bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of poly (adp-ribose) polymerase inhibitors (PARPi) in metastatic castration resistant prostate cancer (mCRPC) patients stratified by homologous recombination repair mutations.
Authors: Thomas Roby Antony , Vasudevan Anupama , Blanc Simon , Choksi Rushir J. , English Sandy , Aton Lindsay , Tierno Marni Brisson , Gart Mike
Published: June 2023

e17053

Background: Approval of the PARPi in May 2020 caused a paradigm shift in the treatment of mCRPC patients with homologous recombination repair (HRR) mutations. Gaps remain in the optimal prescribing of PARPi in eligible patients, with negative consequences on clinical outcomes. The goal of this study was to look at PARPi prescribing practices in patients with HRR mutations overall and by sub-mutation. Methods: The Integra Connect PQ-deidentified real-world database was used, comprising over 1 million cancer patients across 275 sites of care, of which 80% were community practices and 20% academic settings. We performed medical chart reviews and identified 261 patients with HRRm mCRPC that received therapy between 5/1/2020 to 1/24/2023. We segmented patients into BRCA-positive with or without other HRR mutations, ATM positive without BRCA mutations and with or without other HRR mutations, and other HRR mutations without BRCA or ATM mutations. We compared utilization of PARPi in HRRm patients by sub-group. Descriptive statistics were used to assess proportions of utilization of PARPi treatment among HRRm patients. Proportions were compared using the two-proportion z-test. Results: Among HRRm mCRPC patients with prior next-generation hormonal agent (NHA) treatment, the use of PARPi is 61% (158 of 261). Among HRRm mCRPC patients who received PARPi after prior NHA treatment, 76% (78 of 103) were in the BRCA positive group, 62% (48 of 78) in the ATM positive group and 40% (32 of 80) in the other HRR mutations positive group. Patients in the BRCA positive group were more likely to receive a PARPi than those in either the ATM or other HRR mutations group (p < 0.01). Patients harboring ATM mutations were more likely to receive a PARPi than patients with non-BRCA HRR mutations (p < 0.01). Conclusions: This real-world study shows an opportunity to increase rates of PARPi treatment in patients with HRRm mCRPC across all HRR gene mutations. mCRPC patients with BRCA and ATM mutations were more likely to receive PARPi than those with other HRR mutations.
The association between antibiotics administration and outcomes in men with chemotherapy-naive metastatic castration-resistant prostate cancer: Secondary analysis of two randomized clinical trials.
Authors: Ni Xudong , Wei Yu , Ye Ding-Wei , Zhu Yao
Published: June 2023

e17054

Background: The associations of antibiotics with overall survival (OS) and radiographic progression-free survival (rPFS) in trials in chemotherapy-naive metastatic castration-resistant prostate cancer remain unclear. Methods: COU-AA-302 (NCT00887198, n = 1088) and ACIS (NCT02257736, n = 982) patients were stratified by antibiotics administration. Since there was evidence of a threshold phenomenon, the association of duration of antibiotics administration and OS was assessed using a segmented linear regression model. Kaplan–Meier survival analysis was used to compare OS and rPFS. Hazard ratios were calculated using a multivariable Cox proportional-hazard model. Results: Using segmented linear regression models, we selected ≥30 days as the threshold for antibiotics administration in clinical trials. In COU-AA-302 Abiraterone + Prednisone (AAP) subgroup, antibiotics administration was associated with prolonged OS (50.4 vs. 33.8 months, HR0.57, 95%CI 0.38–0.84, P = 0.004) and prolonged rPFS (27.7 vs. 12.8 months, P = 0.0095). In COU-AA-302 Placebo + Prednisone (PLA) subgroup, antibiotics administration was also associated with prolonged OS (50.4 vs. 29.0 months, HR0.41, 95%CI 0.26–0.63, P < 0.001) and prolonged rPFS (16.46 vs. 5.72 months, P < 0.001). Antibiotics administration also improved patients’ outcomes in ACIS. In ACIS Apalutamide + Abiraterone + Prednisolone (AAAP) subgroup, antibiotics administration was associated with prolonged OS (43.3 vs. 27.3 months, HR0.68, 95%CI 0.54–0.85, P < 0.001) and prolonged rPFS (30.5 vs. 18.2 months, P < 0.001). In ACIS Placebo + Abiraterone + Prednisolone (PAAP) subgroup, antibiotics administration was also associated with prolonged OS (45.4 vs. 30.2 months, HR0.62, 95%CI 0.50–0.78, P < 0.001) and prolonged rPFS (23.4 vs. 13.4 months, P < 0.001). Conclusions: Within the limitations of post-hoc sub-analyses, antibiotics administration is associated with prolonged OS and rPFS in men with chemotherapy-naive metastatic castration-resistant prostate cancer. Further pharmacological researches and prospective clinical trials are needed to increase the indications for these drugs to benefit prostate cancer patients.
Tolerability of lutetium-177–PSMA-617 in men with prostate cancer and baseline cytopenia.
Authors: Abdelrazek Ahmad S , Mahmoud Ahmed , Johnson Geoffrey , Johnson Derek R , Bach Corrie R , Orme Jacob , Rodrigo Rodrigues Pessoa , Nabavizadeh Reza , Thorpe Matthew , Kwon Eugene D. , Kendi Ayse T. , Childs Daniel S
Published: June 2023

e17057

Background: Results from the VISION trial (NCT03511664) led to the approval of lutetium-177 (177Lu)–PSMA-617 for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This trial excluded patients with baseline cytopenias, thus safety in this frequently encountered patient population is unknown. We aimed to use real-world data to describe the tolerability of radioligand therapy in those with poorer bone marrow reserve. Methods: We retrospectively reviewed the records of all patients, who received a first dose of 177Lu–PSMA-617 at Mayo Clinic in the interval of April 26, 2022, to December 1, 2022. Patients were categorized as having poor marrow reserve on the basis of pre-treatment hematologic parameters, including: (1) an anemia cohort with hemoglobin (Hg) less than 9 g/dL, (2) a thrombocytopenia cohort with platelets (Plt) less than 100 x 109/L, (3) a leukopenia cohort with white blood cell count (WBC) less than 2.5 x 109/L, and (4) a multiple cytopenia cohort. These were exclusionary parameters from the VISION trial. Longitudinal laboratory data and clinical outcomes were collected and analyzed using descriptive statistics. Results: At data cutoff, 185 patients had received one or more doses of 177Lu, including 26 (14%) with at least one baseline cytopenia prior to their first cycle of treatment. In total, there were 19 (73%) patients with anemia, 3 (12%) with thrombocytopenia, 2 (8%) with leukopenia, and 2 (8%) with multiple cytopenias at baseline. The median number of cycles received thus far is 3, including 14 (54%) who are still receiving therapy and 12 (46%) who have permanently discontinued treatment. Median longitudinal changes in blood counts for the anemia cohort are presented in Table 1. Reasons for treatment discontinuation include: toxicity (n = 2), disease progression (n = 5), death (n = 4), or other (n = 1). Dose reductions or treatment delays for worsening myelosuppression were utilized in 3 (12%) and 5 (19%) patients, respectively. Transfusions of packed red blood cells or platelets were required for 16 (62%) patients. A total of 6 (23%) received care in the emergency department or were hospitalized. Conclusions: Treatment discontinuation for toxicity was rare among men with mCRPC and baseline cytopenias, while receiving 177Lu; however, these patients have an overall poor prognosis. [Table: see text]
The expression of PKM1 and PKM2 in benign and cancerous prostatic tissues.
Authors: Li Lin , Cheng Siyuan , Yu Xiuping
Published: June 2023

e17058

Background: Prostate cancer (PCa) is the most diagnosed cancers in American men. After androgen deprivation therapy (ADT) fails, there is an increase in the aggressive neuroendocrine (NE) phenotype. Currently, there is no effective treatment for NE prostate cancer (NEPC). The metabolic reprogramming, one of the cancer hallmarks, regulates PCa progression and therapy resistance. However, the energy metabolism in NEPC has not been well studied yet. Pyruvate kinase (PK), catalyzing the final step of glycolysis, has PKM1, PKM2, PKL and PKR four isoforms. PKL and PKR are expressed in the liver and erythrocytes, respectively. Alternative splicing of PKM results in two isoforms, PKM1 and PKM2, which are expressed in most tissues. In prostate adenocarcinoma, loss of PKM1 promotes PCa progression whereas loss of PKM2 suppresses tumor growth. However, the expression pattern of PKM1 and PKM2 in NEPCa remains largely unknown. Methods: Immunofluorescence (IF), immunohistochemistry (IHC), Western blot and RT-qPCR were conducted to examine the expression of PKM1 and PKM2 in both murine and human prostatic tissues. The bioinformatics analysis was done using the publicly available RNA-Seq data obtained from the cBioportal, the Cancer Genome Atlas (TCGA), and the Cancer Cell Line Encyclopedia websites (CCLE). Results: TRAMP is a widely used PCa mouse model. TRAMP mice develop prostatic intraepithelial neoplasia (PIN) and the tumors progress into NEPC following castration. We found that PKM1 expression was detected in normal prostate but not in the PIN lesions. In the TRAMP NEPC tumors, PKM1 expression was detected in the NE areas but not in the adjacent PIN lesions. Compared with the adjacent PIN, NEPC cells displayed lower PKM2 expression. Further, we examined the expression of PKM1 and PKM2 in human prostatic tissues including benign prostatic hyperplasia (BPH), low-grade adenocarcinomas (AdPCa), high-grade AdPCa, and NEPC. We found that in BPH, basal epithelial cells express both PKM1 and PKM2. In PCa, PKM1 was robustly expressed in the stromal cells but its expression was absent in the cancer cells in majority of the specimens examined except a small number of samples where low level of PKM1 was detected in the cancer cells. However, PKM1 expression was detected in 9 out of 12 NEPC samples and colocalized with NE marker chromogranin A. This co-expression was also detected in the NE cells scattered on the prostate adenocarcinoma tissues. As for PKM2, its expression was detected in all the samples examined. However, different from previous report, PKM2 expression levels did not correlate with cancer grade in this cohort. Conclusions: PKM1 is expressed in the basal epithelial cells of benign prostates, a small subset of prostate adenocarcinomas, and 75% NEPC tumors. PKM2 is expressed throughout prostate development, in both benign and cancerous prostate. However, PKM2 expression does not correlate with tumor grade.
Racial and income characteristics and the burden of illness among metastatic prostate cancer patients.
Authors: Poolakkad Sankaran Satheesh kumar , Epstein Joel Brian , Adjei Boakye Eric , Alam Naheed , Pili Roberto
Published: June 2023

e17064

Background: The incidence of metastatic prostate cancer has increased dramatically between 2010 and 2017 in the United States. Since the racial and ethnic mix of the population of the United States (U.S.) have changed between the years 2010 and 2020–it is extremely important to understand its effects on prostate cancer outcomes. Therefore, we investigated the burden of illness across racial groups and income levels among patients diagnosed with metastatic prostate cancer. Methods: This study utilized the U.S. 2017 National Inpatient Sample database to identify hospitalizations with a primary diagnosis of prostate cancers. We evaluated associations between race and income levels, and the burden of illness (total charges and length of stay (LOS)) adjusting for patient and clinical factors with multivariable generalized linear models. Results: A total of 63,880 metastatic prostate cancer patients were included in the study, and the median [IQR] age was 74 [66, 82]. There were 65.6% Whites, 20.6% Blacks, 7.7% Hispanics, and 6.1% Asians and Others. Blacks had a higher prevalence in the age group 45-55 (34.2%), when compared to 55-64 (29.8%), or > 65 (17.6%) age group. There were only 10% Blacks and 4.9% Hispanics living in high-income neighborhoods, whereas this was 75.5% for Whites. In the adjusted analysis, compared to the Whites, Hispanics (1.43; 95%CI-1.29- 1.57), and Asians and Others (1.39; 95%CI- 1.25- 1.56) had a higher total charge; and compared to Whites, Blacks had a higher LOS (1.28; 95%CI-1.15-1.44). Compared to high-income neighborhoods, those living in the 26th to 50th percentile had a lower total charge (0.86; 95%CI- 0.78-0.94). Compared to the > 65 years age group, the 44-55 age group had a lower total charge (0.73; 95%CI-0.61-0.89). Compared to patients with Medicare, those with Private Insurance (0.87; 95%CI- 0.80-0.94) and Self-pay and Others (0.73; 95C%CI-0.62–0.86) had a lower total charge. And when compared to non-elective admissions, elective admissions had a higher total charge (1.44; 95%CI-1.29- 1.59). Conclusions: Hispanics and Asians and Others had a higher burden of illness, and Blacks had a higher LOS. Patients who reside in lower income neighborhoods had lower total charges. Understanding prostate cancer outcomes by race and income is crucial to designing strategies to improve access to care.
Personalized precision combination therapies based on potential actionability and coalterations and therapeutic opportunities for CDK12-mutated prostate cancer.
Authors: Li Hong Zheng , Wang Haitao
Published: June 2023

e17068

Background: Translational studies have reported that CDK12 aberrations in metastatic castration-resistant prostate cancer (mCRPC) are related to homologous recombination (HR) deficiency and focal tandem duplications(FTDs), characterized by gene fusions and fusion-induced neoantigens (FINAs). In prostate cancer,CDK12 aberrations as a biomarker have been reported associated with poor prognosis, whether hormonal and taxane therapies as well as to PARP inhibitors. Herein, we aimed to molecularly, pathologically, and clinically characterize CDK12-aberrant mCRPC. Methods: Clinical data and molecular analyses are collected from the mCRPC patients treated in our center. Thirty-two patients with prostate cancer underwent soft tissue biopsy or sufficient ctDNA(Circulating Tumor DNA) for NGS and confirmed the CDK12 aberrations. Twenty-eight patients had advanced to the stage of mCRPC, and twenty-seven of them had exhausted standard treatment.All of the twenty-seven patients consented to the individualized therapiees based on NGS.PSA50 response rate and progression-free survival(PFS) are used to describe clinical features and outcomes to various individualized therapies, including sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) and PD-1/PD-L1 inhibitors monotherapy or combined with other off-label drugs. Results: Of the 32 patients with CDK12-aberrant prostate cancer, 19(59.4%) had detected biallelic CDK12 alterations. At diagnosis,17 (68%) patients' PSA≥100ng (only 26 patients retained the PSA data), 27 (93.1%) had Gleason grade group 4-5(only 29 patients retained the pathology),16(51.6%) had lymph node metastasis, 16(51.6%) had bone metastasis.13 patients received PARPi combine NHT(Novel hormone therapy) or not after NHT therapy resistance,only 1 patient PSA response reached PSA50.9 patients received PARPi combine temozolomide,2 reached PSA50,1 patient's liver metastases were significantly reduced ang reached PR.In that five patients,4 of 5 were monotherapied by PARPi.21 patients accepted PD-1/PD-L1 combined with PARPi or other off-label drugs based on the NGS or not.Four patients accepted immune monotherapy,only 1 reached PSA50. In the remaining 17 combined treatment patients, PSA50 responses were noted in 23.5%. What is noteworthy is that,4 of 16 happened HPD(hyperprogressive disease) with clinical manifestations such as rapid increase of PSA and significant decrease of ECOG score. Conclusions: CDK12-aberrant mCRPC is an aggressive subtype and have worse prognosis to PARPi. PARPi combine with temozolomide may be a effective therapeutic schedule. Along with NGS development,more therapeutic drugs are available to us to benefits for patients.But immunotherapy is questionable to CDK12-aberrant mCRPC because of the lower response rate and higher risk of HPD.
Real world data of apalutamid in the treatment of prostate cancer: Data of the German multicenter AmPel trial.
Authors: Hegele Axel , Schultheis Stefan , Skrobek Lennart , Hollwegs Sebastian , Weber Jost , Ludwig Martin , Bartsch-Polle Anke , Maywurm Manfred , Huwe Petra , Khalil Samuel , Häußermann Rainer , Thiemer Markus , Varughese Denny
Published: June 2023

e17073

Background: Apalutamide (Apa) is a competitive inhibitor of the androgen receptor binding directly to the ligand-binding domain. In metastatic castration-sensitive prostate cancer (mCSPC) as well as non-metastatic castration-resistant prostate cancer (nmCRPC) Apa demonstrated a survival benefit in Phase-III trials. Nevertheless Real World data are still lacking. Methods: In the retrospective, multicenter AmPel trial (Apalutamid in prostate cancer in middle-Hessen) data of mCSPC and nmCRPC pat were collected before and during Apa treatment in routine clinical practice. Beside pat and tumor specific data side-effects, dose-modifications, response and subsequent therapies were assessed. Results: To date 100 pat were included since 11/2021. General data are summarized in table 1. mCSPC (n = 74): mFU 10 month (1-30). 75% showed mets at initial diagnosis: 56% with osseous, 15% with viszeral and 29% with oss/visz mets. PSA before therapy 13.5 ng/ml decreased to 0.2 ng/ml (-98.9%) after 3 mo. 77.4% showed a PSA decrease > 90% and 49% a PSA level of < 0.2 ng/ml after 6 mo. AEs ≥ 3: 12.3%. In 12.3% dose reduction was necessary. In 21% therapy was stopped due to toxicity (10.9%), progression (5.5%) and patient will (5.5%). 3 patients died: 1 due to PCA progression. PFS is not reached. nmCRPC (n = 26): mFU 15 month (3-30). Time after initial diagnosis: 6 y (1-22). PSA-Doubling time 3.9 mo (1-10). PSA before therapy 7.2 ng/ml with a decrease of 94.7% after 3 mo (0.45 ng/ml) and 62.5% with a PSA decrease > 90%. AEs ≥3: 5%. In 15.4% dose-reduction was necessary. In 24% therapy was stopped due to toxicity (5%), progression (9.5%) and patient will (9.5%). MFS is not reached. No increased adverse events were observed in case of statin and anticoagulant medication. Conclusions: Compared to Phase III trials this first real-world data of the AmPel-trial showed treatment of older and more co-morbid mCSPC and nmCRPC patients in clinical practice. Apa treatment resulted in a rapid PSA-response, was safe and effective with tolerable and manageable side effects in real world unselected patients. PSMA-PET/CT is not used in daily practice as well as Conference decisions before therapy. Updated data of the ongoing AmPel trial will be presented. [Table: see text]
Darolutamide and time to pain progression by disease volume in ARASENS.
Authors: Smith Matthew Raymond , Tombal Bertrand F. , Saad Fred , Fizazi Karim , Sternberg Cora N. , Crawford E. David , Aragon-Ching Jeanny B. , Schostak Martin , Tutrone Ronald , Mohamed Ateesha F. , Littleton Natasha , Li Rui , Srinivasan Shankar , Hussain Maha H. A.
Published: June 2023

e17075

Background: In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) + docetaxel significantly reduced risk of death by 32.5% (hazard ratio [HR] 0.68, 95% confidence interval [CI[ 0.57–0.80; P< 0.0001) and significantly delayed time to pain progression (HR 0.79, 95% CI 0.66–0.95; P= 0.006) vs placebo (PBO) + ADT + docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We report time to pain progression in patients (pts) with high/low disease volume (HV/LV). Methods: Pts with mHSPC were randomized to oral DARO 600 mg twice daily or PBO, both + ADT + docetaxel. Pain was assessed by the Brief Pain Inventory short form “pain at its worst” score (WPS). Pain progression was defined as WPS increase ≥2 points from nadir (and absolute WPS ≥4 if > 0 at baseline) or initiation of opioid therapy for ≥7 consecutive days. A sensitivity analysis assessed pain progression after completion of docetaxel. HV/LV subgroups were defined per CHAARTED. Results: 1305 pts (DARO 651, PBO 654) were analyzed. At baseline, the mean WPS was 1.5 (standard deviation 1.9) vs 1.4 (1.8) in the DARO vs PBO groups; 258 (40%) vs 274 (42%) pts had no pain (WPS 0). DARO + ADT + docetaxel had a robust impact on delaying time to pain progression vs PBO + ADT + docetaxel in the post-docetaxel sensitivity analysis (stratified HR 0.75, 95% CI 0.62–0.90) and in the HV subgroup (unstratified HR 0.75, 95% CI 0.61–0.93) (Table). Overall, median time to pain progression was longer in the LV vs HV subgroup. WPS change from nadir was the main driver of pain progression events. Conclusions: In pts with mHSPC, the addition of DARO to ADT and docetaxel provided clinically meaningful benefit through delayed time to pain progression, notably in pts with HV disease. Increased overall survival, a delay in time to pain progression, and a favorable safety profile set DARO + ADT + docetaxel as a new standard of care for pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]
Transcriptomic heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer.
Authors: Sutera Philip , Shetty Amol , Hakansson Alexander K. , Van der Eecken Kim , Song Yang , Liu Yang , Fonteyne Valerie , Verbeke Sofie , Song Daniel Y. , Ross Ashley , Feng Felix Y , Gillessen Silke , Attard Gerhardt , James Nicholas D. , Lotan Tamara L. , Davicioni Elai , Sweeney Christopher , Tran Phuoc T. , Deek Matthew Pierre , Ost Piet
Published: June 2023

e17083

Background: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly partitioned into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes, however less is known about any potential underlying biologic differences between these disease states. Herein we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. Methods: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous vs metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease time. Median genomic scores between groups were compared with Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from time of metastasis. Survival analysis was performed with the Kaplan-Meier Method and Multivariable Cox regression. Results: 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-yr OS (39% vs 79%, p<0.01) and demonstrated lower median Androgen Receptor Activity (AR-A) (11.78 vs 12.64, p<0.01) and Hallmark Androgen Response (HAR) (3.15 vs 3.32; p<0.01). Multivariable cox-regression identified only high-volume disease (HR=4.97, 95%CI 2.71-9.10; p<0.01) and HAR score (HR=0.51, 95%CI 0.28-0.88; p=0.02 significantly associated with OS. Finally, patients with synchronous (HR=0.47, 95%CI 0.30-0.72; <0.01) but not metachronous (HR=1.37, 95%CI 0.50-3.92; p=0.56) disease were found to have better OS with Androgen Receptor (AR) + non-AR combination therapy as compared to monotherapy (p value for interaction = 0.05). Conclusions: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low volume disease, those with metachronous low volume disease have a more hormone dependent transcriptional profile and exhibit a better prognosis than synchronous low volume disease. [Table: see text]
Relationship between androgen biosynthesis linked to 3βHSD1 and resistance to radiotherapy: A germline biomarker for combined androgen blockade with radiation in high-risk prostate cancer.
Authors: Ganguly Shinjini , Lone Zaeem M. , Muskara Andrew , Imamura Jarell , Gupta Shilpa , Ornstein Moshe Chaim , Sharifi Nima , Mian Omar Y.
Published: June 2023

e17084

Background: Around 50% of men with advanced prostate cancer (PCa) have at least one germline copy of the adrenal-permissive (1245C) HSD3B1 allele. This allele leads to higher levels of the steroid biosynthesis enzyme, 3β-hydroxysteroid dehydrogenase (3βHSD1). Inheriting this allele is linked to worse outcomes in men with advanced PCa. To determine if (1245C) HSD3B1 could be causing early resistance to combined androgen deprivation and radiotherapy in localized PCa, we studied its role in modulating radioresistance. Methods: PCa cell lines were used to investigate the reciprocal effects of 3βHSD1 knockdown and overexpression in intrinsically high and low 3βHSD1 lines, respectively. PCa xenografts were used to confirm the results in vivo. The connection between androgen receptor (AR) expression and elevated DNA Damage Response (DDR) gene expression was validated using transcriptomic data from 680 radical prostatectomy specimens The ability of enzalutamide, a non-steroidal anti-androgen, to restore radiosensitivity in 1245C expressing lines was interrogated in vitro and in vivo. Results: 1245C HSD3B1 expressing PCa lines displayed increased clonogenic survival after ionizing radiation. Effects were dependent on the 3βHSD1 substrate, DHEA, confirming intratumoral androgen metabolism was required for radioresistance. Resistant lines showed enhanced DNA double-strand break (DSB) repair and heightened DDR gene expression. PCa xenografts with 1245C HSD3B1 were similarly more resistant to radiation using murine models that faithfully mimic human adrenal physiology. A correlation between AR expression and increased DDR gene expression was confirmed in 680 patient samples. Enzalutamide pretreatment resulted in a decrease in DSB repair ability and re-sensitized 1245C HSD3B1 PCa cells to radiation. Conclusions: 1245C HSD3B1 fuels prostate cancer treatment resistance by elevating regional androgen biosynthesis from adrenal steroid precursors, leading to DDR gene overexpression and enhanced DNA DSB repair kinetics. This work supports clinical validation of biomarker informed selective intensification strategies, e.g., combined androgen blockade, for high-risk men with the 1245C HSD3B1 allele receiving curative intent radiotherapy.
Impact of social determinants of health (SDOH) measures on prescribing advanced androgen blockade (AAB) in patients with metastatic hormone sensitive prostate cancer (mHSPC).
Authors: Ravilla Rahul , Wilson Thomas , Wentworth Chuck , Sundarrajan Sudha , Espirito Janet L. , Robert Nicholas J.
Published: June 2023

e17086

Background: Use of AAB (abiraterone acetate, apalutamide or enzalutamide) has been shown to improve survival in mHSPC, but many patients are not prescribed this treatment. There is substantial interest in the broader role of SDOH in cancer. We explored how SDOH influences prescribing patterns of AAB in patients with mHSPC. Methods: Patients diagnosed with mHSPC between 1/1/2017 and 12/31/2021 were identified using the iKnowMed electronic health record database from The US Oncology Network of community oncology practices. Records were searched for prescriptions for AAB (based on intent to treat). Individual level measures were age, diagnosis year, ECOG, race and type of health insurance. Area level measures were Area Deprivation Index (ADI) at national and state level, and rural status. ADI is a validated metric based on demographic variables from census block groups; high ADI scores for state ( > 8) and national ( > 80) level are markers of low socioeconomic status. Logistic regression models were run on each SDOH variable and adjusted for confounding variables, including a joint distribution model of African American (AA) and ADI (significance at p < 0.05). Results: There were 3,855 patients identified with mHSPC: 40% had a prescription for AAB. Summary measures overall were mean age: 71 years, AA: 10%, Medicaid: 5%, ECOG 0-1 and 2+: 60% and 14% respectively; and diagnosis year 2017-21: 15%, 20%, 21%, 22%, and 21% respectively. Area level scores: National ADI high: 8%, State ADI high: 18%, rural: 5%. Interaction variable: AA + State ADI (high): 2%. Statistical differences between those with/without AAB (not shown) were diagnosis year, ECOG and age. Multivariate logistic models were adjusted for these 3 variables with the single SDOH measure as the primary independent variable and the binary variable AAB as the dependent variable (Table). Conclusions: There was no significant association between AAB prescriptions and AA race, rural status, ADI (state or national), or Medicaid status. These data indicate that SDOH measures do not appear to influence prescribing of these treatments. We believe this study is among the first to examine these particular SDOH measures and their relationship to the prescribing of oncology treatments. Further research should be conducted into the impact of SDOH measures on the fulfillment and compliance of these drugs. [Table: see text]
Darolutamide observational (DAROL) study in patients with nonmetastatic castration-resistant prostate cancer: Second interim analysis.
Authors: Yu Evan Y. , Pieczonka Christopher Michael , Suzuki Hiroyoshi , Bailen James L. , Gotto Geoffrey T. , Hamilton Joelle P. , Uemura Hiroji , Murphy Declan G. , Lebret Thierry , Luz Murilo de Almeida , Ortiz Jorge A. , Adorjan Patrick , Khan Javeed , Briganti Alberto , Armstrong Andrew J.
Published: June 2023

e17095

Background: In ARAMIS (NCT02200614), darolutamide (DARO) significantly improved metastasis-free survival (MFS) by ~2 years (HR 0.41, 95% CI 0.34–0.50) and reduced the risk of death by 31% (HR 0.69, 95% CI 0.53–0.88) compared with placebo in men with nonmetastatic castration-resistant prostate cancer (nmCRPC), with a favorable tolerability profile. The ongoing DAROL study (NCT04122976) aims to understand the real-world safety and effectiveness of DARO in patients (pts) with nmCRPC. We report results from the pre-planned second interim analysis (IA). Methods: DAROL is a global, open-label, single-arm, non-interventional study in pts aged ≥18 years with confirmed nmCRPC for whom the decision to be treated with DARO is decided pre-enrollment. The primary endpoint is safety, including incidence, severity, and frequency of treatment-emergent adverse events (TEAEs). Secondary endpoints are patient demographics and disease characteristics, treatment duration, MFS, overall survival (OS), time to prostate-specific antigen (PSA) progression, and PSA response. Primary and secondary endpoints are reported after 300 pts completed ≥6 mo of treatment. All treated pts were assessed for safety while efficacy was evaluated in pts who did not violate any eligibility criteria and had ≥1 post-baseline assessment (cut-off October 11, 2022). Results: Of the 300 treated pts, the percentage enrolled in North America/Europe/Asia Pacific/Latin America was 45%/30%/25%/ < 1%, respectively. Median age was 80 years; 51% had a reported Gleason score > 7; 92% had a reported ECOG performance status of 0/1. Median baseline (BL) PSA was 3.9 ng/mL (range 0–248.0), with 21% of pts reporting PSA < 2 ng/mL. Median BL PSA doubling time (PSADT) was 5.3 mo (range 0–36.2), with 42% of pts reporting PSADT > 6 mo. At the data cut-off, median follow-up time was 14.8 mo (interquartile range [IQR] 10.9–19.3) and median treatment duration was 13.4 mo (IQR 9.3–17.8). The incidences of TEAEs and DARO-related TEAEs were generally low (Table), consistent with the safety profile of DARO reported in ARAMIS. Fatigue occurred in ≥5% of pts. For the 263 pts eligible for efficacy analysis, median time to PSA progression was 17.6 mo (95% CI 13.2–19.0); MFS/OS data remain immature. PSA declines from baseline of ≥30%, ≥50%, and ≥90% at any time were observed in 80%, 76%, and 54% of pts, respectively. Conclusions: In the DAROL second IA, under real-world conditions, DARO continued to show a favorable safety profile, consistent with the clinical profile of ARAMIS, with no new safety signals. Clinical trial information: NCT04122976 . [Table: see text]
Algorithm-based histologic grade and tumor ratio for radical prostatectomy: Comparison with pathology reports.
Authors: Kwak Tae-Yeong , Lee JaeHeon , Cho Joonyoung , Kim Sun Woo , Chang Hyeyoon , Ha Hong Koo
Published: June 2023

e17096

Background: The histologic grade (Gleason score) as well as the tumor ratio of the resected specimen plays a significant role in assessing the clinical risk of prostate cancer patients who underwent radical prostatectomy. Gleason scoring is known to be prone to inter- and intra-observer discordance, and eyeballing measurement of tumor ratio is possibly coarse and inaccurate. Several deep learning-based tissue image analysis algorithms that perform prostate cancer diagnosis have been developed and are about to be applied clinically. We evaluated the utility of one of those algorithms by comparing its output with the pathology reports. Methods: A total of 29681 H&E-stained tissue slides were collected for 1001 radical prostatectomy cases during 2010-2021 at Pusan National University Hospital and scanned at 40x magnification into whole-slide images. On each slide, we utilized a tissue detection algorithm to identify tissue regions and measure the area. A deep learning-based algorithm was used to identify prostate cancer lesions, measure the area, and determine the grades. The area measurement was converted into the volume figure assuming that the tissue slice thickness was 5mm. The slide-wise algorithm outputs were then aggregated for each case, resulting in the specimen volume, tumor ratio, and Gleason score. In the evaluation, the algorithm-based Gleason scores were compared with the ones in the hospital pathology reports on the ISUP grade group basis. The correlation analysis was performed for the tumor ratio. The specimen density values were calculated from the volume figures and the hospital weight measurement and utilized to exclude the cases with extreme density values. Results: The min, max, and average number of slides per case were 1, 67, and 29.7. For two cases with a single slide collected, both the algorithm and the expert pathologist found no cancer. The pathologist also confirmed that 7 had residual tumors among 15 cases where there was no Gleason score in the pathology reports while the algorithm found cancer. For the remaining 984 cases, the algorithm provided the grade groups equal to, higher than, and lower than the pathology reports for 482, 384, and 118 cases respectively, showing moderate agreement. The min, max, and mean values of the specimen volume (mL) were 0.01, 75.3, and 32.7, while the corresponding values of the specimen density (g/mL) were 0.11, 3001.79, and 4.38. The density values at the lower and upper 2.5% were 0.42 and 1.40 respectively, and the mean of the values between them (inner 95%) was 0.92. The degree of tumor ratio correlation between the algorithm and the pathology reports was high with the coefficient 0.813 (95% CI: 0.791-0.833), which went up to 0.826 (95% CI: 0.805-0.845) for the inner 95% density cases. Conclusions: Our findings support the usefulness of the algorithm-based analysis of prostatectomy specimens, which can benefit clinicians in the hospital.
Machine learning to predict future PSA in patients with prostate cancer managed with active surveillance.
Authors: Ayed Aziz , Saillard Claire-Alix , Onofrey John A. , Moon Intae , Chang Steven Lee , Feldman Adam Scott , Nayan Madhur
Published: June 2023

e17098

Background: Active surveillance (AS) for prostate cancer (PCa) requires serial assessments and there is a need to optimize resource utilization by personalizing AS. Evaluating serial PSA values is fundamental in AS and a model predicting future PSA may aid decision-making on optimizing the timing of the subsequent assessment. In this study, we use a machine learning (ML) approach to predict future PSA in AS patients. Methods: We searched electronic health record data at two tertiary academic centers for patients with a diagnosis of PCa or reason for visit related to PCa (e.g. elevated PSA) between 1990 and 2020. Within this group, we identified patients diagnosed with PCa and managed with AS. We trained different ML models (Table 1) to predict the next PSA value given a sequence of historical PSAs and expected date of next PSA assessment, and compared this prediction to the ground truth (actual PSA measured). We augmented the model with clinical features (age, prostate volume, and BMI). We compared the ML models to a baseline method that considers a patient-specific constant slope based on prior PSA values. The test set consisted of AS patients only (10% of all AS patients), not used in training. The dataset was split patient-wise. The primary performance metric was root-mean-square error (RMSE). We compared training using AS patients only to using all patients, still testing on AS patients only. We evaluated feature importance to facilitate model interpretability. Results: We identified 4269 patients (totaling 33371 PSA values) with at least 3 PSA values and complete data for the clinical features. Of these, 1134 were on AS (totaling 10358 PSA values). On average, AS patients were 65 years old (± 7 [standard deviation]), with a mean PSA of 6.5 ng/mL (± 6.4), prostate volume of 48g (± 27) and BMI of 28 kg/m2 (± 5), at diagnosis. The best performing model was the Gradient Boosting Regression model that was trained in the heterogeneous sample of all patients (including those not on AS) (Table 1). Evaluation of feature importance found that increasing the number of previous PSA measurements as input to the model further reduced the RMSE. Conclusions: Our study used machine learning to predict future PSA in PCa patients on AS. We also demonstrate that for our best performing model, a heterogeneous training sample further improved performance. While our model requires further validation, a robust similar model may be useful as a decision-aid tool to personalize AS and optimize resource-utilization. We have deployed our model at https://psa-evolution.streamlit.app/ . [Table: see text]
Cascade genetic testing (CGT) female first-degree relatives (FDR) of men with germline BRCA2 mutations (gBRCA2mut) and prostate cancer (PCa): A cost-effectiveness analysis.
Authors: Carletti Alexie A , Caughey Aaron B , Sokolova Alexandra
Published: June 2023

e17099

Background: g BRCA2mut are associated with increased risk of PCa, breast cancer (BC), and ovarian cancer (OC). ~5% of men with metastatic PCa have g BRCA2mut. CGT is recommended for their relatives as there are implications for cancer prevention and early detection strategies. Little is known about CGT initiated by men with PCa. Here we evaluate the cost-effectiveness of CGT in FDR of men with PCa and g BRCA2mut. Methods: A decision-analytic model was created with TreeAge software to compare BC and OC outcomes for female FDRs who underwent CGT for g BRCA2mut versus no CGT. Our theoretical cohort contained 100,000 females, a conservative estimate of patients who could benefit from CGT. We used literature derived estimates to determine the percentage of patients that would pursue risk-reducing mastectomy, risk-reducing salpingo-oophorectomy, both surgeries, or surveillance after CGT. Outcomes included BC or OC diagnoses, survivorship, and cancer death. We derived all probabilities, costs, utilities, and life expectancies from the literature and discounted quality adjusted life years (QALYs) at a rate of 3%. Incremental cost-effectiveness (ICER) was calculated to determine the cost per QALY gained and set the willingness-to-pay threshold at $100,000/QALY. We assessed the robustness of the model with sensitivity analyses. Results: In our theoretical cohort, CGT of female FDRs resulted in 12,910 less BC diagnoses and 6,360 less BC deaths. CGT was associated with lower BC death rates (26.1%) compared to no CGT (35.8%). OC survival rates were higher with CGT (73.1%) compared to no CGT (36.4%). Our model resulted in lower costs and higher QALYs (a dominant strategy) among the CGT cohort with an ICER of -$7,211.40 per QALY, saving an estimated $595 million. We found that CGT in females was the dominant strategy in 100% of the samples, once uncertainty was incorporated into our model inputs via Monte Carlo simulation. The cost-effectiveness of CGT for male FDRs will be presented at the meeting. Conclusions: In this study, CGT of female FDRs of men with PCa and g BRCA2mut was the dominant strategy to improve BC and OC outcomes, including increased survivorship and reduced BC and OC development. CGT was associated with reduced costs and increased QALYs. CGT for female FDRs of patients with PCa and g BRCA2mut may be a cost-effective approach for identifying and informing individuals with potentially harmful mutations. [Table: see text]
Ten-year outcomes of hypofractionated (45 Gy in 9 fractions) intensity-modulated radiotherapy for localized prostate cancer.
Authors: Zhong Sijin , Liu Yueping , Fang Hui , Tang Ping , Dai Jianrong , Shou Jianzhong , Li Yexiong
Published: June 2023

e17100

Background: We reported 10-year outcomes of localized prostate cancers treated with hypofractionated intensity-modulated radiotherapy of 45 Gy in 9 consecutive fractions. Methods: From October 2011 to April 2017, thirty patients with localized prostate cancer were enrolled in this prospective trial. The median age of the patients was 72.5 years. According to NCCN recurrence risk criteria, eight patients were at low risk group, 17 at intermediate risk group, 5 at high risk group. All patients were treated with hypofractionated intensity-modulated radiotherapy (IMRT) of 45 Gy in 9 consecutive fractions to their prostate with or without seminal vesicles. Before radiotherapy, three gold fiducials were implanted into the prostate. In order to reduce the rectal high dose irradiation volume , an inflated rectal balloon was placed in the rectum at simulation and every treatment and patients were treated with comfortable full bladder. Static Intensity-modulated radiotherapy (SIMRT) was applied in 1 patient, Volumetric Modulated Arc Therapy (VMAT) in 27 patients, and tomotherapy in 2 patients. Image guided radiotherapy (IGRT) with gold fiducial registration was adopted. Twenty-six patients also received androgen deprivation therapy (ADT). The median time of ADT was 6 months. Progression⁃free survival(PFS) and overall survival(OS) were analyzed using Kaplan-Meier analysis. All grade ≥1 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded using Common Terminology Criteria for Adverse Event version 5.0 (CTCAE 5.0) and Radiation Therapy Oncology Group (RTOG) late morbidity criteria , and GU and GI toxicities were cumulatively calculated. Results: After a median follow-up of 102 months (65~131 months), the 10-year OS was 90.0%(95% confidence interval, 83.3%-96.7%), and the 10-year PFS was 86.5% (95% confidence interval, 79.1%-93.9%). According to CTCAE 5.0, grade 1 acute gastrointestinal (GI) toxicity developed in 12 patients, grade 2 in 2 patients, grade 3 in 2 patients, and grade 1 acute genitourinary (GU) toxicity developed in 12 patients, grade 2 in 2 patients, and no grade 3 or higher toxicity occurred. According to RTOG late morbidity criteria, late (≥3 months after radiotherapy) grade 1 GI toxicity developed in 4 patients (13.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%), and late grade 1 GU toxicity occurred in 1 patient (3.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%). No grade 4 or higher GI and GU toxicities developed. Only one grade 3 GI and one grade 2 GU toxicities were observed for the maximum toxicity at the last follow-up. The potency was not evaluated. Conclusions: The 10-year oncologic outcomes of this shortened hypofractionated IMRT regimen for mainly low/intermediate risk prostate cancer patients is favorable with acceptable acute and late toxicities.
Exploring the efficacy of a continuous form of the histologic grade in prostate cancer prognosis prediction.
Authors: Kwak Tae-Yeong , Lee JaeHeon , Cho Joonyoung , Kim Sun Woo , Chang Hyeyoon
Published: June 2023

e17105

Background: Adenocarcinoma of the prostate is the second most common type of cancer among men worldwide. The Gleason grading system remains the gold standard for evaluating the prognosis of prostate cancer by assessing the cancer morphology. However, the current discretized Gleason pattern regime limits the depiction of fine-grained histomorphological changes. We evaluated the efficacy of the algorithm-generated continuous histologic grade value in prostate cancer prognosis prediction. Methods: Whole-slide images of H&E prostatectomy tissue, along with the follow-up data including new tumor event (NTE) and biochemical recurrence (BCR), were obtained for the cases diagnosed as prostate cancer during 2000-2013 from The Cancer Genome Atlas (TCGA) database. Cases with missing data were excluded, resulting in a total of 308 and 397 cases being used for the analysis of NTE and BCR, respectively. Our study utilized a deep learning-based algorithm that performs Gleason scoring as follows. First, it computes per-pixel likelihood values for each of the 4 classes: benign, Gleason 3, 4, and 5. Then, the per-pixel class with the highest likelihood value and the slide-wise ISUP grade group (GG-AI) is successively determined. We tweaked the algorithm to aggregate the likelihood-weighted Gleason grade assigned to each pixel into a continuous form of the histologic grade (c-HG). We compared the prognostic performance of c-HG with that of the original ISUP grade group in TCGA (GG) and that of algorithm-generated GG-AI in predicting the risk of NTE as well as BCR. The Cox regression analysis was conducted, setting the cases from one of three donating institutions (EJ, HC, KK) as the target, fitting the Cox model with the cases from the other institutions, and evaluating the fitted model on the target. Results: The median follow-up duration in months was 32 for NTE and 29 for BCR, respectively. The number of cases with NTE was 51, while the one with BCR was 82. The table presents the c-index values obtained from each institution for GG, GG-AI, and c-HG. Note that the number of cases in each institution is different for NTE and BCR, due to the different number of removed cases with missing data. c-HG showed the best average performance in both NTE and BCR risk predictions. It is also notable that c-HG showed a stable performance for varying institutions. Conclusions: We proposed an algorithm-based method of representing histologic grade as a continuous value, which may give better predictions in disease progression for prostate adenocarcinoma. [Table: see text]