bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient-reported outcomes (PRO) in patients (pts) with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC) receiving niraparib (NIRA) with abiraterone acetate and prednisone (AAP): Results from MAGNITUDE study.
Authors: Rathkopf Dana E. , Roubaud Guilhem , Chi Kim N. , Efstathiou Eleni , Attard Gerhardt , Olmos David , Small Eric J. , Saad Marniza , Castro Elena , Kim Won , Wu Daphne , Bertzos Kristi , Dibaj Shiva , Zhang Jenny , Francis Peter St. John , Smith Matthew Raymond
Published: January 2024

105

Background: MAGNITUDE, an international phase 3 randomized double-blind study, demonstrated that mCRPC pts with BRCA1/2 alterations receiving NIRA + AAP had significantly improved radiographic progression-free survival, and clinically relevant prolongations in time to symptomatic progression and time to cytotoxic chemotherapy compared with placebo (PBO) + AAP. Here, we report PRO results (pain, health-related quality of life [HRQoL], and side effect bother) in the BRCA1/2 subset of mCRPC pts in the final analysis of MAGNITUDE. Methods: Pts were screened prospectively for homologous recombination repair (HRR) gene alterations. Eligible pts had ECOG status ≤1 and a Brief Pain Inventory–Short Form (BPI-SF) worst pain score ≤3 (scale of 0-10), and were randomized 1:1 to NIRA + AAP or PBO + AAP orally daily in 28-day cycles. PRO assessments on day 1 of specified cycles included BPI-SF and Functional Assessment of Cancer Therapy–Prostate (FACT-P). Time to deterioration (TTD) in pain (BPI-SF worst, average, and pain interference, and FACT-P pain-related scale [PRS]) were compared between treatment arms using proportional hazards regression models. Changes from baseline in HRQoL (FACT-P total, scale of 0-156) were compared using repeated measures analysis, and side-effect bother was assessed in both arms as a single item from FACT-P (GP5). Results: PRO compliance for FACT-P and BPI-SF was >85% in 225 pts with BRCA1/2-altered mCRPC. At baseline, mean BPI-SF pain scores was 1.09 (SD, 1.57) in NIRA + AAP and 1.35 (SD, 1.98) in PBO + AAP. Mean FACT-P Total in NIRA + AAP and PBO + AAP was 116.33 (SD, 18.42) and 114.8 (SD, 18.9), respectively. Median TTD in BPI-SF worst pain, pain interference, average pain, and FACT-P PRS were numerically longer for NIRA + AAP vs. PBO + AAP (Table). Repeated measures results showed HRQoL was maintained on treatment for the BRCA subgroup with no clinically meaningful differences in the FACT-P total score over time or between treatment arms. Analysis of FACT-P item GP5 in the BRCA subset showed side effect bother was rated “not at all” or “a little bit” by 87% of NIRA + AAP and 92% of PBO + AAP subjects across treatment cycles. Conclusions: In pts with BRCA1/2-altered mCRPC, NIRA + AAP maintained HRQoL. Pts experienced minimal bother from side effects associated with treatment. These data further support the benefit-risk profile of NIRA + AAP for the treatment of mCRPC pts with BRCA1/2 alterations. Clinical trial information: NCT03748641 . [Table: see text]
Preliminary data from a dose-escalation phase 1 study with HP518, an AR PROTAC degrader: Safety, tolerability, pharmacokinetics (PK), and first assessment of anti-tumor activity in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Azad Arun , Gurney Howard , Underhill Craig , Horvath Lisa , Voskoboynik Mark , Li Xinghai , King Ivan , Shao Lisa , Dai Yiyun , Perabo Frank
Published: January 2024

124

Background: HP518 is an oral proteolysis targeting chimera (PROTAC) protein degrader that target androgen receptor (AR) mutations for the treatment of mCRPC. To evaluate the safety, PK, and anti-tumor activity of HP518, and select a recommended phase 2 dose (RP2D), we conducted a first-in-human, Phase 1, open-label, multicenter, non-randomized, dose escalation study in pts with mCRPC. We report results of the ongoing Phase 1 study at five Australian sites. Methods: Pts with mCRPC with disease progression on at least 1 novel hormonal agent (NHA) and ≤ 1 line of chemotherapy received HP518 QD orally in sequential cohorts (25, 50, 100, 200, and 300, 400, 500 mg per day, Bayesian N-CRM design). Primary objectives were to assess HP518 safety and select the RP2D. Secondary objectives included evaluating the PK of HP518, PSA50 response and radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. Exploratory objectives were to evaluate AR expression in CTCs before and after 12 weeks of treatment and conduct genomic profiling using cfDNA. Results: As of 08Sep2023, a total of 22 pts were enrolled, with current one-daily dosing of 500 mg HP518. Overall, HP518 was well tolerated, with cumulative 10 SAE (1 related/9 unrelated). No DLT was observed. There were 13 Grade ≥3 treatment-emergent adverse events (TEAEs) in 6 pts treated up to 500 mg; no grade ≥4 TEAEs. The most common TEAE in all cohorts was grade 1 or 2 vomiting and nausea which were well managed with prophylactic anti-emetics. Preliminary PK results were obtained from 18 pts dosed with 25 mg to 500 mg per day. Following multiple oral doses of HP518, median peak plasma concentrations were observed at 3 -12 hours post-dose. Over the 5-fold dose range (100 to 500 mg), the increase in Cmax and AUC0-last was approximately dose proportional on day 1. Steady state was reached between day 56 and day 84. Among 16 pts who finished the DLT period, a PSA50 response was seen in 3 pts. 2 pts had confirmed partial responses per RECIST criteria, with 8 pts remaining on treatment. 2 pts received HP518 for ≥24 weeks including 1 pt with a durable PSA50 response for 52 weeks, who also showed PR. Notably, this patient harbored an F877L, E873_F879del AR ligand-binding domain (LBD) mutations. Conclusions: HP518, a novel AR PROTAC degrader, demonstrates in this Phase 1a dose-escalation study, an acceptable safety/tolerability profile and a signal of efficacy in an unselected mCRPC patient population. The presence of AR LBD mutations may predict benefit from HP518, and merits further investigation in pts with mCRPC. Clinical trial information: NCT05252364 .
Long-term outcomes for patients with radiorecurrent prostate cancer treated with salvage combination IMRT and brachytherapy.
Authors: Dattoli Michael J. , Soni Arvind B. , Yanthis Lauren , Fay Jone , Lawrence Gregory
Published: January 2024

125

Background: Effective salvage of locally recurrent prostate cancer after definitive radiation is typically disappointing and may be associated with significant complications. Methods: 133 consecutive prostate cancer patients (ages 46-78) with biopsy proven local failures were treated between 2001 and 2021 and followed, prospectively with respect to clinical and/or biochemical failure and toxicity. Pre-recurrence treatment had consisted of external beam radiation (Photons: 102 patients, Protons: 16 patients) or iodine 125 brachytherapy (15 patients). Prior to salvage treatment, an extensive workup ruled out gross extracapsular extension or distant disease spread. Salvage treatment consisted of an attenuated dose of IMRT to the prostate (1200 cGy/8 fxs) followed by an attenuated Pd-103 brachytherapy boost (median 9000 cGy) within 24-72 hours. The Pd-103 isotope was used given its steep radial dose fall off, thereby reducing dosage to previously irradiated surrounding tissues. All patients were treated with a median 6 months of androgen deprivation. Mean pretreatment PSA was 5.9 ng/mL (range 1.9 - 22.3, median 3.9) with 64 patients having a Gleason score of greater than or equal to 8, 61 patients having a Gleason score of 7, and 8 patients having a Gleason score of 6. Follow-up from date of implant ranged from 3 years to 20 years (median 14 years). Biochemical failure was defined using PSA greater than or equal to 0.2 and nadir +2 at last follow up. All biochemically failing patients underwent transperineal prostate biopsies (median 18 cores). Results: Overall, 72% (96/133 patients) have maintained a PSA less than or equal to 0.2 ng/mL at median 14 years. Biochemical freedom at 5 years was 91%. PSA prior to re-treatment was highly predictive of distant progression with no patient having a PSA greater than 15 being successfully salvaged. Prostate biopsies of failing patients revealed only 3 local failures. 4 patients required post-implant TURP and 2 TURP patients developed low volume stress incontinence, 2 patients developed urethral strictures which were successfully treated to resolution. No patient has developed rectal ulceration, prostatic-vesicorectal fistula, or chronic cystoproctitis. Conclusions: This study helps strengthen the rationale for the use of Brachytherapy-based regimens in the treatment of radiorecurrent prostate cancer. In view of its even steeper radial dose falloff, we are currently exploring the advantages of Cs-131 in these patients.
First-line PARP inhibitors (PARPi) with androgen receptor pathway inhibitors (ARPi) in metastatic castration-resistant prostate cancer (mCRPC): A systematic review and meta-analysis.
Authors: Khan Muhammad Ali , Naqvi Syed Arsalan Ahmed , Imran Manal , Channar Aneeta , Saxena Akshat , Raina Ammad , Khakwani Kaneez Zahra Rubab , Riaz Zaryab Bin , Kase Adam McLain , Humphreys Mitchell R. , Moore Cassandra N. , Orme Jacob , Childs Daniel S , Singh Parminder , Bryce Alan Haruo , Palmer Jeanne M. , Riaz Irbaz Bin
Published: January 2024

173

Background: The data for combining PARPi and ARPi in mCRPC have shown conflicting results. Here, we report a quantitative summary of benefits by clinically meaningful subgroups (HRR mutation status, BRCA mutation status) to guide the use of PARPi and ARPi combination in mCRPC setting. Methods: MEDLINE, EMBASE, and CENTRAL were systematically searched from each database’s inception through September 7, 2023. Phase III studies comparing PARPi + ARPi with ARPi + placebo in mCRPC were included. Radiographic progression-free survival (rPFS) and overall survival (OS) in patient subgroups based on HRR and BRCA mutation status were assessed. Hazard ratios for rPFS and OS with 95% CI were collected at the level of each trial, and a random-effects meta-analysis was conducted using an inverse variance approach. Subgroup differences were assessed and p-value of interaction <0.1 was considered statistically significant. Results: The literature search identified 4976 studies from which 3 trials (11 references) – TALAPRO2, PROpel and MAGNITUDE met the inclusion criteria. A total of 2254 participants were eligible for analysis. PARPi + ARPi prolonged rPFS in patients with HRR mutations (HR: 0.55, 95%CI: 0.38-0.78) as well as in patients without HRR mutations (HR: 0.74, 95%CI: 0.63-0.88). There is no evidence of treatment interaction by HRR mutation status (p = 0.14). In patients harboring HRR mutations, improved rPFS was observed in those with BRCA mutations (HR: 0.28, 95%CI: 0.13-0.62) as well as those without BRCA mutations (HR: 0.72, 95%CI: 0.59-0.87). However, there is evidence that patients with BRCA mutations derived greater rPFS benefit as compared to patients without BRCA mutations (p =0.02). PARPi + ARPi showed no significant improvement in overall survival either in patients with HRR mutations (HR: 0.79, 95%CI: 0.59-1.05) or in patients without HRR mutations (HR: 0.92, 95%CI: 0.74-1.14). Conclusions: Genomic testing for HRR genes is mandatory to guide clinical decision making in mCRPC patients. Patients harboring BRCA mutations are most likely to derive clinically meaningful benefit from combination PARPi + ARPi treatment. [Table: see text]
Detection of neuroendocrine prostate cancer through plasma-based epigenomic profiling.
Authors: Eid Marc , Semaan Karl , Seo Ji-Heui , Davidsohn Matthew P. , Fortunato Brad , Lakshminarayanan Gitanjali , El Zarif Talal , Savignano Hunter , Canniff John , Saliby Renee Maria , Saad Eddy , Pomerantz Mark , Baca Sylvan , Freedman Matthew , Berchuck Jacob E , Choueiri Toni K.
Published: January 2024

201

Background: Neuroendocrine prostate cancer (NEPC) is an aggressive resistance phenotype that can develop in men with metastatic prostate adenocarcinoma (PRAD). Early detection of NEPC has prognostic and therapeutic implications, but is challenging due to spatial heterogeneity, sampling error associated with tissue biopsy, and a lack of distinguishing genetic mutations that can be assessed from cell-free DNA (cfDNA). Herein, we introduce a novel epigenomic-based approach to non-invasively identify NEPC from cfDNA. Methods: Plasma was collected from patients with NEPC and PRAD at the Dana-Farber Cancer Institute. Chromatin immunoprecipitation and sequencing on cfDNA (cfChIP-seq) was performed on 1mL of plasma for the post-translational histone modifications H3K4me3 and H3K27ac. Activity of gene promoters and enhancers was inferred based on H3K4me3 and H3K27ac cfChIP-seq signal normalized to signal at constitutively active regulatory elements. A classifier was built to distinguish NEPC from PRAD based on H3K27ac signal at a published set of regulatory elements with increased chromatin accessibility in neuroendocrine tumors compared to adenocarcinomas (NE-REs). The classifier performance was evaluated using the area under the receiver operating characteristic (AUROC) curve. Results: Our cohort included 30 patients, 10 with NEPC and 20 with PRAD. H3K4me3 signal at the promoter of chromogranin A ( CHGA), a diagnostic marker gene of NE-differentiation, was significantly elevated in plasma from patients with NEPC vs. PRAD (p=4x10-11, Wilcoxon rank-sum test). H3K27ac signal at binding sites for ASCL1, a master transcription factor driving NE-differentiation, was significantly elevated in NEPC vs. PRAD plasma samples (p=7.2x10-5, Wilcoxon rank-sum test). H3K27ac signal at NE-REs accurately distinguished patients with NEPC from patients with PRAD with an AUROC curve of 0.97. Conclusions: We present a non-invasive approach to identify NE-differentiation in patients with metastatic prostate cancer using 1mL of plasma. This method could help overcome practical challenges associated with NEPC detection and further guide therapy selection.
Evaluation of ctDNA in patients with mCRPC with liver metastases.
Authors: Huang Minqi , Gebrael Georges , Sayegh Nicolas , Casado Crystal , Habibian Nicholas , Akerele Opeoluwa , Gupta Kanika , Lieberman Alexandra , Schwartz Jennifer , Layton Jodi Lyn , Sweeney Patrick L , Lewis Brian E. , Agarwal Neeraj , Sartor A. Oliver , Ledet Elisa M.
Published: January 2024

212

Background: Patients with prostate cancer with liver metastases are known to have a worse prognosis. In this study, we evaluated ctDNA in mCRPC (metastatic castration-resistant prostate cancer) patients with and without liver metastases. Methods: A retrospective chart review identified mCRPC patients with liver metastases at Tulane Cancer Center and Huntsman Cancer Institute. Liver metastases were confirmed via molecular or conventional imaging. All patients had ctDNA assessed with a multi-gene cancer panel via the Guardant 360 assay. Alterations with <0.1% allelic fraction, synonymous alterations, and variants of unknown significance were excluded from analyses. Statistical analyses were performed using Fisher’s Exact and Wilcoxon Rank Sum Tests. Correction for multiple testing was not performed, hence these alterations may be subject to a type 1 error. Results: 53 mCRPC patients with liver metastases and 144 mCRPC patients without liver metastases were included in the study. We found seven genes that are more likely to be pathologically altered in ctDNA in mCRPC patients with liver metastases (See Tables 1-3): AR (OR=2.38, 95% CI: [1.25, 4.52], p=0.01), BRAF (OR=2.74, 95% CI:[1.05, 7.18], p=0.05), BRCA2 (OR=5.33, 95% CI:[1.49, 19.02], p=0.01), CDK6 (OR=4.09, 95% CI:[1.35, 12.42], p=0.01), EGFR (OR=3.12, 95% CI:[1.22, 7.99], p=0.02), FGFR1 (OR=5.69, 95% CI:[1.81, 17.86], p-value=0.003), MYC (OR=4.55, 95% CI:[1.63, 12.68], p=0.004), and PIK3CA (OR=4.34, 95% CI:[1.87, 10.06], p=0.01). Additionally, mCRPC patients with liver metastases are more likely to have copy number alterations (CNA) (p= 0.01) compared to mCRPC patients without liver involvement. There were no other significant differences in the remaining 70 genes interrogated. Germline pathogenic alterations did not vary between the two groups. Conclusions: In mCRPC patients with liver metastases, these exploratory analyses suggest ctDNA testing is more likely to detect pathologic alterations in AR, BRAF, BRCA2, CDK6, EGFR, FGFR1, MYC, and PIK3CA. Additionally, mCRPC patients were more likely to have copy number alterations (CNA). Limitations of the Guardant 360 assays are notable in this setting given the incomplete ascertainment of gene deletions and the incomplete number of prostate-relevant genes assessed. [Table: see text]
The impact of SPOP gene alterations in men with metastatic prostate cancer: Results from the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) consortium.
Authors: Yamamoto Kyra Lee , Henderson Nicholas , Hwang Clara , Barata Pedro C. , Bilen Mehmet Asim , Kilari Deepak , Graham Laura , Garje Rohan , Rothstein Shoshana , Koshkin Vadim S , Tripathi Abhishek , Cackowski Frank Cameron , Nauseef Jones T. , Schweizer Michael Thomas , Armstrong Andrew J. , Dorff Tanya B. , Alva Ajjai Shivaram , McKay Rana R.
Published: January 2024

225

Background: Inactivating mutations in the SPOP gene, encoding speckled-type poxvirus and zinc-finger protein, are common among men with localized and metastatic prostate cancer, occurring at a frequency of 6-15%. Previous studies have suggested the presence of an inactivating mutation in SPOP results in increased sensitivity to androgen deprivation therapy (ADT). In this multi-institutional clinical-genomic database, we evaluated the impact of SPOP alterations on survival outcomes in men with metastatic prostate cancer. Methods: Retrospective data from the PROMISE Consortium were utilized for this analysis. Eligible patients had metastatic prostate cancer and had undergone standard of care next-generation sequencing (NGS). Patients with inactivating mutations in SPOP were defined as SPOP mutated, where. as those lacking such alterations were defined as SPOP wild-type. The primary endpoint was overall survival defined as the time from diagnosis of metastatic prostate cancer to death from any cause, censored at the date of last follow-up. Secondary endpoints included time from metastatic disease to castration resistance and time from castration resistance to death. Results: Of the 2097 patients with available NGS testing, 5.5% (n=115) had SPOP alterations. The median age at diagnosis was 63 years, 427 were Black, and 83 were Hispanic. At last assessment, 66% had bone metastases, 7% lung metastases, and 5% liver metastases. The most frequent co-occurring alterations in the SPOP-mutated group were: TP53 (30.4%), APC (25.2%), and AR (21.7%). 1832 patients were included in the survival analysis [n=96 (5.2%) with and n=1736 (94.8%) without SPOP alterations]. Median overall survival was numerically longer, though not statistically significant, in the SPOP-mutated compared SPOP-wild-type group (75.9 versus 59.5 months, p=0.12). In patients with metastatic disease, median time to castration resistance was 14.6 months in the SPOP-mutated group versus 12.2 months in the SPOP-wild-type group (p=0.30). Median time from metastatic castration resistant to death was 45.0 months in the SPOP-mutated group and 40.2 months in the SPOP-wild type group. Conclusions: Our hypothesis generating data support that SPOP-mutated prostate cancer likely represents a unique molecular subtype of prostate cancer that may confer prolonged survival. Future studies of novel androgen-receptor targeting treatments should be tested in this molecular population.
Trends in preferred place of death for prostate cancer in the United States from 2003 to 2020: Analysis of CDC WONDER database.
Authors: Jatwani Karan , Sukaina Mahnoor , Khosla Atulya Aman , Singh Rohit , Singh Navpreet , Walia Kamalpreet Singh , Patel Archit , Muthusamy Kumarasamy Vasanthan , Gopalakrishnan Dharmesh
Published: January 2024

231

Background: Prostate Cancer (PCa) is the most common cancer in men and the second cause of cancer mortality. The identification of the preferred place of death (PPOD) has been shown to improve the delivery of palliative care, reduce healthcare costs, and improve quality of care. We evaluated the trends in PPOD for patients and hospice utilization with PCa in the USA from 2003 to 2020 based on the CDC WONDER (Centers for Disease Control and Prevention for Wide-ranging Online Data for Epidemiologic Research) database. Methods: The US nationwide and state-level data was pooled using the CDC WONDER database from January 01, 2003, to December 31, 2020. The data trends of PPOD for prostate cancer were pooled using the International Classification of Diseases, Tenth Revision as C61: malignant neoplasm of prostate. The analysis of trends in mortality over the past decade was stratified according to age, census region, race, and place of death. Results: The analysis demonstrated that overall mortality due to PCa was 526,783 from 2003 to 2020. Of these deaths, 43,813 (8.32%) were recorded in hospice facilities. The hospice mortality steadily increased from 0.4% in 2003 to the highest of 9.20% in 2019, with a notable decline to 7.6% in 2020. We noticed that the PPOD differed based on racial subgroups. More than half of mortality in the Native American (NA) and African-American (AA) subgroups was observed in a medical facility (51.81% and 58.21%, respectively) compared to Whites (49.15%). Hospice or death at home in NA and AA groups were (48.11% and 41.11%, respectively) compared to Whites (50.85%). The age-stratified mortality analysis revealed increased hospice utilization in 25-44 years (11.95%) vs. 65+ years (8.13%). Upon stratifying the results by census showed the highest hospice utilization in Florida, compared to the lowest in North Dakota (22.6% vs. 0.02%). Conclusions: To our knowledge, this is the first study utilizing the CDC WONDER database to analyze PPOD in PCa-related deaths. We observed a steady increase in hospice utilization from 2003 to 2019 throughout the US, with a decline in 2020, possibly due to the COVID-19 pandemic. The AA and NA groups had higher mortality in medical facilities compared to Whites, whereas the White population utilized more hospice services or died at home. This highlights the existing disparities in end-of-life care in PCa and promotes policy-level changes in the states with lower utilization of hospice services to improve access of care in PCa patients.
Use of the Prostatype P-score to predict adverse pathology (AP) at radical prostatectomy (RP).
Authors: Andriole Gerald L. , Berglund Emelie , Gaal Steven , Bykov Vladimir J.N.
Published: January 2024

276

Background: Men with low or favorable intermediate risk prostate cancer (PCa) may undergo Active Surveillance (AS) or curative treatment. Among the factors patients and clinicians use to determine which approach to take is the likelihood of AP at RP. Nomograms using clinical parameters alone or along with GC’s have been used to aid in the prediction of AP at RP. The Prostatype test has been developed from prostate biopsy specimens of men with localized PCa. It has been validated in 2 large studies to accurately predict 10-year Prostate Cancer Specific Mortality and 10-year Prostate Cancer Metastasis. The Prostatype test is generated from the signature of 3 embryonic stem cell genes (IGFBP3, F3, and VGLL3) measured from the biopsy along with clinical data (PSA, Gleason Score, and T-stage). Its intended use is to guide treatment decisions in men currently on or considering AS. The Prostatype test is CE marked and is available for clinical use in Europe. Methods: To validate the ability of the Prostatype test performed on prostate biopsy tissue to predict AP (Gleason score 4+3 or higher and/or non-organ confined disease (pT3)) at RP, we studied 214 patients (Median age 65 (59,68); Median PSA 7.6 (5.3, 11.1); 20% Gleason 6; 64% Gleason 7; 16% Gleason >8) who underwent RP, of which 117 (55%) had AP. The model to predict AP at RP is an Artificial Neural Network (ANN) algorithm. Results: This ANN showed excellent performance, e.g., great balance between precision and sensitivity and had a high overall accuracy (AUC of 0.88) at predicting AP at RP. This 5-layer ANN model includes IGFBP3, F3, % positive biopsies and biopsy primary Gleason score. Confusion matrix measurement of the performance of the model shows it minimizes misclassification of patients with AP, and together with the Matthews Correlation coefficient (0.639) provides evidence that the ANN model manages false positives and false negatives correctly. Conclusions: This study shows that the Prostatype test is a strong predictor of AP at RP and may be used to guide decision making of clinicians and patients who are currently on or considering AS.
Racial and ethnic differences in the receipt of metabolic syndrome risk factor screening and treatment among individuals with prostate cancer treated with androgen deprivation therapy.
Authors: Barqawi Yazan K. , Borrego Matthew E , Roberts Melissa H , Thompson Todd , Hashemi-Sadraei Neda
Published: January 2024

29

Background: Racial and ethnic health disparities in prostate cancer screening, and treatment constitute the largest of all cancer disparities. Androgen deprivation therapy (ADT) is widely used in the treatment of localized or metastatic prostate cancer. However, ADT is associated with toxic cardiovascular and metabolic adverse events that may occur as early as 6 months of therapy initiation. This study aimed to assess racial/ethnic differences and longitudinal changes in metabolic syndrome risk factor (MSRF) screening/treatment among patients with prostate cancer treated with ADT at a university-affiliated comprehensive cancer center in the southwestern U.S. between 2010-2021. We also aimed to identify patient and healthcare provider factors that influence MSRF screening among study sample. Methods: A retrospective observational cohort study of 803 patients treated with ADT for at least six months at the cancer center was conducted. Patients were followed three months pre- to 12 months post-ADT initiation to evaluate MSRF screening/treatment. Determination of MSRF screening was based on primary care provider referral for MSRF screening/treatment or receipt of blood glucose, lipid profile, and blood pressure screening within six months post-treatment with ADT. Patients were considered treated for MSRF if they were started or continued therapy (within six months of ADT initiation) with science advisory guideline recommended treatments. Results: Guideline-concordant MSRF screening rate approached 23.5%; MSRF treatment rate was 76.9%. A higher treatment rate in MSRF treatment was found for NHW compared to Hispanic men ( p=0.02). We found a significant difference in the proportion of patients receiving MSRF screening across all racial/ethnic groups ( p=0.03). MSRF screening rates from 13.9% to 35.6% were observed over the 10-year data collection period. Patients with dyslipidemia at baseline had higher odds of having MSRF screening than patients without dyslipidemia ( p<0.0001). Oncologists with >20 years of experience had higher odds of providing MSRF screening compared with <10 years of experience ( p=0.006). Conclusions: Minority populations had significantly lower odds of having MSRF screening than NHW patients after adjusting for clinical and socio-economic variables. Closer clinical attention and education, as well as the development and implementation of innovative practice tools and interventions to optimize MSRF screening and treatment are warranted to mitigate the harmful adverse effects of ADT in patients with prostate cancer.
The Capio Prostate Cancer Center model for prostate cancer diagnostics using Stockholm3, MRI, and targeted biopsies: Real-world evidence from 2018 to 2022.
Authors: Palsdottir Thorgerdur , Söderbäck Harold , Jäderling Fredrik , Bergman Martin , Vigneswaran Hari Thambiah , Gronberg Henrik
Published: January 2024

295

Background: The Capio Prostate Cancer Center (Capio PCC) handles approximately 25% of prostate cancer care in Stockholm, Sweden. The Capio PCC Model utilizes Stockholm3 and MRI scans to assess prostate cancer risk, followed by targeted and systematic biopsies for those at increased risk. This study describes the clinical process and real-world evidence of the Capio PCC Model. Methods: If eligible for prostate cancer testing, men undergo a blood test for PSA. Men with PSA ≥1.5 ng/ml are additionally tested with Stockholm3 and men with a Stockholm3 ≥15, undergo MRI. Men with elevated risk on MRI undergo targeted and systematic biopsies. Men were included from 2018-2022 at the Capio PCC, if they underwent PSA and Stockholm3 (for PSA ≥1.5 ng/ml). The results on PSA, Stockholm3, MRI, and biopsies are presented, including the number of clinically significant prostate cancer as defined as ISUP grade ≥2. We compare the biopsy results from Capio PCC to other hospital regions in Sweden and evaluate health economics of the diagnostic pathway. Results: A total of 12,406 men aged 45-75 underwent testing for prostate cancer. Median age was 61 years (IQR: 55-67), median PSA was 1.6 ng/ml (IQR: 0.8 – 3.3), median Stockholm3 was 4 (IQR: 3-11) and 1,064 (8.6%) men were biopsied. A total of 611 (57% of biopsied) men were diagnosed with clinically significant prostate cancer. Of the tested men, 3,496 had PSA ≥3 ng/ml and 2,002 had Stockholm3 ≥15, decreasing the number MRIs by 43%. In total, 2,980 men had PSA between 1.5-2.99 ng/ml and of those, 360 (12%) had Stockholm3 ≥15 with 72 (56% of biopsied) men having clinically significant prostate cancer. In total, 330 men had PSA ≥10 ng/ml and of those, 87 men (26%) had Stockholm3 <15, reducing MRI and biopsy in this higher risk group. Comparing national Swedish prostate cancer data, the Capio PCC Model showed fewer diagnoses of low-risk cancers (14% vs. 25%), more intermediate risk cancers (59% vs. 42%), and less high-risk and advanced cancers (26% vs. 30%). Conclusions: The study demonstrates that the protocol-driven and diagnostic process at Capio PCC leads to an effective care, enabling earlier diagnosis of intermediate risk cancer and reducing the number of MRIs as well as incidence of overdiagnosis of low-risk cancers compared to the prostate cancer care in Sweden.[Table: see text]
Urologist practice divestment from radiation vault ownership and treatment patterns for prostate cancer.
Authors: Faraj Kassem S , Kaufman Samuel , Herrel Lindsey A. , Maganty Avinash , Oerline Mary , Caram Megan Veresh , Shahinian Vahakn B. , Hollenbeck Brent K.
Published: January 2024

304

Background: Urologists practicing in single-specialty groups with ownership in radiation vaults are more likely to treat men with prostate cancer. The effect of urology practice divestment in radiation vault ownership on treatment patterns of men with prostate cancer is unclear. Methods: A 20% sample of national Medicare claims was used to perform a retrospective cohort study of men with prostate cancer, diagnosed between 2010 and 2019, managed by single specialty urology groups. All men were followed through December 31, 2020. Urology groups were categorized by radiation vault ownership for each year as nonowners, owners, and divested owners. The primary outcome was use of treatment and the secondary outcome was use of intensity-modulated radiation therapy (IMRT). Both outcomes were assessed for the 12-month period after diagnosis. Using a difference-in-differences design, multivariable logistic regression was used to measure the effect of radiation vault divestment on outcomes. Subgroup analyses assessed outcomes by non-cancer mortality risk (high (> 50%) vs. low (≤ 50%)) within 10 years of diagnosis. Results: Among 72 urology practices that owned radiation vaults, six divested during the study. Divestment led to a decrease in treatment compared with those managed at continuously owning practices (difference-in-differences estimate, -13%, p=0.03). The use of IMRT also decreased, but this change was not statistically significant (difference-in-differences estimate, -8%, p=0.21). In men with a high non-cancer mortality risk, treatment (difference-in-differences estimate, -28%, p<0.001) and use of IMRT (difference-in-differences estimate, -27%, p<0.001) decreased after divestment. Conclusions: Urology single specialty group divestment in radiation vault ownership leads to a decrease in prostate cancer treatment. This decrease was most pronounced in newly diagnosed men that had a high non-cancer mortality risk. This has important implications for healthcare reform, suggesting that programs that can incentive constraints on utilization may be effective in reducing prostate cancer overtreatment.
Value-based payment models and management of newly diagnosed prostate cancer.
Authors: Maganty Avinash , Kaufman Samuel , Oerline Mary , Faraj Kassem S , Caram Megan Veresh , Shahinian Vahakn B. , Hollenbeck Brent K.
Published: January 2024

309

Background: To examine the effect of urologist participation in value-based payment models on the management of men with newly diagnosed prostate cancer. Methods: Medicare beneficiaries with prostate cancer diagnosed between 2017 and 2019 were assigned to their primary urologist, each of whom was then aligned to a value-based payment model (the Merit-based incentive payment system [MIPS], accountable care organization [ACO] without financial risk, and ACO with risk). Multivariable mixed-effects logistic regression was used to measure the association between payment model participation and treatment of prostate cancer. Additional models estimated the effects of payment model participation on use of treatment in men with very high risk (i.e.,>75%) of non-cancer mortality within 10 years of diagnosis (i.e., a group of men for whom treatment is generally not recommended) and price-standardized prostate cancer spending in the 12 months after diagnosis. Results: Treatment did not vary by payment model, both overall (MIPS— 67% [95%CI 66 to 68%], ACOs without risk—66% [95%CI 66 to 68%], ACOs with risk— 66% [95%CI 64 to 68%]). Similarly, treatment did not vary among men with very high risk of non-cancer mortality by payment model (MIPS— 52% [95%CI 50 to 55%], ACOs without risk— 52% [95%CI 50 to 55%], ACOs with risk— 51% [95%CI 45% to 56%]). Adjusted spending was similar across payment models (MIPS— $16,501 [95%CI $16,222 to $16,780], ACOs without risk— $16,140 [95%CI $15,852 to $16,429], ACOs with risk— $16,117 [95%CI $15,585 to $16,649]. Conclusions: How urologists participate in value-based payment models is not associated with treatment, potential overtreatment and prostate cancer spending in men with newly diagnosed disease.
Development of a patient-centered health-related quality of life (HRQOL) measure for metastatic renal cell carcinoma (mRCC): A three-phase study.
Authors: Bergerot Cristiane Decat , Castro Daniela V. , Bergerot Paulo Gustavo , Mercier Benjamin D. , Nally Elizabeth , Ali Adil A. , Philip Errol James , Buso Murilo , Hutson Thomas E. , Grünwald Viktor , Bex Axel , Psutka Sarah P. , Rini Brian I. , Plimack Elizabeth R. , Master Viraj A. , Albiges Laurence , Choueiri Toni K. , Pal Sumanta Kumar , Powles Thomas
Published: January 2024

365

Background: Patients (pts) with mRCC require a tailored HRQOL assessment. Previous research (Bergerot et al. Oncologist 2023; Bergerot et al. J Clin Oncol 2023) explored FKSI-19, EORTC QLQ-C30, and EQ-5D item relevance. We aimed to develop a tailored HRQOL measure for pts with mRCC through a three-phase approach involving patient engagement, expert input, and advocacy. Methods: In Phase 1, 117 pts with mRCC (83:34 M:F, median age=64) from the US, Europe and Brazil participated in a survey study to assess the relevance of items from established measures (FKSI-19, EORTC QLQ-C30, EQ-5D). In this cohort, 88% of pts had clear cell histology and 35%, 30% and 19% received immunotherapy alone, targeted therapy alone or combination therapy, respectively. Questions identified as relevant (base on ≥66% consensus) were selected for inclusion in a preliminary survey. Phase 2 involved assembling a panel of 11 experts who rigorously reviewed and refined survey questions. In Phase 3, preliminary version were presented to 8 patient advocates (5:3 F:M; 6:2 pts:caregivers) to ensure alignment with pts' needs and experiences. Results: Phase 1 analysis identified 10 items. Pts requested the inclusion of a question about social/family issues and better coverage of emotional symptoms. An 12-item questionnaire was created, and the expert committee refined three items to incorporate patient suggestions and added one item related to functional status (Table). This questionnaire included 1 cancer-specific item, 3 cancer or treatment-specific items, 3 non-specific emotional items, and 4 non-specific physical items. Patient advocates provided feedback, agreeing with the items excluded from previous questionnaires and those included. They suggested minor edits to item wording. Conclusions: The novel approach holds the potential to replace traditional HRQOL measures that may lack relevance to specific clinical circumstances. Further validation is planned in a phase 3 trial, ensuring its applicability in clinical practice. [Table: see text]
Real-world treatment outcomes in patients with advanced renal cell carcinoma who receive axitinib plus pembrolizumab in the first-line setting in Canadian cancer centers.
Authors: Beaulieu Carissa , Ghosh Sunita , Tajzler Camilla , Kirkpatrick McKayla , Castonguay Vincent , Wood Lori , Graham Jeffrey , Soulieres Denis , Bansal Rahul K. , Heng Daniel Yick Chin , Finelli Antonio , Tanguay Simon , Lalani Aly-Khan A. , Bhindi Bimal , Bjarnason Georg A. , Breau Rodney H. , Basappa Naveen S.
Published: January 2024

382

Background: The landscape of management of advanced renal cell carcinoma (aRCC) in the first line setting has changed dramatically over the past decade. Axitinib with Pembrolizumab (AP) is one of the combinations which demonstrated improved outcomes in the KEYNOTE 426 study. We report real-world outcomes and safety with this combination. Methods: The Canadian Kidney Cancer information system (CKCis) is a multi-institutional prospective RCC cohort. Patients ≥18 years with aRCC and clear cell histology who received AP as first-line therapy from January 1, 2017 to June 30, 2022 were included. Descriptive and actuarial statistics were reported for the following: progression free survival (PFS), overall survival (OS) and adverse events. Results: The cohort includes 222 patients.165 (74.3%) were male with a median age of 64.5 (37.0-87.7) years. Sixty-three (28.3%) patients were IMDC favourable-risk, 69 (31.0%) intermediate-risk, 45 (20.3%) poor-risk and 45 (20.2%) unknown. Median follow-up was 26.6 (range: 0.1 – 77.2) months. Of 222 patients, 119 discontinued treatment (53.6%) due to disease progression in 45.4% or toxicity in 29.4%. Median duration of treatment was 18.5 (range 0.1 to 72.4) months. PFS probability at 12 and 24 m was 63.8% and 49.9% respectively with a median PFS of 22.6 months (95% CI: 15.9-30.1). Survival probability at 12 and 24 m was 89.1% and 80.2% respectively with a median OS of 51.5 months (95% CI 38.0-NR). By IMDC criteria, intermediate risk median OS was 44.8 m (95% CI 41.5-61.6) and poor risk 33.6 m (18.5-NR). Most patients experienced toxicity requiring dose interruption/delay or discontinuation (n=180; 81.4%) The most common toxicities were diarrhea (73.3%), fatigue (54.4%), hepatotoxicity (50.0%), anorexia (26.1%), mucositis (22.2%), nausea (21.1%), palmar plantar erythrodysesthesia (15.6%), hypertension (13.3%), weight loss (13.3%) and proteinuria (11.7%). Others included pneumonitis (8.9%), thyroid dysfunction (6.7%) and colitis (4.4%). Conclusions: The real-world experience of patients with aRCC receiving AP in Canada is similar to the KEYNOTE-426 study in both outcomes and safety. These data continue to support its position as a standard of care in the first line setting for aRCC. Longer follow up and characterization of these patients is warranted.
Real world outcomes of first line (1L) nivolumab and ipilimumab (NIVO IPI) in metastatic renal cell carcinoma (mRCC): An update from the International mRCC Database Consortium (IMDC).
Authors: Wells Connor , Ferrier Evan , Lemelin Audreylie , Powles Thomas , Pal Sumanta Kumar , Ebrahimi Hedyeh , Agarwal Neeraj , Beuselinck Benoit , Bjarnason Georg A. , Wood Lori , Canil Christina M. , Saliby Renee Maria , de Velasco Guillermo , McKay Rana R. , Tran Ben , Suárez Cristina , Templeton Arnoud J. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: January 2024

395

Background: NIVO IPI is one of several 1L treatment options for mRCC and is limited to intermediate and poor risk disease in many jurisdictions. We report the outcomes of 1L NIVO IPI from the IMDC. Methods: All IMDC patients who received 1L NIVO IPI were retrospectively analyzed. Key outcomes were compared between IMDC risk groups and included overall survival (OS), time to treatment discontinuation (TTD), time to next treatment (TTNT; defined as time from 1L initiation to next treatment) and response rates. Conditional OS by 6- and 12-month survival are described. Results: 1145 patients received 1L NIVO IPI, including 94 favourable, 559 intermediate, and 313 poor risk patients. 818/980 (86%) of patients had clear cell histology and 14% had sarcomatoid features. The median follow up was 20.0 months. 837/1145 (73%) patients had stopped 1L NIVO IPI and 363/1145 (32%) were deceased. Key outcomes of interest are summarized in Table 1. Subsequent 2L therapy was received by 438/727 (60%) patients and was most frequently sunitinib (37%) and cabozantinib (28%). 3L therapy was received by 160/477 (34%) patients, most often cabozantinib (29%). Immune related adverse events were documented in 48% (274/572) of patients. Conditional survival analysis showed that if a patient was alive at 6 months after starting 1L NIVO IPI, they had an 81% likelihood of being alive for an additional year and a 68% likelihood of surviving two years. If alive at 12 months, there was an 81% chance of surviving one additional year and 68% chance of surviving two additional years. If a patient remained on 1L NIVO IPI for 6 months, there was a 91% likelihood of being alive for one additional year and 76% likelihood of being alive for two years. If they remained on NIVO IPI for 12 months, there was a 94% chance of being alive for one additional year and an 84% chance of surviving two additional years. Conclusions: This large cohort of real-world patients provides benchmark data for clinical trial design and patient counselling, with a median OS surpassing 50 months for intermediate risk patients.[Table: see text]
Regulatory approvals for genitourinary (GU) cancer by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) over 20 years (2003-2023).
Authors: Khanna Sanjay , Sarwar Naveed , Caldwell Reece , Krell Jonathon , Benjamin David Joseph , Hadfield Matthew James , Khaki Ali Raza , Warner Jeremy Lyle , Lythgoe Mark
Published: January 2024

432

Background: The past 2 decades has witnessed a transformation in the GU cancer therapy armamentarium. In this study, we analysed GU cancer therapy approvals (initial & supplemental) by the two largest global regulators (EMA and FDA) by evaluating approval timing, labels, biomarker requirements and drug withdrawal(s). Methods: A cross-sectional analysis of approved drugs and indications made for GU cancer medicines from each regulatory database from 2003-2023 was performed. We compared new approved therapies, indications and biomarker requirements. Results: The FDA approved 40 new therapies, corresponding to 57 indications, with 2 withdrawals. The EMA approved 33 new therapies, corresponding to 43 indications with 1 withdrawal. Overall, the FDA approved new GU cancer therapies 128 days earlier (table). In renal cell carcinoma (RCC), the FDA approved 14 new therapies across 18 indications, compared to 14 new therapies across 16 indications for the EMA. The FDA approved new RCC therapies 113 days earlier than the EMA. For concomitant approvals the FDA label was broader for 5 indications, more restrictive for 2 and equivocal for 9. In urothelial cancer (UC), the FDA approved 9 new therapies across 14 indications, compared to 7 new therapies across 7 indications for the EMA. The FDA approved new UC therapies 110 days earlier than the EMA. For concomitant approvals, the FDA label was broader for 4 indications and equivocal for 3. In prostate cancer (PC), the FDA approved 17 new therapies across 25 indications, compared to 12 new therapies across 20 indications for the EMA. The FDA approved new PC therapies 157 days earlier than the EMA. For concomitant approvals, the FDA label was broader for 2 indications and equivocal for 18. Across GU cancer, 8 therapies (both FDA and EMA) had biomarker-based eligibility with 3 notable differences in urothelial cancer: the EMA uniquely requires a PD-L1 combined positive score (CPS) ≥ 10 and PD-L1 ≥ 1% for pembrolizumab (platinum-ineligible) and Nivolumab (adjuvant), respectively. Although biomarker requirement was similar, the FDA has withdrawn atezolizumab in UC unlike the EMA. Conclusions: Over the past 20 years, there has been a substantial increase in new therapies to manage GU cancers. Patients in the US typically have access to more new therapies, earlier and across broader indications than those in Europe. However, a greater number of therapies are withdrawn after approval in the US. Biomarker-eligibility is broadly similar, with some discordance in UC. [Table: see text]
Impact of body mass index (BMI) on clinical and toxicity outcomes in patients with relapsed metastatic germ-cell tumor (GCT) undergoing high-dose chemotherapy (HDCT) with peripheral blood stem cell transplant (PBSCT).
Authors: Khalid Ahmed Bilal , Pham Phillip , Hassoun Rebecca , Althouse Sandra K. , Abonour Rafat , Abu Zaid Mohammad Issam , Hanna Nasser H. , Adra Nabil , Einhorn Lawrence H. , King Jennifer
Published: January 2024

517

Background: ASCO guidelines recommend full weight-based dosing of cytotoxic chemotherapy for all pts regardless of BMI. The regimen for HDCT in relapsed GCT at our institution uses actual body weight (ABW) dosing for carboplatin and etoposide. There is limited data on the implications of using ABW to dose HDCT in pts with GCT. We describe clinical and toxicity outcomes based on pre-transplant BMI in pts with relapsed metastatic GCT undergoing HDCT with PBSCT. Methods: The prospectively maintained Indiana University testicular cancer database was queried for pts with relapsed GCT treated between 1990-2023 with HDCT and PBSCT. Pts were classified by pre-transplant BMI as BMI <25 (normal weight), BMI 25-29.9 (overweight), or BMI ≥30 (obese). Grade 3 or higher (≥G3) toxicities were assessed using CTCAE. Comparisons between groups were done using Chi-square tests for categorical variables or Wilcoxon test for continuous variables. Kaplan-Meier methods were used to analyze progression-free survival (PFS) and overall survival (OS). The log rank test was used to compare groups. Results: 597 pts met inclusion criteria. Median age at initiation of HDCT was 32.4 (range, 16.7-70.1). Primary site was testis in 85%, retroperitoneum in 8%, and mediastinum in 7%. 76% of patients had non-seminoma. IGCCCG risk was good in 40%, intermediate in 11%, and poor in 48%. HDCT was the 2nd line treatment for 83% of pts and ≥3rd line for 17%. 90% of pts completed both cycles of HDCT. 202 pts (34%) had normal BMI, 223 (37%) were overweight and 172 (29%) were obese. Median carboplatin dose was 2100mg/m2 and median etoposide dose 2250mg/m2 for all pts in both cycles. 63% of obese pts experienced at least 1 G≥3 non-hematologic adverse event vs. 43% of overweight pts vs. 44% of pts with normal weight (p=0.0001). The rate of G≥3 renal toxicity was higher in obese pts at 17% vs. 7% in overweight pts vs. 5% in normal weight pts (p= 0.0001). G≥3 GI toxicity was higher in obese pts at 50% compared to 36% in overweight pts and 37% in normal weight pts (p=0.0079). The table lists toxicity and survival outcomes by pre-transplant BMI. Conclusions: Obese pts with relapsed GCT undergoing HDCT had higher incidence of overall G≥3 toxicity specifically renal and GI toxicity. Treatment-related mortality and survival was not impacted by differences in BMI. [Table: see text]