bluuebunny/crossref_metadata_2025_split huggingface dataset:
Niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations: Second interim analysis (IA2) of MAGNITUDE.
Authors: Efstathiou Eleni , Smith Matthew Raymond , Sandhu Shahneen , Attard Gerhardt , Saad Marniza , Olmos David , Castro Elena , Roubaud Guilhem , Gomes Andrea Juliana , Small Eric Jay , Rathkopf Dana E. , Gurney Howard , Jung Wonho , Mason Gary , Francis Peter St. John , Wang George C. , Wu Daphne , Diorio Brooke , Lopez- Gitlitz Angela Mennicke , Chi Kim N. 
Published: March 2023

170 Background: In the primary analysis of the phase 3 MAGNITUDE study, NIRA/AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations. Here, we report results from IA2 of secondary endpoints in MAGNITUDE. Methods: 423 eligible pts with mCRPC and HRR alterations (HRR+ cohort) were randomized 1:1 to receive NIRA/AAP (n = 212) or placebo (PBO)/AAP (n = 211). At the prespecified IA2, secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]) were formally assessed and the primary rPFS endpoint was updated in the HRR+ cohort, with sensitivity analysis performed for the subgroup of pts with BRCA alterations. Results: Updated descriptive rPFS results at IA2 (cutoff: June 17, 2022) were consistent with the primary analysis in the HRR+ cohort. In the BRCA subgroup, NIRA/AAP extended median rPFS to 19.5 mos vs 10.9 mos with PBO/AAP. NIRA/AAP led to statistically significant benefit in TSP in the HRR+ cohort with consistent benefit in the BRCA subgroup. Continued consistent improvement of TCC was seen with NIRA/AAP in the HRR+ cohort and in the BRCA subgroup. There was a trend towards improved OS with NIRA/AAP in the BRCA subgroup in the primary stratified analysis and the multivariate analysis (MVA), accounting for imbalances in key baseline characteristics. BRCA pts treated with NIRA/AAP experienced delayed time to worst pain intensity (HR, 0.70; 95% CI, 0.44, 1.12; nominal P = 0.1338) and pain interference (HR, 0.67; 95% CI, 0.40, 1.12; nominal P = 0.1275) compared to PBO/AAP. The safety profile at IA2 was consistent with that of the primary analysis, with no new safety signals observed. Conclusions: With 26.8 months of median follow-up, there was a statistically significant and meaningful clinical benefit in TSP and meaningful clinical benefit in TCC. Additionally, updated rPFS results from MAGNITUDE IA2 were consistent with the primary analysis; OS benefit was not conclusive due to immaturity and will be followed through to final analysis. Taken together, these data continue to support the use of NIRA/AAP in pts with mCRPC and BRCA alterations or select other HRR gene alterations. Clinical trial information: NCT03748641 . [Table: see text]
Impact of run-in treatment with abiraterone acetate and prednisone (AAP) in the MAGNITUDE study of niraparib (NIRA) and AAP in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Authors: Castro Elena , Chi Kim N. , Sandhu Shahneen , Olmos David , Attard Gerhardt , Saad Marniza , Gomes Andrea Juliana , Rathkopf Dana E. , Smith Matthew Raymond , Kang Taek Won , Cruz Felipe Melo , Basso Umberto , Mason Gary , del Corral Adam , Dibaj Shiva , Wu Daphne , Diorio Brooke , Lopez- Gitlitz Angela Mennicke , Tural Deniz , Small Eric Jay 
Published: March 2023

172 Background: NIRA/AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations, particularly in BRCA, in the phase 3 MAGNITUDE study. As a practical measure, pts were permitted to receive up to 4 mos of AAP (in 1L mCRPC) prior to randomization to allow time for genomic testing. We evaluated the impact of AAP run-in treatment on the efficacy of NIRA/AAP. Methods: 423 pts with mCRPC and HRR gene alterations were randomized 1:1 to receive NIRA/AAP or placebo (PBO)/AAP. At the prespecified second interim analysis, a sensitivity analysis based on the duration of AAP run-in was conducted. Pts with BRCA alterations were also analyzed separately. Results: Median duration of prior AAP treatment received was 1.9 (range, 0.3–4.1) mos. Pts receiving AAP ≤2 mos had similar benefit (radiographic progression-free survival [rPFS] hazard ratio [HR], 0.69 [95% confidence interval [CI], 0.36-1.30]; time to cytotoxic chemotherapy [TCC] HR, 0.52 [95% CI, 0.24-1.11]; time to symptomatic progression [TSP] HR, 0.32 [95% CI, 0.13-0.79]; Table) to pts not receiving any prior AAP. rPFS benefit was not demonstrated in pts who had previously received AAP >2 – 4 mos: HR, 1.47 (95% CI, 0.66-3.30). Findings were consistent in the BRCA population. Conclusions: Pts receiving a short run-in (≤2 mos) of AAP alone obtained similar benefit from NIRA/AAP as those who received both NIRA/AAP together for initial treatment of mCRPC. While interpretation of data is limited by the small sample size and event numbers, for pts where NIRA/AAP is being considered as therapy, AAP may be initiated during HRR testing and combination treatment should be initiated expeditiously once HRR positivity is established to attain maximal treatment benefit. Clinical trial information: NCT03748641 . [Table: see text]
Oral EPI-7386 in patients with metastatic castration-resistant prostate cancer.
Authors: Pachynski Russell Kent , Iannotti Nicholas , Laccetti Andrew Leonard , Carthon Bradley Curtis , Chi Kim N. , Smith Matthew Raymond , Vogelzang Nicholas J. , Tu Wilson , Kwan Edmond Michael , Wyatt Alexander William , Villaluna Karen , Younginger Brett , Cesano Alessandra 
Published: March 2023

177 Background: EPI-7386 is a next generation aniten, a novel class of compounds designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain. Preclinical data supports disruption of AR regulated gene transcription even in the presence of resistance mechanisms including ligand-binding domain point mutations and truncated splice variants. Here we report results of the Part 1a first-in-human trial of EPI-7386 in mCRPC (NCT04421222). Methods: This Phase 1, open-label, multicenter, dose escalation (Part 1a) and expansion (Part 1b) trial was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of EPI-7386 in mCRPC patients (pts) progressing on standard of care treatment, including next generation antiandrogen(s) and chemotherapy. Originally designed to assess up to 5 doses of EPI-7386 (200, 400, 600, 800, and 1000 mg QD), two additional cohorts were added examining 400 and 600 mg BID due to 600 mg QD showing exposure saturation while demonstrating a favorable safety profile. Results: 31 pts were enrolled in the QD cohorts and 8 in the BID cohorts. Pts had a median of 4 lines of prior therapy for mCRPC: 83% received abiraterone and at least one next generation AR inhibitor, and 58% had at least one line of prior chemotherapy. No DLTs were observed; EPI-7386 was safe and well tolerated at all doses/schedules evaluated. All related adverse events (AEs) were Grade 1 and 2 and consistent with AEs associated with second-generation antiandrogens. For doses above 400 mg QD, exposures were at or above those associated with antitumor activity in animal models. Evidence of antitumor activity (including significant and durable PSA responses and/or decreases in ctDNA, and/or radiographically documented tumor shrinkage) were observed in pts with fewer than 3 lines of treatment for mCRPC, no visceral metastases and no prior chemotherapy (9/31 pts). Conclusions: Part 1a treatment with EPI-7386 monotherapy was safe, well tolerated up to a daily dose of 1200 mg (600 mg BID), achieved target clinical exposures and showed preliminary signals of antitumor activity in heavily-pretreated mCRPC. Part 1b is open with enrollment focused on pre-chemotherapy, post-second generation antiandrogen treated mCRPC pts in one cohort, and treatment-naïve non-mCRPC pts in a window of opportunity proof-of-concept second cohort. Two doses will be evaluated (600 mg BID and QD) based on FDA Project Optimus recommendations. Clinical trial information: NCT04421222 .
Rucaparib for metastatic castration-resistant prostate cancer (mCRPC): TRITON3 interim overall survival and efficacy of rucaparib vs docetaxel or second-generation androgen pathway inhibitor therapy.
Authors: Bryce Alan Haruo , Piulats Josep M. , Reaume M. Neil , Ostler Peter James , McDermott Raymond S. , Gingerich Joel Roger , Pintus Elias , Sridhar Srikala S. , Abida Wassim , Daugaard Gedske , Heidenreich Axel , Krieger Laurence E. M. , Sautois Brieuc , Loehr Andrea , Despain Darrin , Go Jowell , Watkins Simon Paul , Chowdhury Simon , Ryan Charles J. , Fizazi Karim 
Published: March 2023

18 Background: TRITON3 (NCT02975934) is a randomized, multicenter, open-label, phase 3 study of rucaparib vs physician’s choice (docetaxel [DTX], abiraterone [ABI] or enzalutamide [ENZ]) in patients (pts) with chemotherapy-naïve mCRPC with BRCA1/2 (BRCA) or ATM alterations. It was previously reported that rucaparib significantly improved the primary endpoint of radiographic progression-free survival (rPFS) vs physician’s choice in pts with BRCA or ATM alterations. We report here the interim overall survival (OS) and also report on efficacy of rucaparib compared individually with either DTX or ABI/ENZ. Methods: Pts had disease progression after 1 prior second-generation androgen pathway inhibitor therapy in any setting and were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX, ABI or ENZ. An ordered step-down multiple comparisons procedure was used to control the overall error rate. OS was a key secondary endpoint with rPFS as the primary endpoint tested first in the BRCA subgroup, then the intent-to-treat (ITT) population. Subgroup analyses based on physician’s choice were exploratory. Results: As of August 25, 2022, 302 pts with BRCA and 103 pts with ATM alterations were randomized. OS maturity was 54% in the BRCA subgroup and 59% in the ITT population. rPFS and OS are shown. The most frequent treatment-emergent adverse event (TEAE) in the rucaparib, DTX and ABI/ENZ groups was asthenia/fatigue (61.1%, 67.6% and 57.6%, respectively). The most frequent grade ≥3 TEAE in the rucaparib, DTX and ABI/ENZ groups was anemia (23.7%), neutropenia (14.1%), and hypertension (10.2%), respectively. Conclusions: Rucaparib significantly improved rPFS vs either DTX or ABI/ENZ; safety was consistent with prior reports. Interim OS results suggest a trend towards improvement for rucaparib vs DTX or ABI/ENZ in pts with mCRPC and BRCA alterations. Clinical trial information: NCT02975934 . [Table: see text]
RIPK2 as a prognostic biomarker and predictor of aggressive prostate cancer.
Authors: Hammudi Mustafa , Aldhahri Walaa , Kalola Akshar , McCullum Catherine , Motoni Caddie , Martha Antonio , Rajendran Rithika , Nava Victor , Estephan Fayez , Byrne Morgan , Diao Guoqing , Jain Maneesh Rajiv 
Published: March 2023

211 Background: Receptor-Interacting Protein Kinase 2 (RIPK2) has been known to play a significant role in inflammation and anti-microbial response via the NF-KB pathway. Recently, RIPK2 was also shown to stabilize and activate c-Myc, a molecule implicated in the progression of various malignancies including prostate cancer (PCa). Our study aims to determine the prognostic value of RIPK2 expression in PCa using immunohistochemistry (IHC) analysis of biopsy specimens with special focus on a predominantly African American (AA) cohort. Methods: Eligible patients aged ≥18 years diagnosed with PCa at the Washington DC VA Medical Center were randomly selected and retrospectively grouped into indolent, locally advanced, and metastatic disease categories and stratified by age, ethnicity, AJCC stage, PSA and Gleason score at diagnosis. Representative tissue from prostate core biopsy, transurethral resection, or radical prostatectomy was analyzed for each patient. RIPK2 expression and intensity were assessed by IHC and graded by two independent pathologists by the following scale: 0 (no cytoplasmic staining), 1+ (weak cytoplasmic staining similar to benign prostatic tissue), 2+ (moderate cytoplasmic staining), and 3+ (strong cytoplasmic staining). The primary endpoint was RIPK2 expression by disease group, and key secondary outcomes were RIPK2 association with Gleason score, PSA at diagnosis, age and race. Fisher’s exact test was used to evaluate statistical significance of the association between RIPK2 expression level and disease category. Results: A total of 89 patients were selected for analysis, of which 75 (84.3%) were AA. All tumors had at least 1+ level RIPK2 expression and there was a highly significant difference in RIPK2 expression according to disease severity (p < 0.001). Stratified RIPK2 expression was 1.53, 1.83, and 2.28 in the indolent, locally advanced, and metastatic groups respectively. We observed a significant directly proportional correlation between RIPK2 expression and a higher PSA level (p= 0.0021), Gleason score (p< 0.001), higher age (p= 0.0276), and AJCC stage (p< 0.001) at the time of diagnosis. Mean RIPK2 expression was 1.81 in AA patients and 2.15 in White patients (p= 0.0332). Conclusions: PCa is the most prevalent cancer in US males and there is an urgent need for more accurate biomarkers that can predict disease severity and suggest actionable targeted therapy. In this retrospective analysis, we confirm that higher RIPK2 expression is associated with more advanced PCa. We extend these findings to a predominantly AA cohort, which may promote improvements in personalized medicine for this population at higher risk for PCa if RIPK2-targeting drugs such as Ponatinib can be utilized.
Using microfluidic models to evaluate whether monocyte preconditioning plays a role in tumor-associated macrophage mediated resistance to hormone therapy in men with prostate cancer.
Authors: Kosoff David , Bootsma Matthew L , Zhao Shuang , Recchia Emma , Breneman Matthew T 
Published: March 2023

228 Background: While men with metastatic castrate-resistant prostate cancer benefit greatly from 2nd generation androgen targeted therapies (ATTs), the utility of these therapies is inevitably limited by the development of resistance. Tumor associated macrophages (TAMs) are a myeloid immune cell population within the prostate tumor microenvironment (TME) that have been shown to play an integral role in development of ATT-resistance. However, the pathways that underlie TAM-mediated ATT resistance remain under investigation. In particular, many TAMs within the TME are derived from circulating monocytes and it is not yet clear whether the pathways driving TAM-mediated resistance are activated exclusively within the TME or if the activation of critical resistance pathways begins while the cells are circulating as monocytes. In this study, we utilized novel microscale technologies to investigate the transcriptome of monocytes and macrophages derived from patients progressing and responding to ATTs as well as the degree to which the macrophages promote ATT resistance in prostate tumor models. Methods: Primary monocytes were isolated from 22 men with prostate cancer who were either progressing or responding to 2ndgeneration ATTs. A portion of the monocytes from each patient were isolated for transcriptome analysis and the rest were differentiated into monocyte-derived macrophages (MDMs). MDMs were then cultured in monoculture or in co-culture with androgen-independent prostate tumor cells (22Rv1 and C42B). Each culture was then left untreated or treated with enzalutamide therapy. Following culture/treatment, each macrophage condition was isolated for transcriptome analysis and tumor cell populations from each condition were evaluated for treatment cytotoxicity. Results: Viability data from MDM-C42B co-culture demonstrated a 20% increase in tumor cell viability following enzalutamide treatment when C42B cells were cultured with primary MDMs from castrate-sensitive patients as compared to MDMs from castrate-resistant patients. Subsequent transcriptome analysis demonstrated key signatures in monocyte/macrophage populations that were associated ATT response. Conclusions: Leveraging a novel microfluidic culture platform known as Stacks, we were able to utilize primary, patient-derived cells to demonstrate that the role of TAMs in ATT resistance within the prostate TME is dependent, at least in part, on factors that are present prior to extravasation into the TME. Transcriptome analysis identified candidate pathways, which may be driving TAM-mediated differences in ATT response. These findings have the potential to lead to future use of circulating monocytes as a predictive biomarker as well as lead to the identification and targeting of ATT resistance pathways in patients.
Genomic determinants of patterns of failure in metachronous oligometastatic castration-sensitive prostate cancer.
Authors: Sutera Philip , Van der Eecken Kim , Shetty Amol , Song Yang , Hodges Theresa , Verbeke Sofie , Van Dorpe Jo , Fonteyne Valerie , De Laere Bram , Mishra Mark V. , Rana Zaker Hamid , Molitoris Jason K. , Ferris Matthew J. , Roberts Nicholas J , Song Daniel Y. , DeWeese Theodore L. , Pienta Kenneth J. , Deek Matthew , Ost Piet , Tran Phuoc T. 
Published: March 2023

238 Background: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state along the progression of metastatic disease in which patients experience improved outcomes compared to those with higher disease burden. Despite the generally more indolent nature, much heterogeneity still exists with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Here we correlate tumor genomics with modes of progression (MOP) and patterns of failure (POF) following treatment for omCSPC. Methods: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC, who underwent tumor next generation sequencing (NGS) with at least 1 year of follow-up. Descriptive POF and MOP were reported with respect to presence of genomic alterations in pathways of interest. Genomic pathways of interest included TP53, SPOP, WNT ( APC, CTNNB1, RNF43), DNA double strand break repair, cell cycle genes ( Rb1, CCND1–3, CDKN1B, and CDKN2A), and PI3K/AKT/mTOR. MOP were defined as oligoprogression (1-3 lesions), polyprogression (≥4 lesions), or long-term control (LTC, no radiographic progression at last follow-up). POF included location of lesions at first failure. Overall survival (OS) was calculated by the Kaplan-Meier method. Genomic associations with patterns/modes of failure were compared with chi-square test. Results: 221 patients were included for analysis with the majority having either 1 (47.5%) or 2 (27.3%) metastatic lesions at oligometastasis. 5-yr OS was associated with MOP 92% vs 89% vs 69% (p<0.01) for LTC, oligo- and polyprogression respectively. TP53 mutations were associated with significantly lower rates of LTC (24.4% vs 46%, p<0.01) and cell cycle mutations associated with high rates of polyprogression (36.7% vs 15.7%, p<0.01). With respect to POF, bone failure was significantly more common within tumors harboring mutations in TP53 (41.2% vs 23.1%, p=0.01) and less common with SPOP mutations (4.2% vs 27.8%, p=0.02). Finally, visceral failures were more common in tumors harboring either WNT pathway (20% vs 5.1%, p<0.01) or SPOP (17.4% vs 5.2%, p=0.04) mutations. Notably, SPOP and WNT pathway mutations cluster together (p<0.01). Conclusions: Tumor genomics provides novel insight into patterns of failure and modes of progression following treatment for metachronous omCSPC. Patients with TP53 and cell cycle mutations have a higher likelihood of progression and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism.
Survival trends in de novo metastatic prostate cancer: SEER and Veterans Affairs comparison.
Authors: Schoen Martin W. , Owens Lukas , Luo Suhong , Montgomery Robert Bruce , Sanfilippo Kristen Marie , Etzioni Ruth Douglas 
Published: March 2023

28 Background: Advances in treatment for metastatic prostate cancer (mPC) have improved overall survival (OS) in clinical trials for mPC over the last 20 years. It is unclear whether these changes from trials have translated to improvements in survival in the real world. We sought to characterize trends in OS among patients with newly diagnosed mPC in two large national registries. Methods: Patients diagnosed from 2000-2019 were included. Patients from SEER-17 were included if stage at diagnosis was distant. For years prior to 2004, SEER Historic Stage A was used. Patients in the Veterans Affairs Prostate Cancer data core (VA) were included if the SEER summary stage variable was distant in the first record of prostate cancer in VA or oncology registry data for veterans diagnosed after 2018. Results: 55,661 patients were identified in SEER and 14,904 patients were identified in VA. Median age at presentation was 72 years in both datasets, with 16.6% identified as Black in SEER and 28.5% Black in VA. Median OS from 2000-2004 to 2015-2019 in SEER increased from 25 to 31 months, corresponding to a hazard ratio (HR) of 0.82 (p <0.001); median OS in VA increased from 25.8 to 30.9 months, corresponding to a HR of 0.912 (p=0.003). Patients <70 years of age had median OS that increased from 31 to 41 months (HR 0.78, p <0.001) in SEER and 34.4 to 42.2 months (HR 0.87, p=0.003) in VA compared to patients 70+ in SEER (21 to 26 months, HR=0.84, p<0.001) and in VA (21.6 to 25.6 months, HR=0.935, p=0.03). In SEER, black patients had worse survival compared to white patients (HR 1.10, p<0.001). Survival improvement over time in SEER was seen for both black (HR 0.81, p<0.001) and white (HR 0.83, p<0.001) patients. In VA, black patients had better OS compared to white patients (HR 0.96, p=0.0475). Survival improvement over time in VA was seen in black (HR 0.84, p<0.001), but was not significant in white (HR 0.94, p=0.052) patients. Conclusions: This real-world analysis demonstrates that median OS in de novo mPC has improved over the last 20 years, particularly in patients <70 years of age. However, these improvements are less than what has been observed in clinical trials. Black patients had inferior OS in SEER compared to white patients but in the VA black patients had better OS and an improvement in OS over time, potentially reflecting more equal access to care in the VA system. [Table: see text]