bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1/2 trial of oral EPI-7386 (masofaniten) in combination with enzalutamide (Enz) compared to Enz alone in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase 1 (P1) results and phase 2 (P2) design.
Authors: Kyriakopoulos Christos , Chatta Gurkamal S. , Laccetti Andrew Leonard , Iannotti Nicholas , Sokolova Alexandra , Hotte Sebastien J. , Tutrone Ronald F. , Markowski Mark Christopher , Nordquist Luke T. , Pili Roberto , Saad Fred , Zhang Jingsong , Villaluna Karen , Younginger Brett , Le Moigne Ronan , Cesano Alessandra 
Published: January 2024

141 Background: EPI-7386 (masofaniten) is a next-generation aniten that inhibits androgen receptor (AR) activity by binding the N-terminal domain and blocking transcription, irrespective of ligand-binding domain resistance mechanisms. Preclinically, the combination of masofaniten with Enz results in a deeper blockade of the AR pathway and greater antitumor activity than either agent alone. Methods: This is a Phase 1/2 multicenter clinical trial (NCT05075577) enrolling patients (pts) with mCRPC on androgen deprivation therapy and naïve to second-generation antiandrogens (one line of prior chemotherapy in the metastatic hormone-sensitive setting allowed). P1 examines escalating doses of masofaniten + Enz at 120 or 160 mg QD. Primary and secondary endpoints of P1 evaluate the safety and pharmacokinetics (PK) of masofaniten + Enz when co-administered to establish the recommended P2 combination doses (RP2CDs). P2 is designed as a two arm, 2:1 randomized, open-label trial evaluating the antitumor activity of masofaniten in combination with Enz versus Enz alone; approximately 120 pts will be randomized with masofaniten 600 mg BID + Enz 160 mg QD (n=80) vs single agent Enz at 160 mg QD (n = 40). Results: P1 completed enrollment with 18 pts in 4 cohorts with 16 pts evaluable for efficacy as per protocol. The combination regimen was well tolerated with a safety profile consistent with Enz monotherapy. One grade 3 rash was observed in cohort 4 evaluating masofaniten 600 mg BID + Enz 160 mg QD. PK results demonstrated Enz exposure was not impacted by concomitant administration of masofaniten, allowing testing of the full dose of Enz (160 mg). By contrast, masofaniten exposure was consistently reduced by concomitant administration of Enz (CYP3A4 inducer that metabolizes masofaniten) but remained within the clinically relevant range with the highest exposures and Cmin observed using masofaniten BID dosing. Although efficacy data are still maturing, to date, response rates were PSA50 88% (14/16 pts), PSA90 69% (11/16 pts) and PSA <0.2 ng/mL 56% (9/16 pts) in evaluable pts, regardless of their previous chemotherapy status. Conclusions: The RP2CD for P2 was established at masofaniten 600 mg BID + Enz 160 mg QD. Updated results, including long term follow-up of the dose escalation patients, and P2 study design, will be presented. Clinical trial information: NCT05075577 .
Enzalutamide combination treatment (tx) suspension in men with high-risk biochemically recurrent (BCR) prostate cancer: Outcomes from EMBARK.
Authors: Freedland Stephen J. , Sieber Paul R. , Gleave Martin , De Giorgi Ugo , Mehlhaff Bryan Allyn , Danila Daniel Costin , Dunshee Curtis , Lallas Costas D. , Pliskin Marc , Tang Yiyun , Haas Gabriel P. , Rosales Matt , Tarazi Jamal Christo Christo , Zohren Fabian , Russell David , Shore Neal D. 
Published: January 2024

156 Background: The 3-arm EMBARK trial found statistically superior and clinically meaningful improvements in metastasis-free survival (MFS) with enzalutamide + leuprolide acetate (enza combo) and enza monotherapy vs placebo + leuprolide (alone) in patients (pts) with high-risk BCR prostate cancer. Tx was suspended at week 37 in 321 (90.9%) pts in the enza combo arm and 240 (67.8%) in the leuprolide-alone arm based on prostate-specific antigen (PSA) response. Outcomes in the enza combo vs leuprolide-alone arms by tx suspension status are reported. Methods: The phase 3 EMBARK study enrolled pts with high-risk BCR, defined as PSA doubling time ≤9 months, and PSA ≥2 ng/mL above nadir post-radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) ± postoperative RT. Pts were randomized 1:1 to enza 160 mg/day + leuprolide (22.5 mg every 12 weeks) or leuprolide alone. Tx was suspended at week 37 if serum PSA was <0.2 ng/mL at week 36 and restarted when PSA reached ≥2 ng/mL (primary RP) or ≥5 ng/mL (no primary RP). A secondary endpoint was the proportion of pts with undetectable PSA 2 years after suspension. MFS (per blinded independent central review) was analyzed descriptively between tx arms by suspension status. P-values were nominal. Results: The 3-year MFS rate (95% CI) in the suspension group was 94.4% (91.2–96.5%) with enza combo and 90.0% (85.3–93.2%) with leuprolide alone; in the no suspension group, 3-year MFS rates were 76.2% (33.2–93.5%) and 66.9% (55.4–76.1%), respectively. MFS in the suspension group was improved with enza combo vs leuprolide alone (HR 0.470, 95% CI 0.308–0.717; P=0.0003); no difference in MFS was observed in the no suspension group (HR 0.719, 95% CI 0.225–2.295; P=0.5763), although sample size was small for enza combo (n=9). Compared with no suspension, a higher proportion of pts in the suspension group received prior RP and a lower proportion received prior RT (Table). Two years after suspension, 16.8% (95% CI, 12.9–21.4%) of enza combo pts and 9.6% (95% CI, 6.2–14.0%) of leuprolide-alone pts had undetectable PSA ( P=0.0089). Conclusions: MFS was improved with enza combo vs leuprolide alone for pts with BCR who suspended tx. No difference in MFS was observed in the no suspension group, but firm conclusions were precluded by the limited number of pts who did not suspend tx with enza combo. Pts who suspended tx had higher rates of prior RP vs those who did not. Pts who had received enza combo prior to tx suspension were more likely to have undetectable PSA 2 years thereafter compared with those who received leuprolide alone. Clinical trial information: NCT02319837 . [Table: see text]
Efficacy of olaparib (O) plus abiraterone (A) versus placebo (P) plus A in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with single homologous recombination repair gene mutations (HRRm) in the PROpel trial.
Authors: Shore Neal D. , Clarke Noel , Armstrong Andrew J. , Oya Mototsugu , Procopio Giuseppe , Guedes João Daniel Cardoso , Arslan Cagatay , Mehra Niven , Brown Emma , Schlürmann Friederike , Joung Jae Young , Sugimoto Mikio , Vianna Karina , Hosius Christian , Barnicle Alan , Liu Yu-Zhen , Harrington Elizabeth , McGuinness David , del Rosario Paula Michelle , Saad Fred 
Published: January 2024

165 Background: PROpel (NCT03732820) met its primary endpoint and showed a significant investigator-assessed radiographic progression-free survival (rPFS) benefit with O + A vs P + A in first-line mCRPC (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.001). At final prespecified analysis, median overall survival (OS) with O + A vs P + A was 42.1 vs 34.7 months (HR 0.81, 95% CI 0.67–1.00; P=0.0544). We report gene-by-gene efficacy of O + A vs P + A for pts from PROpel with a HRRm. Methods: PROpel was a Phase 3 randomized (1:1), double-blind trial. Pts were enrolled irrespective of biomarker status and received O (300 mg twice daily [bid]) or P, plus A (1000 mg once daily) and prednisone/prednisolone (5 mg bid). rPFS by investigator assessment was the primary endpoint (data cutoff [DCO]: 7/30/2021). OS was a key secondary endpoint (DCO: 10/12/2022). Following randomization and before primary analysis, HRRm status was assessed by tumor tissue (FoundationOne CDx) and ctDNA (FoundationOne Liquid CDx) tests and is reported using aggregated results from both tests. Genes assessed were ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. HR and CIs are not reported in subgroups with <5 events in either arm for both rPFS and OS. Results: 28.4% pts had an HRRm.For most pts with a single gene HRRm, there was a lower proportion of rPFS events and deaths in the O + A arm relative to the P + A arm (Table). The most prevalent gene mutations were BRCA2, ATM and CDK12; HRs for rPFS and OS numerically favored O + A (rPFS: BRCA2, HR 0.20, 95% CI 0.08–0.44; ATM, HR 0.55, 95% CI 0.20–1.38; CDK12, HR 0.51, 95% CI 0.20–1.18. OS: BRCA2, HR 0.20, 95% CI 0.07–0.48; ATM, HR 0.79, 95% CI 0.33–1.77; CDK12, HR 0.57, 95% CI 0.24–1.27). Conclusions: BRCA2, ATM and CDK12 were the most prevalent single gene mutations and clinical benefit was observed with O + A. Other single gene mutations were rare, limiting interpretation. The greatest treatment benefit was observed in pts with BRCA mutations. Clinical trial information: NCT03732820 . [Table: see text]
Overall survival with darolutamide vs placebo in combination with androgen-deprivation therapy (ADT) and docetaxel: A sensitivity analysis from ARASENS accounting for subsequent therapy.
Authors: Shore Neal D. , Tombal Bertrand F. , Hussain Maha H. A. , Saad Fred , Fizazi Karim , Sternberg Cora N. , Crawford E. David , Fralich Todd , Li Rui , Smith Matthew Raymond 
Published: January 2024

166 Background: Darolutamide (DARO) + ADT + docetaxel (DOC) is approved for metastatic hormone-sensitive prostate cancer (mHSPC) based on the phase 3 ARASENS study (NCT02799602). To address the impact of informative intercurrent events (eg, use of subsequent therapy) in censored patients (pts), as defined by the European Medicines Agency, we performed a post hoc sensitivity analysis of OS. Methods: Pts with mHSPC were randomized 1:1 to oral DARO 600 mg twice daily or placebo (PBO) + ADT + DOC. The primary endpoint was OS using a log-rank test, with HR (95% CI) calculated by Cox model, stratified by extent of disease (EoD; nonregional lymph node vs bone ± lymph node vs visceral ± lymph node/bone metastases) and alkaline phosphatase (< vs ≥ upper limit of normal). Pts with no documented death were censored at last known alive or data cut-off date, whichever was earlier. The post hoc sensitivity analysis counted initiation of subsequent systemic antineoplastic therapy as an event in censored pts still alive at end of follow-up. In addition planned sensitivity analyses used an unstratified log-rank test/Cox model, a log-rank test/Cox model with stratification factors from electronic case report forms, and a log-rank test/Cox model with EoD stratification factors from central imaging review. Results: In the primary analysis DARO + ADT + DOC significantly improved OS ( P<0.0001; Table), despite a high percentage of pts who entered follow-up in the PBO group receiving subsequent life-prolonging systemic therapies (374/495, 76%). Time to first subsequent systemic antineoplastic therapy (a key secondary endpoint) was significantly longer with DARO + ADT + DOC vs PBO + ADT + DOC (HR 0.39, 95% CI 0.33–0.46, P<0.001). Findings from the post hoc sensitivity analysis counting initiation of subsequent systemic antineoplastic therapy as an event in censored pts (pts with events: DARO 300/651, 46.1%; PBO 476/654, 72.8%) and the planned sensitivity analyses were consistent and supported the primary OS analysis (Table). Treatment-emergent adverse events (TEAEs) were similar between groups. TEAEs led to DARO/PBO discontinuation in 13.5%/10.6% of pts. Conclusions: The results of the post hoc and planned sensitivity analyses were consistent with and supportive of the ARASENS primary OS analysis. These data reinforce DARO + ADT + DOC as an effective and well tolerated new standard of care for early treatment intensification in pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]
Optimal sequential therapy for metastatic castration-resistant prostate cancer after androgen receptor pathway inhibitors in the up-front era.
Authors: Naito Yushi , Nagayama Jun , Sano Yuta , Inoue Satoshi , Matsuo Kazuna , Sano Tomoyasu , Ishida Shohei , Matsukawa Yoshihisa , Kato Masashi , Akamatsu Shusuke 
Published: January 2024

168 Background: The optimal sequential therapy for metastatic castration-resistant prostate cancer (mCRPC) following the use of up-front androgen receptor pathway inhibitors (ARPIs) for metastatic hormone-sensitive prostate cancer (mHSPC) is still unclear. Methods: A total of 220 patients who received systemic therapy for de novo mHSPC at Nagoya University Hospital and its affiliated institutions between 2014 and 2022 were included in the study. Patients who received up-front therapy with ARPI as first-line therapy for mHSPC, followed by ARPI as primary therapy for mCRPC were defined as the AA group, followed by docetaxel (DOC) as primary therapy for mCRPC were defined as the AD group. On the other hand, the vAA group was defined as patients who received androgen deprivation therapy alone or combined androgen blockade as “vintage” first-line therapy for mHSPC, followed by two consecutive ARPIs as sequential therapy for mCRPC, and the vAD group was defined as patients who received ARPI followed by DOC as sequential therapy for mCRPC. Patient characteristics and progression-free survival (PFS) of the second agent after the first ARPI were compared in each group. Results: We identified 14 patients in the AA group, 16 in the AD group, 84 in the vAA group, and 59 in the vAD group. There were no differences in patient background such as initial PSA, Gleason score, and metastatic burden between the groups, while patient age was lower in the AD and vAD groups compared to the AA and vAA groups. The PFS of the second agent in the AA group was significantly shorter than that in the vAA group (median, 6.8 vs. 1.9 months; hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.25-0.87; p=0.017). In contrast, there was no significant difference in PFS of the second agent in the vAD and AD groups (median, 7.0 vs. 4.0 months; HR, 0.63; 95%CI, 0.29-1.34; p=0.235). Conclusions: The effect of each agent after ARPI therapy in the UP-FRONT era may be poorer than that in the VINTAGE era. In the setting after up-front ARPI, sequential therapy with DOC may be more appropriate than sequential therapy with ARPI.
A double-blinded, placebo-controlled, cross-over pilot trial in healthy men to study the effects of Angelica gigas herbal supplement on prostate cancer–relevant inflammatory cytokines.
Authors: Strong Anne-Laure , Karelia Deepkamal N. , Schell Todd D. , Hershock Diane , Fan Tongyao , Sun Dongxiao , Zhu Junjia , Proctor Elizabeth , Jiang Cheng , Joshi Monika , Lu Junxuan 
Published: January 2024

170 Background: The ethanol extract of the root of Angelica gigas Nakai (AGN) dose-dependently inhibits animal models of prostate cancer. Multi-omic analyses have implicated immune and anti-inflammatory responses in the anti-cancer action. In our single dose-PK study (NCT02114957) in healthy volunteers with AGN dietary supplement CognI.Q, we observed a near doubling of the natural killer (NK) mRNA signature in peripheral blood mononuclear cells (PBMC) at 24 h after dosing while the inflammatory cytokine IL-8 mRNA was decreased by one half over the pre-dose baseline. Given NK incapacitation and inflammation have been linked to prostate cancer, the current trial (NCT03630328) was designed to assess safety and to delineate CognI.Q-specific immune and anti-inflammation functions. Methods: We used a double-blinded, placebo-controlled and crossover trial design to monitor hepatic and renal safety metrics based on Comprehensive Metabolic Panel (CMP) and compare the immune cell and cytokine responses to CognI.Q and placebo. Supplement period of 3 weeks was followed with a 2-week washout period. We employed the Ella microfluidic multiplex immunoassay to evaluate select plasma cytokines. Results: Fourteen healthy men completed the trial protocol. Physical examination on study visit days did not reveal any adverse events. Blood CMP monitoring detected abnormal hepatic integrity values in three subjects, all in the second washout period and were attributed to use of anti-allergy medication, an herbal tea for tooth ache, and excessive alcohol, respectively. Analysis of plasma cytokines detected corresponding elevation of MIG, CCL4, CXCL10 and IL-8 with these hepatic damage events. With the exclusion of these subjects or time point, the plasma cytokine measurement did not reveal a significant response to CognI.Q supplement vs. placebo. Conclusions: CognI.Q supplement at the current recommended dose (400 mg, twice per day) did not impair hepatic integrity or renal function, nor did it modulate select plasma cytokines in healthy men. Phase I dose-escalation trials should be implemented to establish safety profile and assess immune and inflammation modulatory effects of AGN supplement beyond the current dose. Clinical trial information: NCT03630328 .
Primary sarcoma of prostate: A genomic landscape study.
Authors: Batayneh Osama , Jacob Joseph M , Bratslavsky Gennady , Spiess Philippe E. , Kamat Ashish M. , Grivas Petros , Necchi Andrea , Cheng Liang , Ross Jeffrey S. , Basnet Alina 
Published: January 2024

181 Background: Primary sarcoma of prostate is exceedingly rare and not well-studied. We sought to describe the genomic landscape of this rare entity and identify potential therapy targets. Methods: From 19,057 cases of prostate cancers, only 11 (<.01%) cases of primary sarcomas were identified and underwent comprehensive genomic profiling (CGP) using FDA-approved hybrid capture-based system to assess all classes of genomic alterations (GA). Genomic-based ancestry, genomic signature, gLOH, MSI and TMB status were determined by CGP. Germline status was predicted using a Somatic-Germline-Zygosity algorithm. PD-L1 expression was determined by IHC (Dako 22C3 TPC scoring). Results: The routine histology and IHC stains from all 11 cases were reviewed centrally. There were 9 stromal sarcomas, and 1 each leiomyosarcoma and rhabdomyosarcoma. All patients (median age 57) were clinically advanced stage at the time of CGP. The primary tumor site was used in 6 patients and metastatic sites (3 bone, 1 ureter and 1 lung metastasis) in 5 patients. The mean number of GA per case was 2.3 (1 to 4 GA/sample). The most frequent GA were in TP53 (36.4%), RB1 (27.3%), ATRX (18.2%). Potentially targetable GA were rare and included MTOR pathway inhibitors for GA in TSC2 and PTEN (1 case each) and PIK3CA inhibitors (GA in PIK3CA in 1 case). There were 3 cases with non “targetable” gene rearrangements including a STAT6- NAB2 fusion in a stromal sarcoma (possible solitary fibrous tumor of prostate), a BCOR- MAML3 fusion and a TMPRSS2- ERG fusion in a stromal sarcoma with an adjacent focus of Gleason 6 prostate adenocarcinoma. 1 case featured a predicted germline mutation of the FLCN gene. All cases were microsatellite stable. TMB ranged from 0 to 9.8 mutations/Mb with median of 3.4 mutations/Mb with no cases at ≥10 mutations/Mb. gLOH scores were low, ranging from 0% to 10.9% (median 2.6%). Genomic ancestry was European in 7 patients and Admixed American in 4 others. There were no specific genomic signatures identified. PD-L1 was tested in 4 cases (all negative). Conclusions: Prostate sarcoma is an exceedingly rare primary cancer of the prostate with limited opportunities for targeted therapy or immunotherapy strategies. These tumors do not appear to be driven by “targetable” gene fusions and individual “targetable” mutations are uncommon. [Table: see text]
Prognostic value of PSMA-extracellular vesicles in oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy: A multi-center observational study.
Authors: Lucien Fabrice , Andrews Jack R. , Kim Yohan J , Horjeti Edlira , Arafa Ali , Sutera Philip , De Bruycker Aurélie , Mercier Carole , Phillips Ryan , Song Daniel , Kiess Ana Ponce , Ost Piet , Tran Phuoc T. , Childs Daniel S , Sartor A. Oliver , Orme Jacob , Park Sean Sunghun 
Published: January 2024

191 Background: Two randomized clinical trials have demonstrated that SABR can prolong time to progression in oligometastatic castration-sensitive prostate cancer (omCSPC) patients. However, there is a need for predictive tools to identify patients who will benefit from SABR alone or with systemic therapy. We investigated the prognostic value of PSMA-positive extracellular vesicles (PSMA+EVs) in a blinded observational study using blood samples from three independent patient cohorts. Methods: We obtained plasma samples from 157 omCSPC patients treated with SABR from the ORIOLE cohort (N=30, JHU) and STOMP-like cohorts (N=80, UGhent; N=47, Iridium Net). Baseline PSMA+EV levels (EV/ml) were measured by nanoscale flow cytometry. Primary clinical endpoints were biochemical progression (bPFS) and radiographic progression (rPFS). Optimal cutoffs for PSA (ng/ml) and PSMA+EV (EVs/ml) were defined as the point with the most significant log-rank test split. Kaplan-Meier curves and univariate Cox regression models were used to determine the association of PSMA+EV levels with clinical outcomes. Results: Twenty percent of patients (N=157 total) were diagnosed with bone scan, 79% with PET imaging, and 1% with other modalities. Ninety-four percent of patients presented with ≤3 metastases on imaging. In the pooled STOMP-like cohorts, median bPFS was 27.9 and 18.0 months for PSMA+EV low and high groups, respectively (p=0.039). Median rPFS was 36.0 versus 27.0 months (p=0.029). In the ORIOLE cohort, median bPFS was 24.3 and 5.9 months in PSMA+EV low and high, respectively (p=0.021). Median rPFS was 36.0 versus 11.1 months (p=0.019). High baseline PSMA+EV levels were associated with higher risk of both biochemical and radiographic progression (Table). Combination of baseline PSA low and PSMA+EV low outperformed either biomarker alone and better predicted risk of disease progression after SABR. Conclusions: While prospective biomarker-guided trials are warranted, a PSMA+EV blood test can aid patient selection by identifying omCSPC patients who may have durable responses to SABR without ADT. [Table: see text]