Progressive Metastatic Castration-resistant Prostate Research Articles

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer

Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Assessing the clinical utility of rapid post-therapy whole-body digital SPECT/CT in evaluating early treatment response of 177Lu-PSMA-617 treatment.

32 Background: Multi-detector cadmium-zinc-telluride (CZT) based whole-body digital SPECT/CT is a new generation of imaging system. We aim to assess the clinical utility of rapid post-therapy whole-body SPECT/CT scan in evaluating early treatment response of 177Lu-PSMA-617 treatment. Methods: We retrospectively reviewed patients with progressive metastatic castration resistant prostate cancer (mCRPC) who were treated with at least two cycles of 177Lu-PSMA-617 at our institution from June 2022 to June 2023. Post-therapy whole-body digital SPECT/CT (GE StarGuide) was performed from vertex to mid-thigh at 1-2 hours after 177Lu-PSMA-617 infusion. Post-therapy SPECT/CT images were quantified with MIM software. Lu177-PSMA positive lesions were delineated with liver parenchyma uptake as cut-off. Lu-PSMA positive total tumor volume (Lu-TTV), tumor SUVmax and SUVmean were obtained. Post-therapy SPECT/CT image after cycle 1 was used as baseline for comparison with SPECT/CT after cycle 2 and 3. Overall survival, PSA progression free survival (PSA-PFS) as defined by PCWG3 and PSA decline > 50% from baseline (PSA50) at any time after treatment were measured. Changes in post-therapy SPECT/CT were correlated with clinical outcomes to assess quantitative SPECT/CT as a tool for early treatment response. Analyses were performed with SPSS. Results: A total of 56 patients (76±8, mean ± SD, range 60-93 years old) who were imaged with at least 2 post-therapy SPECT/CT were included in the analysis. Post-therapy whole body SPECT/CT was acquired in ~12 mins. All scanned patients tolerated the rapid whole-body SPECT/CT very well. With median follow up of 10 months, median PSA-PFS was 5.0 months (range 1.0-15 months), 33 of 56 patients (58.9%) achieved PSA50 at any time after treatment, and 42 of 56 patients (75%) were alive at data cutoff. Quantitative analysis of SPECT/CT images showed that 36 of 56 patients (64%) had a >30% decrease in Lu-TTV on early follow-up post-therapy SPECT/CT after cycle 2 or 3. Kaplan-Meier survival analysis showed that a >30% decrease in Lu-TTV was associated with longer overall survival (median not reached vs 6 months, P = 0.008) and longer PSA-PFS (6 months vs 1 months, P < 0.001). Decrease in SUVmax or SUVmean, however, was not associated with PSA-PFS or overall survival. Conclusions: Rapid post-therapy whole-body digital SPECT/CT was well tolerated in post-therapy SPECT/CT imaging following 177Lu-PSMA-617 treatment. Quantitation of post-therapy SPECT/CT may be useful in evaluating early treatment response of 177Lu-PSMA-617. Prospective validation and larger patient cohorts are needed to further elucidate the role of post-therapy SPECT/CT imaging in guiding patient management in 177Lu-PSMA-617 therapy.

Abstract CT122: Phase I dose-escalation study of prostate-specific membrane antigen (PSMA)-targeted alpha emitter 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC)

Abstract Background: PSMA may be targeted by antibodies or small molecule ligands labeled with potent alpha emitters. Certain sites of PSMA expression such as salivary/lacrimal glands, kidneys, and small bowel are not accessible to antibodies such as J591. Following binding, immunoreactivity, and xenograft studies, we performed a first in human study of 225Ac-J591. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abiraterone/enzalutamide) and taxane chemotherapy (or unfit/refuse chemo) without limit of # prior therapies (including radium-223 or prior PSMA therapy) provided adequate organ function were eligible. Baseline 68Ga-PSMA11 PET was performed, but not used for eligibility. Initially single-subject cohorts were treated until transition to 3+3 with dose level 5 (the dose level predicted by historical J591 dosimetry to have moderate toxicity) with a single infusion of 225Ac-J591 (13.3 KBq/kg with planned escalation up to 93.3 KBq/kg). Dose-limiting toxicity (DLT) was defined as attributable grade 4 hematologic toxicity or grade 3/4 non-heme toxicity. Imaging, genomic, patient-reported outcomes, and immune correlates are included. Results: In the dose-escalation phase, 22 men were treated on 7 dose levels; median age 72.5 (range 58-89), PSA 146.5 (4.8-7168.4); 82% with at least 2 prior potent AR pathway inhibitors, 64% chemo, 23% radium-223, 55% prior 177Lu-PSMA. 1 (4.5%) CALGB (Halabi) good prognostic risk, 10 (20.7%) intermediate, and 11 (50%) poor prognostic risk category. One of 6 subjects in cohort 6 (80 KBq/kg) had DLT (grade 4 anemia and platelets); no other subjects had any attributable grade >2 non-hematologic or grade >3 heme AE (including 0 of 6 at the highest dose level 93.3 KBq/Kg). Low grade temporary AE's include: 17 (77%) with fatigue, 11 (50%) pain flare, 11 (50%) nausea, 6 (27%) with Gr 1 xerostomia (5 of 6 with prior 177Lu-PSMA), 4 (18%) AST elevation. Despite the heavily pre-treated population including the majority with prior PSMA-TRT and no selection for PSMA expression, 14 (63.6%) with any PSA decline, 9 (40.9%) with >50% PSA decline. Interestingly, 15 (68%) had initial PSA increase followed by subsequent decline from peak (delayed effect). With follow up ongoing 2 with response > 1 year despite prior 177Lu-PSMA with correlative assays in process. Of 15 with paired baseline and 12-week CTC counts (CellSearch), 8 declined (45-100% decline), 4 remained undetectable, 3 increased. Conclusions: PSMA-targeted alpha-emitter 225Ac utilizing intact antibody J591 is tolerable with early evidence of clinical activity including long-term responders in a pre-treated population. Correlative studies are in progress and enrollment into a Simon 2-stage expansion cohort has been initiated. Clinicaltrials.gov NCT03276572 Citation Format: Scott T. Tagawa, Joseph Osborne, Charlene Thomas, Escarleth Fernandez, Muhammad J. Niaz, Shankar Vallabhajosula, Panagiotis Vlachostergios, Ana M. Molina, Cora Sternberg, Sharon Singh, Amie Patel, Angela Tan, John Babich, David M. Nanus, Karla Ballman, Neil H. Bander. Phase I dose-escalation study of prostate-specific membrane antigen (PSMA)-targeted alpha emitter 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT122.

Dose-escalation results of a phase I study of 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC).

114 Background: Prostate-specific membrane antigen (PSMA) can be targeted by antibodies (Ab) or small molecule ligands labeled with potent α emitters (e.g. 225Ac). Unlike ligands, Ab biodistribution does not include non-tumor organs such as the salivary glands, kidneys and small bowel. We performed a phase I single ascending dose Ab study. Methods: Eligibility: progressive mCRPC following at least 1 potent AR pathway inhibitor (ARPI; e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function. Baseline 68Ga-PSMA11 PET was performed but not used for eligibility. Single-subject cohorts received a single infusion of 225Ac-J591 until grade (Gr) > 1 attributable toxicity or dose level 5, then transition to 3+3 design. Cohort 1 = 13.3 KBq/kg with planned escalation up to dose level 7 (93.3 KBq/kg). Dose-limiting toxicity (DLT) defined as attributable Gr 4 heme or Gr 3/4 non-heme toxicity. Results: 22 men were treated on 7 dose levels; median age 72.5 (range 58-89), PSA 146.5 (4.8-7168.4); 82% with >2 prior ARPI, 64% chemo, 45% sipuleucel-T, 23% radium-223, 55% prior 177Lu-PSMA. By standard imaging 82% bone, 36% lymph node, 9% liver mets. At the time of data cutoff, 1 of 6 men in cohort 6 (80 KBq/kg) had DLT (Gr 4 anemia and platelets); he had 4 prior cycles of 177Lu-PSMA. No other attributable Gr >2 non-hematologic or Gr >3 heme AE (including 0 of 6 at the highest dose level). Low Gr temporary AE’s include: 16 (73%) with fatigue, 11 (50%) pain, 11 (50%) nausea, 6 (27%) with xerostomia (5 of 6 with prior 177Lu-PSMA), 3 (14%) AST elevation. With follow-up ongoing, 60% with any PSA decline, 35% with >50% PSA decline. Of 10 with detectable baseline and 12-week CTC counts (CellSearch), 8 declined (45-100% decline); 5 (50%) with CTC count conversion. While PSMA uptake was not a prerequisite for treatment, all had some PSMA uptake on 68Ga-PSMA11 PET/CT; 64% with SUVmax >5x liver SUV, 14% 2.5x – 5x liver, and 23% with SUVmax 0-2.5x liver SUV. Conclusions: PSMA-targeted alpha-emitter 225Ac utilizing intact Ab J591 is well tolerated with early evidence of clinical activity in a pre-treated population, including the majority with prior 177Lu-PSMA. Clinical trial information: NCT03276572.

849PD - Preliminary results of a phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC)

BackgroundPSMA is overexpressed in PC with limited expression in other organs. PC is radiosensitive with dose-response. Dose-fractionation allows delivery of higher total dose per cycle, may result in less radioresistance due to repopulation compared with doses 6-12 wks apart. Initial Ph I safety results of the dose-escalation portion of this study [ESMO 2018] were without DLT at all dose levels. MethodsEntry criteria: progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and taxane (or unfit/refuse chemo) without limit of # prior therapies, adequate organ function, ECOG performance status 0-2. No preselection for PSMA expression. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15. In the Ph I dose-escalation cohort, men received 7.4 to 22 GBq. In Ph II, a Simon 2 stage design enrolled pts at the 22.2 GBq dose level. Pre- and post-treatment 68Ga-PSMA11 PET/CT and post-treatment 177Lu-PSMA-617 imaging was performed in addition to standard serial CT and bone scans. Cellsearch CTC count at baseline and 12 wks. Results44 men (29 in Ph I, 15 in Ph II; total 21 at 22.2 GBq) with median age 69 (range 55-91), median PSA 182.97 (range 0.89-5541) were treated. 93% with bone, 45% nodal, 18% lung, 9% liver, 9% other visceral metastases. 55% with at least 1 prior chemo regimen, 52% >1 prior potent AR therapy, 27% with Ra223, 30% sip-T, 5% 177Lu-J591; 66% Halabi poor risk, 30% intermed risk. With follow up ongoing, 61% with >50% PSA decline (71.4% at 22.2 GBq), median overall survival 16 months (95% CI 11-NR). Of 26 with paired CTC counts, 57.7% decreased, 7.7% stable, 34.6% increased; 34.6% converted from detectable to undetectable at 12 weeks). 61.4% with all grade xerostomia, 29.5% fatigue, 25% thrombocytopenia, 25% anemia, 25% pain, 15.5% nausea. While not required for eligibility, all pts had some PSMA uptake in at least 1 site on PSMA PET, with 2.2% highest lesion SUV < liver SUV, 4.5% 1-2.5x, 13.6% 2.5-5x, and 79.5% highest lesion SUV > 5x liver. ConclusionsA single fractionated cycle of up to 22.2 GBq of 177Lu-PSMA-617 is safe, with encouraging early efficacy signals, even without selection for PSMA expression by imaging. A trend for dose-response was observed. Clinical trial identificationNCT03042468. Legal entity responsible for the studyWell Cornell Medicine. FundingWeill Cornell Medicine, Prostate Cancer Foundation, US Department of Defense, US National Institutes of Health, Endocyte. DisclosureS.T. Tagawa: Advisory / Consultancy, Research grant / Funding (institution): Endocyte. H. Beltran: Advisory / Consultancy: Endocyte. S. Vallabhajosula: Research grant / Funding (institution): Endocyte; Full / Part-time employment: NCM USA. O. Sartor: Research grant / Funding (institution): Endocyte. All other authors have declared no conflicts of interest.

A Single-arm, Open-label, Phase II Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

A Single-arm, Open-label, Phase II Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

TheraP: A randomized phase II trial of [177Lu]-PSMA-617 theranostic versus cabazitaxel in progressive metastatic castration-resistant prostate cancer.

TPS332 Background: Lutetium-177 [177Lu]-PSMA-617 is a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), which is commonly overexpressed in prostate cancer. This treatment has demonstrated promising activity and tolerability in men progressing after multiple lines of chemotherapy and endocrine therapy. This trial will determine the activity and safety of 177Lu-PSMA-617 compared to cabazitaxel chemotherapy in men with progressive metastatic castrate resistant prostate cancer. Methods: TheraP is an open-label, randomised, two-arm, multi-centre, phase 2 trial comparing the activity and safety of experimental treatment with [177Lu]-PSMA-617 versus standard 2nd line chemotherapy with cabazitaxel. Key eligibility criteria include prior chemotherapy with docetaxel; rising serum PSA; sufficient PSMA avidity according to central reviewed of imaging with PSMA PET/CT and FDG PET/CT; no discordance between FDG PET and PSMA PET. The trial will include 200 participants randomised in a 1:1 ratio to either [177Lu]-PSMA-617 intravenously every 6 weeks, 8.5 GBq for cycle 1, decreasing by 0.5 GBq with each subsequent cycle, up to maximum 6 cycles (experimental group); or, chemotherapy with cabazitaxel (20 mg/m2) intravenously every 3 weeks, for 10 cycles (standard group). In the event of an exceptional response to [177Lu]-PSMA-617, according to centrally-reviewed, post-therapy SPECT imaging, treatment is suspended but can recommence subsequently on progression. The primary endpoint is a 50% or greater reduction from baseline in serum PSA. Secondary endpoints include overall survival, progression-free survival (PFS), PSA-PFS, pain-PFS, radiographic-PFS, health-related quality of life, pain response, and adverse events. The outcomes of patients excluded because of discordant disease on FDG PET and PSMA PET will be reported as a tertiary objective. The study has accrued 79 of 200 planned participants from 29 January 2018 to 23 October 2018. Clinical trial information: NCT03392428.

799PD - Phase I dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC)

799PD - Phase I dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC)

A phase 1/2a trial of docetaxel plus ribavirin for reprogramming efficacy in patients with progressive metastatic castration resistant prostate cancer who have previously received docetaxel alone: DRREEM trial.

329 Background: We previously reported a novel cell reprogramming approach, termed drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs targeting the cancer stemness-related gene network, and identified ribavirin as a candidate drug for overcoming docetaxel-resistant castration-resistant prostate cancer (CRPC). We conducted this phase 1/2a trial of docetaxel plus ribavirin for reprogramming efficacy in patients with progressive metastatic castration resistant prostate cancer who have previously received docetaxel alone. (DRREEM trial) Methods: In this clinical study, patients received intravenous docetaxel at 60-75 mg/m2is intravenously administered on Cycle1-Day1 in combination with the investigational drug (ribavirin). Docetaxel is administered at 3-week intervals (1 cycle) (total: 3 cycles). During administration, the dose may be reduced based on the subject’s condition if necessary. The primary endpoint was safety. Accessory evaluation items included prostate-specific antigen (PSA) response, objective response rate, health-related quality of lifel. Exploratory items included changes in CTC count, cfDNA, and exosome. Patients with progressive CRPC based on PSA and/or radiographic criteria, performance status (PS) 0–1, and normal renal and hepatic function were eligible. Results: Six patients were enrolled in this study; average age was 71.7±4.2. Average serum PSA concentration was 100.1±128.0 ng/ml (range: 3.0-336.8). The median cycle of docetaxel received before the study was 6 cycles. Safety: Grade 3/4 adverse events requiring dose modification were not observed. Two patients showed PSA reduction. Three patients showed stable disease. Changes in the blood concentrations of ribavirin, docetaxel, and prednisolone were within normal range. Conclusions: This combination of ribavirin with docetaxel was well tolerated with a promising response rate that justifies further investigations in docetaxel-resistant CRPC. This clinical study provides a useful drug re-positioning model in the area of translational medicine. Clinical trial information: UMIN000021107.

A phase 1/2 study combining ipilimumab with abiraterone acetate plus prednisone in chemotherapy- and immunotherapy-naïve patients with progressive metastatic castration resistant prostate cancer (mCRPC).

e16507Background: We hypothesized that combining abiraterone acetate (AA), an androgen biosynthesis inhibitor shown to induce prostate cancer apoptosis for patients (pts) with mCRPC, with Ipilimuma...

Molecular characterization of circulating tumor cells (CTC) and CTC subpopulations in baseline and progressive metastatic castration resistant prostate cancer (mCRPC).

Molecular characterization of circulating tumor cells (CTC) and CTC subpopulations in baseline and progressive metastatic castration resistant prostate cancer (mCRPC).

Prognostic Impact of the Neutrophil-to-Lymphocyte Ratio in Men With Metastatic Castration-Resistant Prostate Cancer

BackgroundWe retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel. MethodsThe SUN-1120 phase III trial comparing prednisone combined with sunitinib (n = 584) or placebo (n = 289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (prostate specific antigen [PSA] or radiographic) and treatment group. Patients were categorized into risk groups. ResultsComplete data was evaluable for 784 men. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-lactate dehydrogenase level (LDH) level (HR 2.86 [95% CI = 2.29, 3.56], P < .001), hemoglobin (0.80 [0.74, 0.85], P < .001), > 1 organ involved by metastatic disease (1.49 [1.21, 1.84], P < .001), log-alkaline phosphatase (1.13 [0.99, 1.28], P = .074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P = .031), progression on docetaxel (1.35 [1.00, 1.81], P = .049), log-PSA (1.06 [1.00, 1.12], P = .075) and log-NLR (1.55 [1.32, 1.83], P < .001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715. ConclusionHigh NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation.

The molecular and pathway characterization of patients with metastatic castration resistant prostate cancer (mCRPC) refractory to therapy with abiraterone acetate or enzalutamide: Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).

79 Background: Progressive metastatic castration resistant prostate cancer (mCRPC) has historically been challenging to biopsy and characterize on a molecular basis because of its bone tropism. Since mechanisms of resistance to androgen signaling inhibitors such as enzalutamide or abiraterone are not fully understood, both an unbiased and a targeted assessment of the molecular landscape of these patients is required. Methods: Patients (pts) with mCRPC undergo biopsy at one of five West Coast Prostate Cancer Dream Team (WCDT) clinical sites, using a uniform biopsy protocol, following central radiologic review. Tissue is both frozen, and formalin fixed/paraffin embedded (FFPE). Frozen tissue undergoes laser capture microdissection (LCM) for RNA seq, DNA seq, and array comparative genomic hybridization (aCGH). An RNA seq process was developed that allows using extremely small quantities of RNA (approximately 1 ng). FFPE tissue undergoes a CLIA-certified assessment of a 37-gene mutational panel, FISH for AR, and IHC for PTEN. Peripheral blood is collected for miRNA, immune responses, and CTC analysis including aCGH. Pathway assessment integrating clinical, RNA seq, DNA seq, aCGH data is undertaken using PARADIGM analysis. Results: Thirty six of 300 planned mCRPC pts have undergone a metastasis biopsy: 17 from bone, eight from liver, one from lung, and 10 from distant lymph nodes. Tumor is present in around 75% of the frozen specimens. To date, LCM has been undertaken in 11 samples, with RNA seq done in six, DNA whole exome seq in one, aCGH in four. FFPE tissue has been evaluated by mutational panel sequencing (n=9), FISH for AR (n=11), and IHC for PTEN (n=13). CTC have been isolated in 33 pts. aCGH has been successfully undertaken in paired CTC and biopsy specimens. Expression data from patients with full RNA sequencing have been analyzed by PARADIGM, with top disrupted pathways identified. Conclusions: Biopsies of mCRPC, including from bony sites, can be undertaken and used for molecular and pathway analysis. Sufficient tissue for unbiased and targeted assessment can be obtained. Linkage of results from these studies to the clinical characteristics of these patients will reveal important insights into mechanisms of resistance.

Molecular characterization of circulating tumor cells (CTC) and CTC subpopulations in progressive metastatic castration resistant prostate cancer (mCRPC).

132 Background: Numerous resistance mechanisms have been postulated in progressive mCRPC. Determining the presence of putative predictive biomarkers in patients requires a real-time tumor assessment because the biology changes under the influence of the specific therapy(ies) that a patient (Pt) has received. We examined CTC and CTC subpopulation incidence and molecular characterization of tumors from Pts with progressive mCRPC to assess if determinants of resistance can be assessed through a CTC test. Methods: 48 samples from 21 unique progressive mCRPC pts treated with androgen receptor targeted (AR tx) therapies, 9 (43%) on Abiraterone plus Prednisone (AA+P) and 12 (57%) on Enzalutamide (E). Samples were collected and shipped to Epic Sciences, where cells were stained and CTC identified by fluorescent scanners and algorithmic analysis. CTCs, defined as classic (CK+ CD45- w/intact DAPI nuclei and distinct), apopotic (CK+, CD45-, non-intact nuclei) and CK- (CK-, CD45-, intact and distinct) were identified. CTCs reported per mL of blood and were examined for AR, PTEN &amp; ERG. CTC data were analyzed in context of PSA, Veridex CTC (reported per 7.5mL of blood), and clinical history. Results: With Epic, all 21 pts had detectable CTCs (mdn 23 cells/ml, range 2 to 249), whereas with Veridex, 14 (67%) pts had &gt; 5 CTC/7.5 ml (mdn 5 cells/7.5 ml, range 0 to &gt;200). 0/7 (0%) with high AR responded to AA+P or E, 8/14 (53%) with low AR had a PSA decline and stable radiographic disease (median follow-up 12 wks). Variations in AR protein expression and localization heterogeneity was seen in all pts to varying degrees. 6/21 (29%) Pts demonstrated CK- CTC/CTC ratio &gt;50% (mdn 9 cells/ml, range 5-38). ERG rearrangement and PTEN loss were correlated. Conclusions: Epic CTC analysis provides higher detection rates, while enabling individual cell analyses for predictive biomarkers of sensitivity to AR directed therapies. Notable was the marked heterogeneity of detection of AR, ERG, and PTEN of individual CTCs. Studies are ongoing to further explore associations with outcomes. [Table: see text]

Evaluating 18F-16β-fluoro-5α-dihydrotestosterone (FDHT) and FDG PET as prognostic biomarkers for patients (pts) treated with abiraterone acetate (AA).

56 Background: There are no available imaging biomarkers that can prognosticate for clinical outcomes for patients treated with AA. FDG and FDHT PET demonstrate glucose metabolism and androgen receptor expression, respectively. This is the first study of FDG and FDHT PET as a prognostic biomarker for pts treated with AA. Methods: Pts with progressive metastatic castration resistant prostate cancer (mCRPC) starting AA underwent FDG and FDHT PET scans on an imaging clinical trial. PSA, SUVmax (hottest slice of hottest lesion), and SUVmaxavg (average SUVmax of 5 index lesions) were collected. An SUV value of 1 was imputed for calculating SUVmaxavg in the absence of 5 index lesions. Imaging characteristics were compared to PFS, defined as time to radiographic progression, biochemical relapse or death. The Cox proportional hazards model was used to determine the association between the PET measurements and PFS. The statistics used to measure the association was the concordance probability estimate (CPE). Results: 24 scans sets were obtained. Median pt characteristics were: age 70 (48-85), Gleason score 8 (range 6-10), PSA 85 (2-459). Radiographic and PSA progression occurred in 15/24 (63%), radiographic only 4/24 (17%), and biochemical only 2/24 (9%). 1 pt died on study, 1 elected to discontinue tx, and 1 remains on AA. 16/24 (67%) and 18/24 (75%) of FDG and FDHT PET scans respectively had ≥ 5 hypermetabolic lesions. Median FDG SUVmax was 8 (2-15), FDG SUVmaxavg 5 (1-11), FDHT SUVmax 11 (3-28) and FDHT SUVmaxavg 7 (1-16). The correlation between PET measurements and PFS is described (Table). Conclusions: Preliminarily, baseline FDG SUVmax and SUVmaxavg appear to be prognostic for PFS in pts treated with AA. Higher SUV values prognosticate for a shorter time to progression. Further evaluations of FDG/FDHT PET in mCRPC are underway to better define the role each modality has as a prognostic and response biomarker for AA. Clinical trial information: NCT00588185. [Table: see text]

Abstract IA11: Cabozantinib (XL-184) and prostate cancer: Preclinical and clinical profile of a novel agent

Abstract The evolving understanding of the biology of prostate cancer has fueled therapeutic research with agents targeting androgen signaling, bone microenvironment, apoptosis, and immune modulation amongst others that are being evaluated in clinical trials and an expanding portfolio of FDA approved agents. Metastasis particularly to bone is a hallmark of prostate cancer and reflects the lethal phenotype of the disease. This process is complex and involves interactions between the cancer cell and several elements of the bone microenvironment including osteoblasts, osteoclasts, endothelial cells and cortical bone. The receptor tyrosine kinase MET and its ligand, hepatocyte growth factor (HGF), drive tumor cell invasion and metastasis. Bone metastases are associated with high levels of MET expression. MET and VEGFR2 synergize to promote angiogenesis, and HGF and VEGF direct crosstalk between tumor cells, osteoblasts, and osteoclasts. In prostate cancer, MET overexpression increases with progression and metastasis to bone and lymph nodes and overexpression of HGF has also been reported. Preclinical data suggest that androgen deprivation increases MET expression, and clinically increased plasma levels of HGF in castration resistant disease is associated with decreased overall survival. Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) that simultaneously blocks MET and VEGFR in vivo. In transgenic mouse models it blocks metastatic spread from primary tumors and inhibits prostate xenograft tumor growth in bone. In cell culture studies, cabozantinib elicits a unique profile of effects on bone microenvironment cells, with dose-dependent inhibition of osteoclast differentiation, and biphasic effects on osteoblast differentiation and function. Results from a recently completed phase II trial in 171 patients with progressive metastatic castration resistant prostate cancer indicate that cabozantinib has moderate but manageable toxicities similar to other TKIs with the most common being fatigue, GI and hand and foot syndrome. Cabozantinib had substantial antitumor activity irrespective of prior docetaxel therapy. Specifically it resulted in 68% overall objective disease control at 12 weeks of therapy and 74% measurable disease regression. Of note is the unique and significant observation of a high rate of partial or complete resolution of bone scans which was observed in 76% of patients and was accompanied by pain improvement in patients with pain at baseline and decreases in bloodbased markers of osteoclast and osteoblast activity. The overall median progression free survival was 29 weeks. Several clinical trials are ongoing or planned to better characterize cabozantinib activity and effect. Citation Format: Maha H. Hussain. Cabozantinib (XL-184) and prostate cancer: Preclinical and clinical profile of a novel agent [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA11.

Bone scan “flare” in patients receiving abiraterone acetate (AA) for metastatic castration resistant prostate cancer (mCRPC): Analysis of data from a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium.

4545 Background: The utility of bone scintigraphy in metastatic prostate cancer is limited by the risk of false positive findings. False positives can occur for many reasons, including a “flare” phenomenon due to the osteoblastic response that occurs as a result of bone healing after successful anti-neoplastic therapy. The incidence of bone flare in metastatic prostate cancer is unknown clinically but is important because it can result in patients (pts) being taken off active agents too soon on the basis of a potentially erroneous bone scans. Methods: 33 pts with progressive metastatic castration resistant prostate cancer (mCRPC), normal organ function, and no prior chemotherapy were enrolled on a phase II trial of Abiraterone acetate (AA) plus prednisone. PSA was obtained monthly and bone scan (BS) results, as reported locally, were evaluated along with PSA changes at baseline, just prior to starting cycle (c) 4 and c7. BS flare was defined as BS findings interpreted by a local radiologist as “disease progression” in the face of a ≥50% decline in PSA, which on follow up scan revealed an improved scan (i.e. disease regression). Results: A ≥50% decline in PSA at the time of c4 day 1 imaging was seen in 25/33 (76%) pts. Of these 25 pts, 23 were evaluable for flare (i.e. bone scans were evaluable at baseline, c4, and c7). Of 23 evaluable pts (each had a PSA response), 12 had discordant (worse) bone scans at c4 (52%). Of these 12 pts, 10 (83%) had subsequent improvements in BS at c7. Thus, overall BS flare was observed in 10/23 (43.5%) evaluable pts or 10/33 (30%) enrolled pts. Conclusions: Discordant bone scans occurred in over half of the mCRPC pts responding to AA by PSA criteria (12/23 patients). Over 80% of these scans were subsequently found to be flare phenomena, as demonstrated by improved follow up bone scans. Thus, overall, the flare phenomenon was a common event (43% of responding patients and 30% of all pts enrolled). BS “flare” and potentially false declarations of disease progression are common in this setting and should not be misconstrued as a treatment failure. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ortho Biotech Oncology (Cougar Biotechnology)

Abiraterone acetate and prednisone in patients (Pts) with progressive metastatic castration resistant prostate cancer (CRPC) after failure of docetaxel-based chemotherapy

5019 Background: A proportion of CRPC overexpress androgen synthetic enzymes and are dependent on androgens for growth. Abiraterone acetate (AA) inhibits 17 α-hydroxylase and C17,20-lyase to decrease serum androgen to undetectable levels. Methods: AA plus prednisone was studied in Pts with metastatic CRPC who had progressed on docetaxel based chemotherapy. Pts received oral AA 1000 mg QD, and prednisone 5 mg BID in 28 day cycles. The primary endpoint a >50% decline in PSA from baseline. Changes in bone and soft tissue disease were also monitored, as were pre- and post-therapy circulating tumor cell (CTC) number. Results: 43 Pts were screened and 38 treated. The median (interquartile range) age was 73 years (64–81) and PSA 86.3 ng/mL (33–311.5) while 32 (84%) had > 5 CTC per 7.5 ml of blood at baseline. Prior systemic therapy included 3 or more hormone in 29 (76%), including ketoconazole in 17 (45%); while 26 (68%) received 1, and 12 (32%) 2 lines of chemotherapy. Sites of metastases were bone only in 10 (26%), bone and lymph nodes in 15 (39%), bone and visceral in 11 (29%), while 2 had soft tissue and no bone disease. Of 35 evaluable patients (3 are too early), 11 (31%) progressed within 3 months (m), 9 (26%) within 6 m, and 2 (6%) after 6 m. Seven and 6 pts remain on treatment for 3–6 and 6+ months respectively. At 3 m, 14 of 35 pts (40%, 95% CI 26–57%) achieved a decline in PSA >50% from baseline. CTC were <5 pre- or <5 after therapy in 6 and 11 pts, of whom 3 and 7 are still on treatment; CTC count remained >5 in 21 pts, of whom 15 progressed (P =0.099) There was no grade 3 or 4 hypertension or hypokalemia. One pt discontinued treatment due to transaminitis and myositis. Conclusion: AA plus prednisone is well tolerated and active in progressive CRPC post-chemotherapy. Classifying these patients as hormone-refractory is a misnomer with the potential to deny patients potentially effective treatments. A phase III trial is planned with this regimen. (Supported by Cougar Biotechnology) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cougar Biotechnology Cougar

Phase I/II trial of the prostate-specific membrane antigen (PSMA)-targeted immunoconjugate MLN2704 in patients (pts) with progressive metastatic castration resistant prostate cancer (CRPC)

4500 Background: MLN2704 is an immunoconjugate that utilizes the PSMA-targeted monoclonal antibody MLN591 to deliver the maytansinoid antimicrotubule agent DM1 directly to prostate cancer cells. This multicenter trial was designed to determine the tolerability, optimal dosing schedule and efficacy of MLN2704 in pts with progressive metastatic CRPC. Methods: Pts aged ≥18 yrs with progressive metastatic CRPC received MLN2704 i.v. over 2.5 hr q1wk, q2wks or q3wks for 12 wks, with additional doses permitted in responders. Doses within a given schedule were escalated in 40% increments in the absence of excessive dose-limiting toxicity (DLT). Results: 61 pts have been treated. The most common adverse events (AEs) were nausea, fatigue, and schedule-dependent neurotoxicity. The only DLT was gr 3 hepatic transaminitis in 1/6 pts at 330 mg/m2 q2wks; the only gr 4 AE was transient neutropenia, in 2 pts (330 mg/m2 q2wks and q3wks). Declines in PSA were most frequent at 330 mg/m2 q2wks ( table ), including 49–88% PSA declines in 4/6 pts. However, given the frequency of grade 2–3 peripheral neuropathy an additional cohort is being treated with 330mg/m2 on days 1 and 15 of a 6-wk cycle. Initial results with this 6-wk schedule indicate PSA declines with a lower incidence of gr 2–3 toxicities, particularly neuropathy. Conclusions: Accrual to the dose-escalation phase is complete. Dose-dependent antitumor effects were seen. Peripheral neuropathy has limited continuous dosing at higher dose levels prompting a schedule change. Accrual to the 6-wk schedule is continuing. [Table: see text] [Table: see text]