bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1 study of PSCA-targeted chimeric antigen receptor (CAR) T cell therapy for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dorff Tanya B. , Blanchard Suzette , Martirosyan Hripsime , Adkins Lauren , Dhapola Gaurav , Moriarty Aidan , Wagner Jamie R , Chaudhry Ammar , D'Apuzzo Massimo , Kuhn Peter , Forman Stephen J. , Priceman Saul
Published: February 2022

91

Background: Chimeric antigen receptor (CAR)-engineered T cell therapies are being pursued for the treatment of mCRPC. Prostate Stem Cell Antigen (PSCA) is highly expressed on the surface membrane in mCRPC and with limited expression on normal tissues. We undertook a phase 1, first-in-human study of a PSCA-targeted 4-1BB-co-stimulated CAR T cell therapy in mCRPC. Methods: CAR T cells were manufactured at City of Hope’s cGMP facility. The trial followed the Target equivalence range design with an equivalence range of.20-.35 and too toxic level of 0.51 following participants in cohorts of 3. The plan was to begin at a dose of 100 million (M) without lymphodepletion (LD) chemotherapy consisting of fludarabine and cyclophosphamide, then add LD to 100M prior to dose escalation to maximum 600M. Patients (pts) were required to have disease progression after at least 1 androgen receptor targeted therapy but there was no limit on prior chemotherapy or other treatments. Primary objective is to define the dose limiting toxicity (DLT) and recommended phase 2 dose as well as to describe preliminary bioactivity and efficacy. Correlative studies include MRI for target bone lesion response, CAR T cell persistence, circulating tumor cells, and serum cytokines. Results: 12 pts have been treated to date, median age 68 (42-72). Three pts were treated at the 100M dose with no DLTs. In the 100M plus LD dose level there 2 pts experienced DLT of grade 3 cystitis non-infective and fatigue. The protocol was amended to reduce the LD dose to 300 mg/m2 cyclophosphamide D1-3 and intensify monitoring with early intervention for cystitis. No DLT occurred in 3 pts treated in the modified LD 100M cohort. Cytokine release syndrome (CRS), DLTs and best response by RECIST are presented by dose level in the table. PSA declines (one >90%) were seen as well as radiographic improvement, though RECIST response was limited to stable disease (SD) by concurrent bone metastases. Correlative studies indicated bioactivity of PSCA-CAR T cells. Conclusions: PSCA-CAR T cell therapy is feasible in pts with mCRPC with DLT of cystitis, and shows preliminary anti-tumor effect at a dose of 100M plus LD. Dose escalation to 300M may proceed. Clinical trial information: NCT03873805. [Table: see text]
Safety evaluation of M9241 in combination with docetaxel in metastatic prostate cancer.
Authors: Atiq Mohammad O. , Chandran Elias Bin Aris , Meininger Luke , Karzai Fatima , Bilusic Marijo , Marte Jennifer L. , Arlen Philip M. , Cordes Lisa M. , Strauss Julius , Redman Jason , Floudas Charalampos S. , Pastor Danielle M. , Owens Helen , Hankin Amy , Williams Monique , Figg William Douglas , Dahut William L. , Schlom Jeffrey , Gulley James L. , Madan Ravi Amrit
Published: February 2022

93

Background: M9241 is an immunocytokine that targets single- and double-stranded DNA which allows the treatment to localize IL-12 to necrotic tumor (Xu, CCR 2017). M9241 was well-tolerated as a monotherapy in a Phase I study with solid tumors (Strauss J, CCR 2019). Additional preclinical data has demonstrated synergy of M9241 with cytotoxic therapy. This is the first study to examine the safety of a novel combination of chemotherapy and immunocytokines in metastatic prostate cancer. Methods: This safety analysis included patients with mCSPC or mCRPC. Patients were enrolled in a 2-dose level (DL) escalation cohort of M9241 (DL 1: 12mcg/kg, DL 2: 16.8mcg/kg) combined with docetaxel (75mg/m2) with 6 patients planned per DL. A third DL of 8mcg/kg will enroll 6 more patients after the 16.8mcg/kg DL has fully enrolled. All patients were treated with ADT. Patients were initiated on treatment with docetaxel with a plan for mCSPC patients to receive six 3-week cycles of combined treatment and mCRPC patients to continue until progression or unacceptable toxicity. M9241 was given starting with the second cycle of treatment for each patient. Dose-limiting toxicity (DLT) was evaluated in the first 6 weeks after start of docetaxel (from cycle 1 day 1 through the end of the first cycle with M9241). Results: The study has enrolled 10 patients out of a planned 18 for the safety portion. Age range is 58-82 with a median of 69 years. Race distribution is 80% White and 20% Black. Gleason scores for patients were 8 (40%), 9 (40%), and 10 (20%). No DLTs were seen with either dose-level. Only 1 patient had a Grade 4 AE, neutropenia. Grade 3 toxicities included anemia, diarrhea, leukopenia, and hypotension (each occurring in 10% of the patients). The most frequent adverse events (AEs) of any grade were anemia (40%) and lymphopenia (40%), followed by fatigue (30%), diarrhea (20%), and fever (20%). Conclusions: We established a safe dose-level of M9241 at ≥ 12mcg/kg. Updated clinical data from the safety cohort (n = 18) will be presented. This demonstrates that an immunocytokine and chemotherapy can be safely combined for treatment in metastatic prostate cancer. A planned expansion cohort will evaluate docetaxel and M9241 in mCRPC. Clinical trial information: NCT04633252.
Phase 2 trial of immunotherapy in tumors with CDK12 inactivation (IMPACT): Results from cohort A of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) receiving dual immune checkpoint inhibition (ICI).
Authors: Alva Ajjai Shivaram , Li Jinju , Chou Jonathan , Reimers Melissa Andrea , McKay Rana R. , Zhang Jingsong , Daignault-Newton Stephanie , Palmbos Phillip Lee , Reichert Zachery R , Cieslik Marcin , Chinnaiyan Arul , Abida Wassim
Published: February 2022

103

Background: Prostate cancer with CDK12 inactivation represents a distinct subtype in mCRPC, tumors are characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens and increased tumor T cell infiltration. Retrospective experiences with ICI in CDK12 inactivation CRPC pts reported PSA and radiographic responses. We conducted a prospective multi-site clinical trial of ipilimumab and nivolumab in CDK12 inactivation or mutated cancers. Herein, we report our findings in the completed cohort A of men with mCPRC. Methods: Eligible pts had mCRPC (ongoing androgen deprivation therapy with serum testosterone £ 50 ng/dL) and putative CDK12 inactivation of function aberrations on any commercial or institutional CLIA/CAP approved next generation sequencing assay. Archival tumor tissue was requested for correlative biomarker analysis. Pts received nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks until disease progression, intolerable toxicity, or consent withdrawal. The primary endpoint was PSA response, defined as a greater than or equal to 50% decline in PSA from baseline. Secondary endpoints included safety/toxicity, secondary efficacy measures including QoL and overall survival. Exploratory objectives included baseline tumor whole exome analysis and changes in circulating immune profiles with therapy. Results: As of data cut-off in Aug 2021, 28 mCRPC pts enrolled in Cohort A; median ECOG PS was 1 (0-2 range), 22/28 had Gleason 8-10 cancer, mean baseline PSA at study entry was 231 ng/dL, all pts had received ≥1 prior oral androgen signaling inhibitor and ≥1 cytotoxic chemotherapy. Unconfirmed PSA ≥30% decline was seen in 6/28 pts (21.4%) and PSA ≥50% decline in 4/28 pts (14.2%). Grade ≥3 possible/probable/definite adverse events were noted in 7/28 (25%) and SAEs in 10/28 pts (35.7%). Six pts (21.4%) experienced a rapid PSA increase by ≥ 10-fold over baseline. Conclusions: Combination immunotherapy was reasonably tolerated in this heavily pre-treated population and was associated with unconfirmed PSA responses in a subset of pts. Ongoing correlative analyses could explain responses mechanistically. Enrollment in Cohort B of non-prostate cancers and Cohort C of nivolumab monotherapy in prostate cancer are still ongoing. Clinical trial information: NCT03570619.
Cohort study of oligorecurrent prostate cancer patients: Oncological outcomes of patients treated with salvage lymph node dissection via PSMA radioguided surgery.
Authors: Maurer Tobias , Mehdi Irai Mehrdad , Rauscher Isabel , Simon Ricarda , Eiber Matthias , van Leeuwen Fijs WB , van Leeuwen Pim , Budaeus Lars , Steuber Thomas , Graefen Markus , Tennstedt Pierre , Heck Matthias , Horn Thomas , Knipper Sophie
Published: February 2022

106

Background: Prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) allows detection of small and/or atypically localized metastatic prostate cancer (PCa) lesions. In a subset of patients with recurrent oligometastatic PCa salvage surgery with PSMA-targeted radioguidance (PSMA-RGS) may be of value. We aimed to evaluate the oncological outcomes of salvage PSMA-RGS for oligorecurrent PCa and determine predictive preoperative factors of improved outcomes. Methods: In this cohort study within two tertiary care centers, patients with biochemical recurrence (BCR) after radical prostatectomy (RP) and imaging with PSMA PET receiving salvage PSMA-RGS between 2014 and 2020 were analyzed. Kaplan-Meier and multivariable Cox regression models adjusted for various parameters were used to test for BCR-free survival (BFS) and therapy-free survival (TFS) differences. Postoperative complications were classified according to Clavien-Dindo. Results: Overall, 364 patients were assessed. At PSMA-RGS, median (IQR) age and preoperative PSA was 67 (61-71) years and 1.0 (0.5-1.9) ng/ml. Metastatic soft-tissue lesions were removed in 356 (94.4%) patients. Within three months from surgery, 25 (6.6%) patients suffered from Clavien-Dindo complications grade III-IV. During follow-up, 235 patients experienced BCR and 129 patients received further therapy. Median follow-up for patients who did not experience BCR and who did not receive further therapy was 11.1 months and 10.5 months, respectively. Median (IQR) BFS and TFS was 7.8 (5.4-10.9) and 34.9 (24.7-43.5) months. At two years of follow-up, BFS rate was 31.9% and TFS rate was 56.6%. In multivariable analyses, higher preoperative PSA (HR: 1.06), higher number of PSMA-avid lesions on preoperative imaging (HR: 1.2) and multiple (pelvic plus retroperitoneal) localizations (HR: 1.7), as well as retroperitoneal localization (HR: 2.0) of lesions in PSMA PET imaging were independent predictors of BCR after PSMA-RGS. Limitations are the retrospective design and lack of a control group. Conclusions: As salvage surgery in oligorecurrent PCa currently constitutes an experimental treatment approach careful patient selection is mandatory based on life expectancy, low PSA values and low number of PSMA PET avid lesions located in the pelvis. Further studies are needed to confirm our findings and define the oncological value of salvage surgical procedures in oligorecurrent PCa.
Treatment outcomes of patients with metastatic prostate cancer and co-morbid diabetes mellitus.
Authors: Govindan Srinivas , Luo Suhong , Cheranda Nina , Riekhof Forest , Schoen Martin W.
Published: February 2022

113

Background: In metastatic castrate resistant prostate cancer (mCRPC) there is a lack of studies that explore the interaction of comorbidities on treatment outcomes, which presents a challenge in choosing the right drug. In patients with diabetes mellitus, two common therapies, enzalutamide (ENZ) and abiraterone (ABI) have different effectiveness due to different mechanisms of action and because ABI requires co-administration of prednisone. Thus, in this study, we aim to assess the survival of patients with comorbid diabetes treated with ENZ and ABI. Methods: Patients treated with AA or ENZ for mCRPC from September 10, 2014, to June 2, 2017 were identified within the Veterans Health Administration. For these patients, presence of diabetes or complicated diabetes was determined using the Charlson method from the International Classification of Diseases (ICD) 9/10 codes. A Kaplan–Meier time to event analysis and the cox proportional hazards modeling was used to analyze the data with the latter including covariates such as age, Charlson Comorbidity Index, body-mass index, treatment with bone-directed therapy, black race, and baseline PSA at start of treatment with ENZ or ABI. Results: We identified 5822 patients treated for mCRPC, of which 2202 had diabetes and were treated using either ENZ (n = 1041) or ABI (n = 1161). Median survival of patients with diabetes treated with ENZ was 3 months longer than in patients treated with ABI (23.8 vs. 20.8, p = 0.002 by log-rank). In 3620 patients without diabetes, no significant difference in median survival (24.7 vs. 22.7 months, p = 0.065) was seen between ENZ (n = 1463) and ABI (n = 2157). In a multivariable model, ENZ was associated with improved survival in patients with diabetes (adjusted HR 0.87, 95% CI 0.79-0.97) and in patients without diabetes (adjusted HR 0.90, 95% CI 0.83-0.98). Conclusions: ENZ was associated with improved 3-month median survival in patients with diabetes compared to ABI in unadjusted analyses. Additionally, in adjusted analyses the cox proportional model also showed significantly better survival in mCRPC patients treated with ENZ both with and without diabetes, although the findings are more robust for patients with diabetes. The cause of these differences is unknown, so there may be differences in efficacy and adverse events between the two agents in real-world use. Further assessment of patient outcomes with comorbid disease is appropriate to improve care of patients with advanced prostate cancer.
Community oncologists’ perceptions of and barriers to access for 177LU-PSMA-617 in metastatic castration-resistant prostate cancer.
Authors: Gajra Ajeet , Estupinian Ricardo , Fortier Stephanie , Jeune-Smith Yolaine , Feinberg Bruce A. , Vaishampayan Ulka N.
Published: February 2022

120

Background: Metastatic castration-resistant prostate cancer (mCRPC) is a difficult-to-treat cancer with poor patient outcomes. In June 2021, 177Lu-PSMA-617 was granted U.S. FDA breakthrough designation for the treatment of mCRPC based on results from the phase III VISION trial showing a 4-month increased median overall survival (15.3 v 11.3 m; HR 0.62 [0.52-0.74], P < 0.001) and a 5.3-month increased radiographic progression-free survival (8.7 v 3.4 m; HR 0.40 [0.29-0.57] for 177Lu-PSMA-617 versus standard of care (SOC). If approved, 177Lu-PSMA-617 has the potential to improve patient outcomes, but its impact will depend significantly on how community-based medical oncologists (cbMO) plan to integrate it into patient management. The present study surveyed cbMO regarding their perceptions of the VISION trial data and potential barriers to 177Lu-PSMA-617 use in mCRPC. Methods: Between June and October 2021, practicing U.S.-based cbMO were invited to attend a virtual meeting and were presented with the VISION trial data. Their reactions to the data and preferences were collected using audience response technology. Results are presented using descriptive statistics. Results: Among the 287 participating cbMO, median years in practice was 17 (1-45), and median time spent in direct patient care was 90% (20-100%). In the past year, 46% of cbMO managed 6-15 patients with mCRPC, and 27% managed 16 or more. CbMO reported that at the time of referral, their patients with mCRPC had commonly been treated with androgen deprivation therapy (77%) and one (49%) or two plus (20%) novel hormonal agents. After reviewing the recent data from the VISION trial showing improved survival outcomes in mCRPC, 51% of cbMO reported that both the safety and efficacy data were compelling, and they were very likely to prescribe 177Lu-PSMA-617 if approved; 33% indicated that the efficacy data alone was compelling and were likely to prescribe 177Lu-PSMA-617. The top 2 limitations of the VISION trial were identified as PSMA gallium positivity for eligibility (54%) and the disallowance of radium-223 on the SOC arm (48%). Regarding perceived barriers to future use of 177Lu-PSMA-617, 68% and 64% of cbMO reported availability of a PSMA-gallium scan and availability/access of the therapy itself, respectively, would be the greatest barriers. Additional barriers included cost (42%) and difficulty with reimbursement (30%), highlighting the importance of addressing access and financial considerations associated with 177Lu-PSMA-617. Conclusions: Most cbMO found the VISION trial data of 177Lu-PSMA-617 in mCRPC compelling and indicated that they are likely to incorporate it into their patient management, if approved. However, major barriers such as the incorporation of PSMA-gallium scans, 177Lu-PSMA-617 availability, and cost will need to be addressed to encourage widespread adoption of this new therapy.
Overall survival (OS) after progression on first novel hormonal therapy (NHT) in patients (pts) with metastatic castration-sensitive versus castration-resistant prostate cancer (mCSPC versus mCRPC).
Authors: Sayegh Nicolas , Tripathi Nishita , McFarland Taylor Ryan , Kessel Adam , Nussenzveig Roberto , Chigarira Beverly , Li Haoran , Tandar Clara , Goel Divyam , Nordblad Blake , Cheney Jackson , Sahu Kamal Kant , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj
Published: February 2022

121

Background: Novel hormonal therapy (NHT) i.e. novel androgen receptor or androgen synthesis inhibitors have been approved for treatment of pts with mCSPC and mCRPC based on improved OS. However, OS of patients after progression on first-line NHT for mCSPC is not well characterized. It is currently unknown whether the OS in pts “after” progression on first-line NHT in mCSPC versus mCRPC is significantly different. Herein, our objective was to assess OS after disease progression on NHT given as the first-line therapy in the mCSPC vs first-line therapy in mCRPC setting. Methods: In this IRB-approved study, patient-level data were collected retrospectively, only those treated with NHT as first-line therapy for mCSPC or mCRPC were included. For patients receiving NHT in the mCRPC setting, no prior NHT was allowed in the mCSPC setting. Median overall survival and hazard ratios were determined by Kaplan-Meier analysis. Results: A total of 173 pts (45 mCSPC and 128 mCRPC) were eligible and included in the analysis. Median OS in the mCSPC versus mCRPC were similar: 23 vs. 17 months, hazard ratio: 0.9855, (95% CI: 0.6225 – 1.560, P=0.951). See the table. Conclusions: These results suggest median OS is similar after progression on one NHT whether given in the first-line mCSPC or first-line mCRPC setting. These data have implications on patient counseling and prognostication as well as the design of clinical trials in patients experiencing disease progression on an NHT. These hypothesis generating data need external validation.[Table: see text]
BXCL701: First-in-class oral activator of systemic innate immunity combined with pembrolizumab, in patients with metastatic castration-resistant prostate cancer (mCRPC) of small-cell neuroendocrine carcinoma (SCNC) phenotype—Phase 2a interim results.
Authors: Tagawa Scott T. , Zhang Jingsong , Monk Paul , Zhu Xinhua , Jones Robert , Linch Mark David , Costin Dan , De Bono Johann S. , Karsh Lawrence Ivan , Petrylak Daniel P. , Borderies Pascal , Deshpande Rashmi Majali , O'Neill Vincent , Aggarwal Rahul Raj
Published: February 2022

126

Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP 8/9 & DPP 4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 & IL-1ß, bridging innate & adaptive immunity. BXCL701 is evaluated in a phase 1b/2 study in combination with pembrolizumab, in mCRPC patients with SCNC phenotype (and in adenocarcinoma). SCNC is highly proliferative and aggressive and does not express androgen receptor or PSA. Here are reported the interim results of the phase 2a after enrollment of 16 patients for the SCNC cohort. Methods: Phase 2a patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy may be eligible following discussion with the sponsor). Patients received pembrolizumab (200 mg IV q21-days) + BXCL701 0.2 mg BID for a week with step-up to 0.3 mg BID on days 8-14, and 0.3 mg BID on days 1-14 of subsequent cycles. Primary endpoint is Composite Response defined as RECIST 1.1 ± PSA50 ± CTC count conversion. Study uses a Simon 2-stage minimax design with 15 evaluable patients in stage 1 and 13 in stage 2. Baseline markers and changes in relevant immune effector cells also evaluated. Results: As of 9/27/21, 16 patients with SCNC were enrolled (10 evaluable, 6 in active treatment): at the 7/08/21 data extract, 9 of the evaluable patients had prior chemotherapy and a median of 2 prior lines of therapy (range 1-4); 33% have bone only disease. Median follow-up duration is 9 weeks (range 1-27)/ 3 cycles. Although follow-up was short, anti-tumor activity was observed. 3/ 10 evaluable patients showed responses—1 RECIST-defined confirmed PR + 1 unconfirmed PR (both 18 weeks/ 6 cycles) + 1 CTC conversion—amounting to a 30% Composite Response rate, meeting protocol-defined expansion criteria from stage 1 to stage 2. BXCL701 + pembrolizumab demonstrated acceptable tolerability without evidence of increased immune-related AEs compared to historic controls with checkpoint inhibitors. AEs consistent with cytokine activation were observed (hypotension, fever, fatigue). Conclusions: Oral BXCL701 in combination with pembrolizumab demonstrates encouraging anti-tumor activity in very late-line, refractory mCRPC SCNC for which there is currently no standard of care. BXCL701 BID dosing continues to demonstrate an acceptable safety profile. Additional interim phase 2a study results will be presented. Clinical trial information: NCT03910660.
Progression-free survival, PFS, depending on the site of lymph-node metastases in patients after salvage lymph node dissection, sLAD, in lymph node only recurrent prostate cancer.
Authors: Pfister David , Nestler Tim , Haidl Friederike , Paffenholz Pia , Hartmann Florian , Heidenreich Axel
Published: February 2022

131

Background: To analyze the influence of anatomic site in patients with lymph node only recurrent disease in 68Ga-PSMA-PET. Methods: We retrospectively analyzed PFS after salvage lymph node dissection in 98 patients. Patients were stratified to Group 1 advanced (retroperitoneal) (=9), Group 2 atypical (pararectal, presacral)(n=5), Group 3 typical (A iliaca externa, interna, Fossa obturator, A iliaca communis) (n=74) and Group 4 multifocal (combination of all groups)(n=10) recurrence. There were no statistically significant differences in the four patient groups in preoperative clinical parameters. Results: The most obvious PSA reduction after sLAD could have been demonstrated in patients with atypically located lymph node metastases (3.6ng/ml to 0.25ng/ml) although this did not reach statistic significance. Patients in the advanced group showed stable PSA values (3,55ng/ml to 3.26ng/ml). Significant results are seen in Group3 (2,52ng/ml to 1,7ng/ml)(p=0.01). Even patients with multifocal disease had a significant decrease in PSA (3.24ng/ml to 1.41ng/ml). 6- and 12 months PFS for Group 1-4 was 41.7% and 13.9%, 60% and 40%, 52.7% and 25.7% and 60% and 40% respectively. Conclusions: SLAD is an individual treatment approach for patients with lymph node only recurrent disease after radical prostatectomy and or radiotherapy. In our preliminary results we could not demonstrate a significant difference in early oncologic results in the four patient groups. Nevertheless, there might be an influence by patient numbers in the different groups so that a validation in a larger cohort is recommended.
A microRNA-based classifier for identification of neuroendocrine differentiation in metastatic castration-resistant prostate cancer.
Authors: Saini Sharanjot , Bhagirath Divya , Patel Nikhil , Sharma Ashok , Lee Tae Jin
Published: February 2022

149

Background: Therapy-induced neuroendocrine prostate cancer (NEPC) is an extremely aggressive variant of castration-resistant prostate cancer (CRPC) that is increasing in incidence with the widespread use of second generation of androgen receptor (AR)-pathway inhibitors (APIs) such as enzalutamide (ENZ) and abiraterone. This aggressive variant arises from CRPC-Adenocarcinomas (CRPC-Adeno) via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED) wherein cells undergo a lineage switch and exhibit neuroendocrine (NE) features, characterized by expression of neuronal markers such as enolase 2 (ENO2), chromogranin A (CHGA) and synaptophysin (SYP). Currently, histopathological assessment combined with immunohistochemical detection in PCa tissues/serum levels of neuronal markers including SYP, NSE, CHGA and CD56 is currently used to monitor NED in CRPC patients. However, these markers are not sufficiently specific, highlighting the urgent need of novel molecular markers to assess emergence of NED in CRPC patients. Recently, we demonstrated that progression of advanced CRPC with adenocarcinoma characteristics to CRPC-NE is associated with a characteristic set of miRNA alterations that promote plasticity of advanced PCa to NEPC (Bhagirath et al., Oncogene, 2020). Importantly, we could develop a ‘novel miRNA classifier’ to robustly stratify CRPC-NE tumors from CRPC-Adenocarcinomas. Here we further validate the classifier in independent clinical cohorts and deduce the optimal miRNA genes required for NEPC diagnosis. Methods: Human clinical samples with corresponding clinical information were procured from two independent sites of Prostate Cancer Biorepository Network (PCBN). FFPE sections from clinical samples were microdissected, RNA were extracted and small RNA sequencing was performed using an Illumina NextSeq 500 platform. Sequencing data were analyzed and machine learning algorithms were applied. The performance of classifier was measured using receiver operating characteristic (ROC) analysis with area under the curve (AUC) as the primary evaluation metric. Results: Unsupervised analysis of sequencing data by principal component analyses (PCA) revealed distinct clustering of the CRPC-NE tumors from CRPC-Adenocarcinomas based on miRNA profiles suggesting that miRNA profiles can be used to stratify these tumor types. We applied the ‘43-miRNA classifier data’ we deduced earlier to these validation cohorts. Our analyses showed that a set of 5 miRNAs of the classifier are important in distinguishing between CRPC-Adeno vs CRPC-NE with an AUC=0.8318. Conclusions: A ‘5- miRNA’ classifier was validated to be of significance in two independent validation cohorts. We propose this miRNA classifier as an important tool for diagnosing NED in CRPC patients.
Interrelation of functional homologous recombination deficiency and hrr pathway alterations in prostate cancer.
Authors: Zhu Jason , El-Refai Sherif Mohamed , Mauer Elizabeth , Leibowitz Benjamin D. , Brown Landon Carter , Grigg Claud , Kearns James T , Matulay Justin T. , Clark Peter E , Raghavan Derek , Burgess Earle F
Published: February 2022

151

Background: The use of PARP inhibitors (PARPi) may trigger synthetic lethality of tumor cells in the context of deficient homologous recombination repair (HRR). Approximately 10-20% of patients with prostate cancer harbor mutations in the HRR pathway, but HRR-associated mutations do not consistently predict the response to PARPi. Considering alternative methods to define Homologous Recombination Deficiency (HRD)—the inability to repair double strand breaks—may aid in identifying additional tumors that are sensitive to PARPi. Here, we evaluate the relationship between HRD status and HRR mutations amongst a large cohort of patients with prostate cancer. Methods: Retrospective analysis of 1,022 de-identified patients with prostate cancer that underwent next generation sequencing (NGS) with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, whole-exome capture RNA-seq) was performed. Comparison groups were defined based on HRR alterations—either mono- or bi-allelic alterations of BRCA1 or BRCA2 ( BRCA1/2), ATM, or other HRR pathway genes. HRD status was determined via the Tempus RNA-based HRD algorithm. Results: Among this cohort, mono (-/+) or biallelic (-/-) alterations of HRR genes were found in 432 patients: BRCA1/2 -/- (n = 31), BRCA1/2 -/+ (n = 87), ATM-/- (n = 24), ATM-/+ (n = 67), other HRR-/- (n = 54), other HRR-/+ (n = 169) or no HRR alterations (n = 590). The BRCA1/2-/- group had a higher frequency of Asians (17% vs. < 7% in all other groups) and were diagnosed at younger ages (median 62 years vs. > 65 for all other groups). We identified 130/1022 (13%) patients with prostate cancer to be HRD-positive (HRD+) and observed significant differences in HRD positivity according to the type of HRR alteration observed (Table). Notably, 54% (70/130) of HRD+ patients had no mutations in any genes associated with the HRR pathway. Conversely, 89% (278/314) of patients with non- BRCA1/2 HRR mutations were HRD negative. Amongst all individuals with biallelic loss of any HRR gene, HRD positivity was most enriched for BRCA2-/- (16/29, p < 0.001) and PALB2-/- (3/4, p = 0.082). Conclusions: By using an RNA-based HRD algorithm, we found 13% of patients with prostate cancer are HRD+. This RNA-based HRD signature not only captures patients with HRR mutations but also identifies a substantial population of HRD+ patients who are currently undetectable by methods based solely on sequencing HRR genes. Further research is needed to assess the clinical response to PARPi in this HRD+ population, as well as the response to PARPi in the HRD negative population who harbor HRR gene alterations.[Table: see text]
Prognostic and predictive utility of DNA damage response (DDR) aberrations detected in cell-free DNA (cfDNA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Fettke Heidi , Hauser Christine , Kwan Edmond Michael , Dai Chao , Zheng Tiantian , Wang Amy , Tan Winston , Du Pan , Ng Nicole , Bukczynska Patricia , Foroughi Siavash , Graham Lisa-Jane K. , Horvath Lisa , Mahon Kate Lynette , Jia Shidong , Kohli Manish , Azad Arun
Published: February 2022

153

Background: The prognostic significance of DDR alterations in mCRPC remains unclear, with conflicting data from prior reports. Whether DDR alterations are predictive of outcomes with therapeutic agents other than PARP inhibitors in mCRPC is also poorly understood. With increasing use of molecular profiling in mCRPC, understanding the full prognostic and predictive utility of plasma DDR alterations is paramount. Methods: A next-generation sequencing Predicine liquid biopsy assay was used to profile cfDNA and germline DNA in 407 mCRPC patients (pts) from two independent international cohorts (n=162 Australia, n=245 US). DDR genes profiled were BRCA2, ATM, BRCA1, MLH1 and MSH2. Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between DDR alterations and clinical outcomes including PSA response rate (PSA RR), progression-free survival and overall survival (OS). Results: Median age was 74 (IQR 67-79), with median follow up 74 months and median OS 23 months. 65/407 (16%) harboured pathogenic DDR alterations, including 21 patients with ³1 alteration. Frequency of genomic aberrations are shown in the table. BRCA2 alterations were further classified as heterozygous loss (66%), homozygous loss (14%), monoallelic mutation (11%) and biallelic mutation/loss of heterozygosity (9%). Aberrations in any DDR gene, ATM, MLH1 + MSH2 or BRCA2 were associated with shorter OS on univariable analysis, but only any DDR or BRCA2 aberration remained significant upon adjusting for clinical prognosticators and ctDNA fraction (Table). Pre-treatment BRCA2 aberration was associated with significantly shorter OS and lower PSA RR compared to BRCA2 wt for pts receiving an AR pathway inhibitor (ARPI) (18 vs 32 months, p=0.006; 36 vs 60%, p=0.04 respectively) but not for taxane chemotherapy (17 vs 20 months, p=0.3; 45 vs 66, p=0.1 respectively). Conclusions: Detection of an aberration in any DDR gene or BRCA2 was an independent poor prognostic factor across 2 large independent cohorts of mCRPC patients. Intriguingly, patients with a BRCA2 alteration appeared to have worse outcomes with ARPI but not chemotherapy, suggesting predictive utility of DDR profiling. Our data collectively speak to the potential role of DDR alterations, in particular BRCA2, as prognostic and/ or predictive biomarkers in mCRPC.[Table: see text]
Effect of androgen receptor directed therapy in prostate cancer patients with COVID-19.
Authors: Unlu Serhan , Shin Junghee Jenny , Par-Young Jennefer , Vinetz Joseph , Petrylak Daniel P. , Kang Insoo , Kim Joseph W.
Published: February 2022

161

Background: TMPRSS2 is one of the two key enzymes that SARS-CoV-2 requires for its entry to the cell. TMPRSS2 is regulated by androgen receptor. It is well described Androgen Receptor Directed Therapy (ARDT) downregulates the expression of TMPRSS2. We hypothesized that the ARDT has a protective role in patients with prostate cancer (PCa) from poor outcome of COVID-19. Methods: A retrospective chart review of PCa patients with COVID-19 between March to October 2020 in the Yale-New Haven Health System was performed. Demographics, comorbidities, home medications, laboratory data, treatment, and clinical outcomes of COVID-19 were collected. ARDT was defined as the use of GnRH agonist, GnRH antagonist, or androgen receptor antagonist. This study was reviewed and approved by the Institutional Review Boards of Yale University. Results: A total of 146 (1.1%) prostate cancer cases were identified from the 13,642 cases of COVID-19. The clinical characteristics are summarized in the table. Twenty-five (17%) were on active ARDT and 121 (83%) not on ARDT (non-ARDT). The rates of hospitalization were the same: 52%, between the ARDT and non-ARDT group. Of those admitted, mean duration of hospitalization were 9.2 days (Range 1-25) and 14.9 days (Range: 2-47) in ARDT and non-ARDT groups, respectively (p=0.14). Rates of hospital stay >30 days were 0% versus 14.3% (9/63) in ARDT and non-ARDT groups, respectively (p=0.15). Intubation rates were 0% versus 11% (7/63) for ARDT and non-ARDT groups, respectively (p=0.21). Mortality rates were 8% and 13.2%, in ARDT and non-ARDT groups, respectively (p=0.47). Conclusions: The prevalence of PCa was infrequent. Despite advanced stage of the cancer in ARDT group, there was a trend toward decreased severity of COVID-19 and mortality rates compared to non-ARDT group. Our data support further investigation on a protective role of hormone therapy in PCa patients with COVID-19.[Table: see text]
Immune profiling of advanced prostate cancer harboring homologous recombination deficiency.
Authors: Soleimani Maryam , Kung Sonia H.Y. , Saxena Neetu , Thi Marisa , Fazli Ladan , Nappi Lucia
Published: February 2022

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Background: Most patients with metastatic prostate cancer (mPCa) do not derive benefit from immune checkpoint inhibitors (ICI). Homologous recombination deficiency (HRD) affects up to 30% of patients with metastatic castrate-resistant prostate cancer (mCRPC) and is predictive of response to PARP inhibitors. The potential activity of ICI in this subset of patients is unknown and the tumour microenvironment (TME) associated with HRD is poorly understood. We used mPCa tumours of patients with known HRD alterations as a model to study clinically relevant, therapeutically targetable drivers of tumour immunology. Methods: Archival tumor tissue of patients with known germline or somatic HRD alterations enrolled in our institutional GU Biobank (n = 13) was used for immunohistochemistry to evaluate the expression of the following immune markers in both tumour cells (TC) and stromal lymphocytes (SL): CD8, adenosine receptor 2a (A2aR), GAL9, IL-2, LAG3, PD-L2, and TIM-3. The same markers were analyzed in untreated (n = 104), and neoadjuvant hormone therapy treated (NHT) (n = 16) tissue. Two-tailed t-test and Pearson R correlations were performed for analysis. Results: Among screened HRD alterations, BRCA1/2 were the most frequently identified ( BRCA1/2 n = 6, FANCC n = 1, FANCD2 n = 2, PALB2 n = 1, CDK12 n = 1, ATR n = 2). CD8+ cells were primarily localized in the stroma of HRD cohort specimens rather than in the glandular epithelia. The HRD cohort had higher levels of A2aR, in TC and SL (p≤0.0001 for both). When compared to the untreated cohort, PD-L2 levels were higher in SL of the HRD cohort (p≤0.05) while lower in the TC (p≤0.01). Lower levels of LAG3 were found in the HRD cohort TC compared to NHT cohort (p≤0.01). There were significantly lower levels of GAL9 in the TC of the HRD cohort compared to untreated (p < 0.0001) tumours. There were no differences in TIM-3 levels between the cohorts. Conclusions: Evaluation of stromal and tumour cell immune profiling indicates that compared to other subtypes, mPCa with HRD alteration have a unique immune profile abundant in CD8+ cell, and high in PD-L2 and A2aR expression. Not only does this indicate an immune active TME but also identifies therapeutically actionable pathways which may render clinical benefit in this patient population.
Correlation of ABI1 and PTEN expression during prostate tumor progression.
Authors: Kotula Leszek , Hryniewicz-Jankowska Anita , Li Xiang , Augoff Katarzyna , Papp Csaba , Das Disharee , Kung Sonia H.Y. , Fazli Ladan , Jasmaspishvili Tamara , Berman David Monty , Zhang Fan , Porter Baylee , Sikorski Aleksander , Gleave Martin , Kuznetsov Vladimir , Bratslavsky Gennady
Published: February 2022

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Background: Mechanisms of tumor invasion are not well defined. PTEN, a key tumor suppressor frequently inactivated in epithelial cancers, acts as a central node that controls tumor invasion. Despite PI-3 kinase-phospho-Akt pathway activation resulting in enhanced tumor growth, prostate tumors with PTEN loss undergo p53-mediated senescence that restricts tumor invasion. Methods: ABI1 downregulation is associated with epithelial-mesenchymal transition in highly invasive prostate tumors; these tumors frequently loose PTEN; therefore we set to examine genetic interaction of ABI1 and PTEN using novel mouse model of prostate cancer. We analyzed the correlation of ABI1 and PTEN expression in human PCa tumor tissue. Results: Here, using Abi1/Pten KO mouse model we identified a novel mechanism that guards tumor invasion. In Pten-null tumors upregulation of Abi1 leads to sequestration of activated Src kinase. In the absence of Abi1, this regulation is lost leading to activation of non-canonical WNT-SRC-STAT3 axis and enhanced invasion through activation of MMP2 activity. This molecular mechanism explains progression of tumors with Pten loss from PIN to invasive carcinoma upon concomitant Abi1 inactivation. In human tumors with low Abi1 and Pten are associated with aggressive phenotype, biochemical recurrence and metastasis. Conclusions: ABI1 acts as failsafe mechanism in PTEN null tumors by restricting SRC-mediated tumor invasion. ABI1 might have a predictive value in clinical setting in context of PTEN levels.
Circulating tumor DNA responses to high-dose testosterone injections in CRPC patients.
Authors: Caputo Sydney , Jaeger Ellen B. , Fleming William , Manogue Charlotte , Huang Minqi , Lieberman Alex , Light Malcolm , Sussman Isabelle P. , Miller Patrick , Barata Pedro C. , Lewis Brian E. , Layton Jodi Lyn , Ledet Elisa M. , Sartor A. Oliver
Published: February 2022

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Background: Some proportion of men with CRPC have favorable responses to high doses of testosterone (HDT) and some do not. Genomic determinants of these responders and non-responders are poorly understood. Herein ctDNA predictors of response are assessed using a responder/non-responder analysis. Methods: All men with CRPC had been pretreated with abiraterone, enzalutamide, or both. A ctDNA test was obtained prior to high doses of testosterone (administered as a dose of 400 mg IM testosterone cypionate every 3-4 weeks). Guardant 360 was used to analyze ctDNA (with an allelic fraction cut-off of > 0.5%) to ascertain the presence or absence of pathogenic mutations. Lower allelic fractions were not analyzed. Responders had a PSA decline of 50% or more (N = 16), non-responders received at least two doses of testosterone but never had any PSA decline at all (N = 20). All patients were treated at Tulane Cancer Center. Results: AR amplifications were more commonly detected (p = 0.036) pre-treatment in the ctDNA of responders (5/16) as compared to non-responders (1/20). No differences were found in those with common AR mutations; T878A was detected in 2/16 responders and 2/20 non-responders, L702H was detected in 1/16 responders and 2/20 non-responders. No differences were seen with regard to TP53 mutations, 6/20 non-responders and 7/16 responders. Non- AR/non- TP53 mutations were not distinct in the two groups but trended (P = 0.15) toward being more common in non-responders (5/16 in responders versus 11/20 non-responders). Pre- and post- ctDNA analyses were conducted in 5/6 patients for those with AR amplification at baseline. In all 5 of these patients, the degree of AR amplification diminished after testosterone injections. Conclusions: In this analysis of CRPC patients who were responders and non-responders to 400 mg testosterone cypionate q 3-4 weeks (post-abiraterone and/or enzalutamide), only AR amplifications in ctDNA were predictive of response. In all measured patients, the degree of AR amplification in the ctDNA diminished after testosterone injections.
Analysis of the role of PI3K-AKT and DNA damage repair (DDR) genomic biomarkers as predictors of clinical outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Gagnon Richard , El Hallani Soufiane , Lee-Ying Richard M. , Kolinsky Michael Paul , Khalaf Daniel Joseph , Cook Sarah , Vasquez Catalina , Samuel Divya , Lewis John D , Faridi Rehan , Borkar Minal , Heng Daniel Yick Chin , Alimohamed Nimira S. , Ruether Joseph D. , Gotto Geoffrey , Fairey Adrian S. , Bismar Tarek A. , Yip Steven
Published: February 2022

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Background: Clinically relevant outcomes in nmCRPC treated with androgen receptor-axis-targeted therapies (ARAT) may be inferior in patients with tumors harboring mutations bypassing androgen receptor signalling. This final update of a retrospective, multicenter analysis explores the association between genomic mutations in the PI3K-AKT and DDR signalling pathways with ARAT treatment outcomes in nmCRPC patients. Methods: Relevant clinical endpoint were collected for high-risk nmCRPC patients treated with an ARAT at APCaRI affiliated cancer centers, including median metastasis-free survival (MFS), overall survival (OS), PSA decline ≥ 50% (PSA50), and second progression free survival (PFS2). Archival tumor tissue was accessed for next generation gene sequencing, examining for genomic alterations in 500 genes, including those involved in the DDR and the PI3K-AKT signalling pathways. Comparison of outcomes of patients with DDR and PI3K-AKT pathway mutations was conducted using Cox proportional hazards regression using wildtype cases as the reference group, adjusting for PSA doubling time and pelvic lymphadenopathy. Results: Of the 37 patients included, 30 (82%) received apalutamide, 5 (13%) received darolutamide, and 2 (6%) received enzalutamide. 10 patients (27%) had PI3K-AKT pathway mutations (4 PTEN, 3 PIK3Ca, 2 PIK3C2G, 1 PIK3C2b), 8 patients (22%) had DDR gene mutations (3 ATM, 2 CHEK1, 1 BRCA2, 1 CDK12, 1 CHEK2, 1 FANCD2, 1 FANCL), and 1 patient (3%) had 2 MLH1 mutations (microsatellite instability). Of those who had subsequent treatment, 1 received enzalutamide and 5 received abiraterone. Patients with PI3K-AKT pathway mutations had significantly shorter MFS (4.8 mo; HR 4.2; 95% CI 1.2 – 15.0; p = 0.025). Those with DDR mutations had a trend towards shorter MFS (23.3 mo HR 3.7; 95% CI 0.71 – 13.4; p = 0.134). OS data remains immature. 4 (11%) patients did not achieve PSA50, including a patient with 2 MLH1 mutations. Conclusions: This final analysis demonstrates that nmCRPC with PI3K and DDR signalling pathway mutations have poor clinical outcomes when treated with ARAT, likely secondary to decreased reliance on the androgen receptor signalling pathway. These results highlight the potential value of exploring targeted therapies, such as PARP or AKT inhibitors in patients with these mutations.
Patient derived tumor xenograft study with CDK4/6 inhibitor plus AKT inhibitor for management of metastatic castrate resistant prostate cancer.
Authors: Kase Adam McLain , Tan Winston , Gleba Justyna , Miller James , Meurice Nathalie , Petit Joachim , Copland John A.
Published: February 2022

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Background: Despite androgen deprivation therapy, prostate cancer will develop resistance known as castrate resistant prostate cancer (CRPC). Androgen signaling is associated with pathways that influence cell proliferation and survival via cell cycle regulation. AR signaling results in inactivation of Rb tumor suppressor by way of AKT and reduction in intrinsic CDK4/6 inhibitors. Since PTEN loss is found in 40% of mCRPC and AKT pathway is a mechanism of CDK4/6 inhibitor resistance, we hypothesize adding an AKT inhibitor to a CDK4/6 inhibitor will have synergistic activity while delaying CDK4/6 inhibitor resistance. Preclinical xenografts have been shown to recapitulate patient response, therefore, can be used to guide clinical trials using novel combinations. Methods: We have established patient derived tumor xenograft models (GUR-017M, TMA-027 and PRJ-88T) from patients with mCRPC with each having a unique genomic alteration profile. In the clinical setting, GUR-017M was resistant to abiraterone, enzalutamide, cabazitaxel and had exposure to docetaxel. TMA-027 and PRJ-88T were resistant to enzalutamide. We combined a CDK4/6 inhibitor with an AKT inhibitor and treated each of these patient tumors in NOD-SCID mice for a total duration of 40 days. Mice were implanted and separated into 4 groups (placebo, CDK4/6 inhibitor, AKT inhibitor and CDK4/6 + AKT inhibitor) with 10-13 mice in each group. Tumor volumes were measured twice a week. For GUR-017M, abemaciclib (50 mg/kg) was combined with MK2206 (120 mg/kg) and was compared to each placebo and each single agent alone. For TMA-027, palbociclib (50 mg/kg) was combined with ipatasertib (50 mg/kg). After 40 days, tumors were harvested for immunohistochemistry analysis. PRJ-88T was grown as 3D spheroids in ultra-low attachment plates and treated with palbociclib + ipatasertib (10 uM-100uM) to evaluate for synergy. Results: GUR-017M and TMA-027 showed significant delayed tumor growth compared to placebo or either single agent alone. In the GUR-017M group, the final mean tumor volume for the combination group was 149 mm3, compared to 377 mm3 (abemaciclib), 358 mm3 (MK2206) and 527 mm3 placebo group, representing a percent decrease compared to control by 72%, 29%, and 32%, respectively. For TMA-027, the final mean tumor volume for the combination group was 102 mm3, compared to 259 mm3 (palbociclib), 416 mm3 (ipatasertib), and 402 mm3 placebo group, representing a percent decrease compared to control by 75%, 36%, and 4%, respectively. PRJ-88T 3D spheroids showed synergy with palbociclib + ipatasertib. In vivo experiments using PRJ-88T are in progress. Conclusions: The preclinical results show combining CDK4/6 inhibitors with AKT inhibitors is a promising treatment strategy and provides the basis for a clinical trial in patients with mCRPC.