVG-HP was 42.3% and 41.8% (p = 0.97). Median MFS was not different (18.3m control versus 18.9m pTVG-HP, HR = 1.6, p = 0.13). Changes in PSA DT, and immunity to the PAP target, were not different between study arms. A pre-planned subset analysis showed median MFS was significantly longer in patients with rapid PSA DT ( < 3m) treated with pTVG-HP (6.1m versus 12.0m, n = 21, HR = 4.4, p = 0.03). In patients with baseline metastases detected on NaF PET/CT, total activity (SUVtotal) increased 17% with GM-CSF alone, but decreased 29% with pTVG-HP from baseline to month 6 (n = 27, p = 0.07). Conclusions: This trial did not demonstrate an overall increase in 2-year MFS following treatment with pTVG-HP, but suggested a modest effect in patients with rapidly progressive disease. NaF PET/CT imaging suggests that pTVG-HP has a detectable effect on decreasing metastatic activity in bone. A separate trial suggests that pTVG-HP is an immune activating agent that improves activity of PD-1 blockade. A trial using pTVG-HP in combination with nivolumab in patients with M0 prostate cancer is currently underway. Clinical trial information: NCT01341652.