bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection rate of 18F-rhPSMA-7.3 PET in patients with suspected prostate cancer recurrence: Results from a phase 3, prospective, multicenter study (SPOTLIGHT)
Authors: Schuster David M. ,   SPOTLIGHT Study Group
Published: February 2022

9

Background: 18F-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) ligands offer a longer half-life and improved spatial resolution compared with 68Ga-PSMA. Here, we report the detection rate (DR) of 18F-rhPSMA-7.3, a novel high affinity theranostic PET ligand with potential for low bladder activity. Methods: SPOTLIGHT (NCT04186845) assessed the coprimary endpoints of patient level Correct Detection Rate (CDR - % of all patients scanned with ≥1 true positive lesion) and region level Positive Predictive Value (all PET positive regions combined) of 18F-rhPSMA-7.3 using histopathology and/or conventional imaging as a composite Standard of Truth (SoT). These metrics were also evaluated in a subset of patients with a histopathology-only SoT. Prespecified statistical thresholds of at least 36.5% and 62.5% were set for CDR and PPV, respectively. Overall DR stratified by PSA was also documented. Men with prostate cancer recurrence underwent PET 50-70 minutes after IV administration of 296 MBq 18F-rhPSMA-7.3. Image guided biopsies of PET lesions took place ≤60 days post-PET and any confirmatory imaging took place ≤90 days. Three blinded central readers evaluated the scans with majority read accepted as final interpretation. A separate Truth Panel established SoT for each patient. Results: The overall DR in the 389 men (median [range] PSA, 1.10 [0.03-134.6] ng/mL) who had an evaluable 18F-rhPSMA-7.3 scan is 83% by majority read (See Table). In the 366 men (median [range] PSA, 1.27 [0.03-134.6] ng/mL) with a composite SoT, the patient level CDR is 56.8% (95% CI, 51.6-62.0), meeting the prespecified threshold. The region level PPV is 59.7% (54.7-64.7), not meeting the prespecified threshold. In the subset of patients with a histopathology-only SoT, the patient level CDR and region level PPV are higher at 81.2% (69.9-89.6) and 71.6% (62.5-80.7), respectively. Both of these values would have met the prespecified thresholds. Conclusions: 18F-rhPSMA-7.3 has a clinically meaningful CDR that meets the prespecified threshold. While the region level PPV does not meet the prespecified threshold, the data in patients with a composite SoT are limited by the high proportion of prostate/bed scans (92%) that relied on conventional imaging, a suboptimal SoT. For the subset of patients with the more robust histopathology SoT for at least one region per patient, a high PPV is seen and the lower bound of the 95% CI would have exceeded the prespecified threshold. Together, these data support the clinical utility of 18F-rhPSMA-7.3 PET in men with recurrent prostate cancer across a wide PSA range. Clinical trial information: NCT04186845. [Table: see text]
Prostate-specific antigen (PSA) outcomes in black (B) and white (W) chemotherapy-naïve (CN) prostate cancer (PC) patients (pts) treated with enzalutamide (ENZA).
Authors: Morgans Alicia K. , Hong Agnes , Murty Sharanya , El-Chaar Nader N. , Ramaswamy Krishnan , Coutinho Anna D. , Nimke David , Freedland Stephen J.
Published: February 2022

20

Background: Population-level data suggest that B men are more likely to be diagnosed and die from PC. In juxtaposition, across multiple treatments for advanced PC, studies suggest B men have better survival than W men, including with novel hormone therapies (NHTs) such as ENZA. Whether improved survival is driven by better clinical response is unknown as data on racial differences in treatment response for ENZA are limited. This study assessed real-world PSA outcomes (response and progression) of ENZA-treated B vs W CN PC pts in the US. Methods: This retrospective cohort study included PC pts who initiated ENZA in the IntrinsiQ Specialty Solutions urology electronic medical records database from Sept 1, 2014 to Feb 28, 2018. The index date was the first prescription for ENZA. Patients with evidence of prior chemotherapy and/or abiraterone were excluded. Baseline characteristics, PSA response (PSA decline ≥50% or ≥90%), and clinical progression-free survival (cPFS) were assessed by race. Kaplan-Meier and Cox models adjusting for baseline characteristics were used to estimate PSA response and cPFS. Results: The study included 214 B and 1,332 W CN PC pts. Black pts were younger and had a higher baseline median PSA than W pts. Charlson Comorbidity Index (CCI), median duration of therapy, follow-up time, and number of post-index PSA tests were similar between races. In adjusted analyses, the chances of pts achieving ≥50% PSA decline was similar, whereas a numerically higher trend was observed for ≥90% PSA decline in B pts (Table). In addition, B men had significantly better cPFS (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.68, 0.98; p=0.03) [Table]. Conclusions: This real-world study found similar PSA response in B and W CN PC pts treated with ENZA but suggests that B pts may have better cPFS than W pts. Further research is warranted to validate these findings.[Table: see text]
Hormonal treatment for newly diagnosed metastatic prostate cancer: A population-based study of 15,435 cases from the California Cancer Registry (2009-2018).
Authors: Benjamin David Joseph , Fellman Dimitra , Shrestha Anshu , Rezazadeh Arash
Published: February 2022

22

Background: Androgen deprivation therapy (ADT) is considered standard of care in the treatment of metastatic prostate cancer (mPC). Over the past ten years, the approval of novel androgen receptor-axis-targeted therapies has changed the treatment landscape of mPC. All these novel therapies have only been approved for use in addition to ADT. Despite these new therapeutic advances, it remains unclear how often men with mPC receive standard of care treatment with ADT. Methods: Male adults aged 20 years and older with newly diagnosed metastatic (stage IV) prostate cancer between 2009 and 2018 were identified through the California Cancer Registry (n = 15,435). Patient characteristics including age, year of diagnosis, race/ethnicity, insurance status, socioeconomic status (SES), Charlson co-morbidity score, and death within 3 months of diagnosis were analyzed. Results: 23.1% (n = 3,568) of men with newly diagnosed mPC did not receive ADT. The highest rate of receiving ADT was in men between ages 75-84 (79.6%), and the lowest rate was in men aged over 85 (72.0%) as shown in the table. There was a trend toward more newly diagnosed men receiving ADT in 2018 (81.3%) compared to 2009 (68.8%). Asian men (n = 1077) had a larger proportion of receiving ADT (79.7%), followed by American Indian men (n = 152; 76.4%), Hispanic men (n = 2,368; 75.1%), non-Hispanic White (n = 6,790; 75.6%), and lastly non-Hispanic Black men (n = 1,312; 74.8%). Men from the highest SES had the highest rate of receiving ADT (77.3%), and lowest rate was in lowest SES (73.5%). There was no significant difference among men not receiving hormonal therapy based off Charlson comorbidity score: 0 (26.0%), 1-2 (25.3%), and 3+ (24.9%). Conclusions: Despite significant advancements in the treatment of mPC in recent years, nearly a quarter of patients in California did not receive ADT, which is the backbone for all new systemic therapies. Further statistical analysis of this data set is currently ongoing. This data set might be able to help addressing some of the prostate cancer care disparities in California. [Table: see text]
Predictive factors for effectiveness from novel androgen-receptor-axis-targeted agents in patients with metastatic prostate cancer.
Authors: Nishimoto Koshiro , Nakajima Kenichi , Oyama Masafumi , Kaneko Go , Takahashi Satoru , Matsuyama Hideyasu , Shiina Hiroaki , Ichikawa Tomohiko , Horikoshi Hiroyuki , Hashine Katsuyoshi , Sugiyama Yutaka , Miyao Takeshi , Kamiyama Manabu , Harada Kenichi , Ito Akito , Mizokami Atsushi ,   PROSTAT-BSI Investigators
Published: February 2022

33

Background: About a half of men with prostate cancer progress to metastatic castration-resistant prostate cancer (mCRPC) one year after the initiation of androgen-deprivation therapy (ADT), whereas approximately 20 % of men keep the sensitivity to ADT more than 5 years. Several novel androgen-receptor-axis-targeted agents (ARATAs) were developed for the treatment of mCRPC, and improved overall survival (OS) in patients with mCRPC; however, to which patients these ARATAs were more beneficial is yet to be determined. We conducted this study to identify factors that predict effectiveness from ARATAs for mCRPC. Methods: We previously performed a multicenter study to determine prognostic factors including bone scan index (BSI) in patients with metastatic hormone sensitive prostate cancer (n = 148) and mCRPC (n = 99), which showed that BSI was one of the significant determinants of 3-year OS (PROSTAT-BSI study). The patients with mHSPC progressed to mCRPC (n = 101). Among these mCRPC patients, 69 patients received treatments with or without ARATAs, because the patients were recruited before and after approval of ARATAs in Japan. We used the data of the 69 patients to identify predictors for effective use of ARTA. The cohort was divided into two groups according to patient factors by several thresholds, and these two cohorts were further divided into two subgroups: those who received and did not receive ARATAs (abiraterone or enzalutamide). OS was compared between these two cohort groups to evaluate contribution of each factor. Categorical values were analyzed in the same way, although no threshold setting was required. Results: Factors, in which the significant treatment effect from ARATAs was observed between subgroups in only one group (eg. age < 71.4 vs age ≥ 71.4), were age ( < 71.4 years); serum levels of C-reactive protein (≥0.16 ng/mL), alkaline phosphatase (≥548 U/L), and type 1 collagen C-terminal telopeptide ( < 6.4 ng/mL); time to PSA progression after ADT ( < 8.9 months); lowest PSA level (≥1 ng/mL) after ADT; and rate of PSA decline 3 month after ADT ( <.987). Whereas, no significant difference was observed between two groups in cohorts divided by hemoglobin level, PSA before ADT, Gleason score, and BSI. Conclusions: This study identified the predictors of the effectiveness from ARATAs. In addition, the number of bone metastases (corresponding to BSI) and Gleason score, which were considered as high-risk factors in the LATITUDE study and disease volume in the CHAARTED criteria, may not be useful for predicting the effectiveness from ARATAs.
Novel framework for treatment response evaluation using PSMA-PET/CT in patients with metastatic castration-resistant prostate cancer (RECIP): An international multicenter study.
Authors: Gafita Andrei , Rauscher Isabel , Weber Manuel , Hadaschik Boris A. , Wang Hui , Armstrong Wesley R , Tauber Robert , Grogan Tristan , Czernin Johannes , Rettig Matthew , Herrmann Ken , Calais Jeremie , Weber Wolfgang A , Benz Matthias R. , Fendler Wolfgang Peter , Eiber Matthias
Published: February 2022

42

Background: We aimed to develop a novel framework for Response Evaluation Criteria In PSMA-PET/CT (RECIP) 1.0 and a composite response classification which combines responses by PSA measurements and by RECIP 1.0 (PSA+RECIP). Methods: This was an international, multicenter, retrospective study. 124 men with mCRPC who underwent 177Lu-PSMA therapy and received PSMA-PET/CT at baseline (bPET) and at interim at 12 weeks (iPET) were included. Pairs of bPET and iPET were interpreted by consensus among three blinded readers for appearance of new lesions. Tumor lesions were segmented and total PSMA-positive tumor volume (PSMA-VOL) was obtained. Appearance of new lesions and changes in PSMA-VOL were combined to develop RECIP 1.0, which was defined as: complete response (RECIP-CR: absence of any PSMA-ligand uptake on iPET), partial response (PSMA-PR: decline ≥30% in PSMA-VOL and no appearance of new lesions), progressive disease (RECIP-PD: increase ≥20% in PSMA-VOL and appearance of new lesions), stable disease (RECIP-SD: any condition but RECIP-PR or RECIP-PD). Changes in PSA levels at 12 weeks by PCWG3 were recorded. Responses by PSA+RECIP were defined as: response (PSA decline ≥50% or RECIP-PR/CR) and progression (PSA increase ≥25% or RECIP-PD). Study's primary outcome measure was the prognostic value of RECIP 1.0 for overall survival (OS). Secondary outcome measure was the prognostic accuracy (C-index) of PSA+RECIP vs PSA responses. Results: Patients with progressive disease (RECIP-PD; n=39; 8.3 mo) had shorter OS compared to patients with stable disease (RECIP-SD; n=47; 13.1 mo; p<0.001) and to those with partial response (RECIP-PR; n=38; 21.7 mo; p<0.001). PSA+RECIP had superior C-indices in identifying responders and progressors compared to PSA only: 0.65 vs 0.62 (p=0.028) and 0.66 vs 0.63 (p=0.044), respectively. Conclusions: PSMA-PET/CT by RECIP 1.0 is prognostic for OS and can be used as a response biomarker to monitor efficacy of 177Lu-PSMA in men with mCRPC. PSA+RECIP may be used as a novel composite endpoint in mCRPC clinical trial design.
Comparison of major adverse cardiovascular events risk after androgen deprivation therapy initiation by body mass index.
Authors: Gordan Lucio N. , Atkinson Stuart , Boldt-Houle Deborah , Lee Andrew K.
Published: February 2022

44

Background: The association between androgen deprivation therapy (ADT) and increased cardiovascular (CV) risk in prostate cancer (PCa) patients is controversial.1-2 Major adverse cardiovascular events (MACE) occurred in 3-6% of patients in a 48-week ADT trial,2 but meta-analysis from a 2011 study found no association between ADT and increased risk of CV death.1 Body mass index (BMI) is a potential risk factor; Lee et al. found a lower risk of MACE in patients with high BMI than those with a normal weight, and patients with low BMI had a higher risk of all-cause mortality.3 This study evaluates the association between BMI and MACE risk in PCa patients on ADT using real-world data. Methods: Analyses of US electronic medical records (2010 to 2020) of PCa patients (n=36,249) receiving LHRH agonist/antagonist injections were conducted to calculate the risk of MACE since ADT initiation for the following BMI groups: <18.5, 18.5 to <25, 25 to <30, 30 to <35, and >35. BMI groups were based on the standard weight status associated with each BMI range (underweight, normal or healthy weight, overweight, obese, and severely obese, respectively).4 The database contained 178,388 LHRH agonist/antagonist injection entries and 965 documented MACE events. Exclusion criteria included lack of ADT initiation date, lack of BMI data, and MACE within 6 months prior to ADT initiation. MACE was defined as myocardial infarction, stroke, and death from any cause based on a recent study in this field.2 Kaplan-Meier event-free survival curves were constructed to compare the risk of MACE between BMI groups. Statistical significance between survival curves was evaluated by log-rank test. Results: Differences in MACE incidence between BMI groups were not significant. (Table). Conclusions: MACE risk was similar across BMI subgroups after ADT initiation. This is consistent with the literature that higher BMIs do not confer additional CV/MACE risk as might be expected (a lower risk of MACE in patients with high BMI than those with normal weight).3 This 10-year analysis in >35,000 patients is likely reflective of the real world, but further study is recommended to evaluate whether BMI should be considered a predisposing risk factor for CV disease in PCa patients undergoing ADT. As the association between ADT and increased CV risk in PCa patients is controversial, future studies evaluating the role of co-morbidities on MACE risk for PCa patients during ADT may be helpful to identify other CV predictors.[Table: see text]
Real-world analyses of major adverse cardiovascular event risk by drug class after initiation of androgen deprivation therapy.
Authors: Crawford E. David , Atkinson Stuart , Boldt-Houle Deborah , Gordan Lucio N.
Published: February 2022

46

Background: Recent literature has suggested an association between androgen deprivation therapy (ADT) and increased cardiovascular (CV) risk in prostate cancer (PCa) patients.1,2 The 1-year incidence of major adverse cardiovascular events (MACE) in patients ≥45 years old was 1.4%,3 whereas a recent study of PCa patients on ADT reported MACE in 2.9% of patients treated with an LHRH antagonist (relugolix) and 6.2% of patients treated with an LHRH agonist (leuprolide acetate) over 48 weeks.4 Thus, MACE risk is an important consideration for PCa patients on ADT. This study aims to evaluate MACE risk after ADT initiation with LHRH agonists vs. LHRH antagonists using real-world data. Methods: Analyses of US electronic medical records (2010 to 2020) of PCa patients (n=45,059) receiving LHRH agonist and antagonist injections were conducted to evaluate the rate of MACE-free survival after ADT initiation by drug class. The database contained 178,388 LHRH agonist and antagonist injection entries and 965 documented MACE events. Exclusion criteria included taking more than one class of ADT and MACE within 6 months prior to ADT initiation. MACE was defined as myocardial infarction, stroke, and death from any cause based on a recent study in this field.4 Kaplan-Meier event-free survival curves were constructed to compare the risk of MACE between patients on agonist vs. antagonist. Statistical significance between survival curves was evaluated by log-rank test. Results: Overall MACE risk for all patients was 1.0% at one year. MACE risk was significantly higher for patients treated with LHRH antagonist compared to agonists in the first seven years after ADT initiation. Conclusions: Risk of MACE was lower than previously reported. Although this may potentially be due to underreporting, our analysis of data over 10 years from >45,000 PCa patients is likely an accurate reflection of the real world. A recent study using large real-world dataset with >50,000 PCa patients over approximately 2 years showed no difference in CV risk following treatment with GnRH agonists and antagonists.5 However, in our analyses MACE risk was lower in patients treated with LHRH agonists vs. antagonists in the first seven years after ADT initiation. Further, we plan to evaluate baseline comorbidities and demographics for imbalances. Future studies evaluating the impact of ADT class and comorbidities on MACE risk for PCa patients during ADT may be helpful to identify CV predictors. 1Ng C-F, et al. Scientific Reports. 2020. 2Zhao J, et al. PLoS One. 2014. 3Miao B, et al. J of the American Heart Association. 2020. 4Shore ND, et al. New England Journal of Medicine. 2020. 5George G, et al. Int J Cancer. 2021.
Statin type and survival of patients with metastatic castrate-resistant prostate cancer receiving abiraterone and enzalutamide: A nationwide retrospective cohort study.
Authors: Yoon Harrison , Luo Suhong , Sanfilippo Kristen Marie , Linneman Travis , Whitmer Alison , Schoen Martin W.
Published: February 2022

50

Background: Studies have suggested that statin use is associated with prostate cancer mortality. However, uncertainties exist in how the solubility profile of statins impact cancer outcomes. Lipophilic statins have greater accessibility in extrahepatic tissues, which may lead to stronger inhibitory effects on cancer cells, whereas hydrophilic statins exhibit greater hepato-selectivity and therefore less likely to cause drug interactions and adverse events. Abiraterone (ABI) and enzalutamide (ENZ) are antiandrogen agents used in metastatic castrate-resistant prostate cancer (mCRPC). In this study, we sought to examine whether statin usage and lipophilicity of statins is associated with survival benefits in mCRPC patients receiving ABI or ENZ. Methods: We conducted a nationwide retrospective cohort study of the Veteran Affairs population. Patients with mCRPC who received statin therapy one year prior to initiation of either ABI or ENZ between 9/10/2014 and 6/3/2017 were included and followed until April 2020. Statins were categorized as lipophilic (atorvastatin, simvastatin, lovastatin, fluvastatin, cerivastatin, pitavastatin) and hydrophilic (rosuvastatin and pravastatin). A cox proportional hazards model was used to estimate adjusted hazards ratio (aHR) with 95% confidence interval (CI) of overall survival after controlling for known prognostic factors including age, Charlson-Romano Comorbidity Index, use of bone-modifying agents, Body-Mass Index, and prostate specific antigen levels. Results: A total of 4919 patients (mean age 75.0 years) were included in our cohort. Of those, 969 patients (19.7%) received lipophilic statins and 452 patients (9.2%) received hydrophilic statins. After adjusting for known factors, statin use was not associated with improved overall survival (aHR 0.93; 95% CI 0.87 – 1.00). Similarly, the use of lipophilic statins (aHR 0.98; 95% CI 0.90 – 1.06) or hydrophilic statins (aHR 0.90; 95% CI 0.80 – 1.01) were not associated with improved overall survival in mCRPC. Conclusions: Our study found no differences in overall survival between mCRPC patients with statin use compared to those without statins. When analyzing statin lipophilicity, we saw a higher trend towards survival in the hydrophilic statin group compared to the lipophilic statin group, which contradicts the direct anticancer benefits of lipophilic statins, but neither group reached statistical significance. Further studies analyzing statin usage and types with specific outcome measures such as cardiovascular events, duration of antiandrogen therapy, and adverse events related to ABI or ENZ will support in optimal therapy choices for mCRPC.
Diagnosis codes overestimate the burden of prostate cancer cases.
Authors: Anglin-Foote Tori , Lee Kyung Min , Robison Brian , Alba Patrick , DuVall Scott L. , Lynch Julie Ann
Published: February 2022

72

Background: Identifying cancer cases within the electronic health record (EHR) or claims data can be challenging because diagnosis codes are often entered into patient records during routine screenings or as “rule out” diagnosis codes when the patient is referred to a procedure. To improve accuracy of prostate cancer (PCa) case ascertainment, we compared algorithms that used diagnoses codes to natural language processing (NLP) tools applied to clinical notes and pathology reports to identify Veterans with prostate cancer (PCa). Methods: This is a retrospective observational cohort study using VA EHR data to identify veterans diagnosed with PCa between 2000 and 2020. Using International Classification of Diseases (ICD-10 CM or ICD-9 CM) diagnosis and procedure codes, we identified veterans who may have PCa. We deployed validated NLP tools to identify the presence of Gleason score, metastatic PCa, and castration sensitivity to identify evidence of PCa within the notes. We conducted a descriptive analysis to compare the results of algorithms that relied exclusively on diagnosis codes compared to use of NLP tools. Results: From 2000 through 2020,1,031,296 veterans had one or more PCa diagnosis code. This number decreased by 11% for each additional PCa diagnosis code required. When we required 4 or more PCa diagnosis codes to be present, only 746,350 veterans had PCa. When we deployed NLP tools to identify mention of a Gleason score or an indicator of mPCa, only 685,847 Veterans had these indicators of PCa, a 35% decrease in the number of PCa cases with a single diagnosis code. Chart review of patients with their first PCa diagnosis codes in 2019 and 4 or more codes in their records illustrated no evidence of Gleason score or mPCa disease in their EHR. Analysis of their pathology reports revealed that these patients had prostatic intraepithelial neoplasia or atypical small acinar proliferation and had not yet developed prostate cancer. Conclusions: Accurate ascertainment of PCa using EHR and claims data requires using NLP tools and clinical notes combined with structured data sources such as diagnosis codes. Relying on ICD diagnosis codes alone will overestimate the burden of PCa up to 30%.
Electronic patient reporting outcomes are a promising predictive factor of prostate cancer patient survival: The Protecty study.
Authors: Helissey Carole , Riviere Clémentine , Becheriat Selma , Vanquaethem Hélène , Parnot Charles , Brureau Laurent
Published: February 2022

76

Background: The benefits of Electronic Patient Remote Outcomes (e-PRO) for telemonitoring are well established, allowing early detection of illnesses and continuous monitoring of patients. We have previously shown high levels of compliance of use of telemonitoring in daily care. This new PROTECTY study assesses the predictive power of patient health status in the first month of treatment on survival, evaluated with the telemonitoring platform Cureety. Methods: This prospective study was conducted at the Military Hospital Bégin on prostate cancer patients. Patients were allowed to respond to a symptomatology questionnaire based on CTCAE v.5.0, personalized to their pathology and treatment. An algorithm evaluates the health status of the patient based on the reported adverse events, with a classification into 2 different states: Good Health status (A) Poor Health status (B) In case of A, the patient received therapeutic advice to help manage each of the reported adverse events. In case of B, the patient is invited to call the hospital. For the purpose of this analysis, we collected their health status during the first month after initiation of treatment. The primary endpoint was to assess if the first month health status is a predictive factor of progression free-survival (PFS) for prostate cancer patient. The secondary endpoint was to assess if the first month health status is a predictive factor of overall survival (OS) for prostate cancer patient. Results: Sixty-one patients were enrolled between July 1st, 2020 and June 30st, 2021. The median age was 74.0 (range 58.0 – 94.0). 62% presented a metastatic stage, and the most represented cancer was mHSPC with 39,5% among metastatic patients. Overall, 2443 questionnaires were completed by the patients, 4.0% resulted in a health classification in state B. 86,9% of patient were classified in group A the first month. 13,1% of patient were classified in group B the first month. The median follow up was 12.3 months. PFS at 12 months was 89% in A group vs 60% in B group, p=0,17 OS at 12 months was 100% in A group vs 86% in B group, p=0,15. Conclusions: Our study is the first to assess the impact of tolerance treatment on survival. The initial results suggest that e-PRO assessment by the platform could help identify in the early stages the patients that require further health assessment and potential therapeutic changes. While further follow-up of more patients will be required, our study highlights the importance of e-PRO in cancer patient care.
A prospective study of the relationship between CRPC patient’s quality of life after enzalutamide and serum testosterone levels measured via LC-MS/MS.
Authors: Miyazawa Yoshiyuki , Nakamura Toshiyuki , Takezawa Yutaka , Shimizu Nobuaki , Matsuo Yasushige , Ogura Haruyuki , Takei Tomoyuki , Arai Seiji , Sekine Yoshitaka , Suzuki Kazuhiro
Published: February 2022

79

Background: Enzalutamide (ENZ) is used to treat patients with castration-resistant prostate cancer (CRPC). Quality of life (QOL) during ENZ treatment for CRPC patients is very important, but the markers that predict QOL are unknown. We investigated the relationship between serum testosterone (T) levels before ENZ and QOL changes in CRPC patients. Methods: We conducted a prospective study from 2014 to 2018 at Gunma University Hospital and related facilities. We analyzed 95 patients who were able to evaluate QOL by FACT-P before, 4 weeks, and 12 weeks after ENZ administration. We measured serum T levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This study was approved by the institutional review board of Gunma University Hospital (No.1177). Results: The study population of 95 patients had a median age of 72 years and median PSA of 21.6 ng/ml. The median overall survival from the time of ENZ administration in 95 cases was 26.8 months. The median serum T levels before ENZ treatment was 50.0 pg/ml. The mean total FACT-P score before ENZ administration, 4 weeks and 12 weeks later were 95.8, 91.7, and 90.1, respectively. 95 patients were divided into two groups, a high T levels (T-High) group and a low T (Low-T) group, and changes in FACT-P were examined. The mean FCAT-P values in the High-T and Low-T groups were 98.5 and 84.6 after 4 weeks and 96.4 and 82.2 after 12 weeks, which were significantly higher in the High-T group (p < 0.05, respectively). In the Low-T group, the mean FACT-P value after 12 weeks was significantly lower than that before administration (p < 0.05). Conclusions: It was suggested that the serum T levels of CRPC patients before ENZ treatment may be useful for predicting marker of QOL changes after ENZ treatment.
Exposure-adjusted safety analyses of the VISION phase 3 trial of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer.
Authors: Chi Kim N. , Adra Nabil , Garje Rohan , Michalski Jeff M. , Lavalaye Jules , Kempel Mette Moe , Brackman Marcia , Perraud Kevin , Holder Geoffrey , Armstrong Andrew J.
Published: February 2022

85

Background: In the VISION trial, targeted radioligand therapy with 177Lu-PSMA-617 significantly prolonged radiographic progression free survival (rPFS) and overall survival when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA)-PET-positive metastatic castration-resistant prostate cancer. There was a higher incidence of treatment-emergent adverse events (TEAEs) with 177Lu-PSMA-617 + SoC vs SoC. However, treatment exposure was more than three times longer in the 177Lu-PSMA-617 + SoC arm and thus relative toxicity may have been overestimated. A post hoc analysis of the relationship between exposure and frequency of TEAEs was performed to facilitate comparison of rates between arms. Methods: In this international, open-label study, adult patients previously treated with ≥ 1 androgen receptor pathway inhibitors and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, ≤ 6 cycles) + SoC or SoC. Safety was a secondary endpoint. TEAEs (regardless of causality) were reported from start of randomized treatment for up to 30 days after last treatment administration (including SoC) or 1 day before subsequent anticancer treatment, whichever occurred first. Overall TEAE incidence was adjusted for treatment exposure by calculating incidence per 100 patient treatment-years (PTY). The analysis was performed for the first occurrence of TEAEs. Results: Exposure-adjusted incidence of any grade, grade ≥ 3 and selected TEAEs are listed in the table. There was similar exposure-adjusted incidence of gastrointestinal events and fatigue and higher exposure-adjusted incidence of musculoskeletal and renal events with SoC compared with 177Lu-PSMA-617 + SoC suggesting an association with treatment exposure rather than 177Lu-PSMA-617. Dry mouth, dry eye and acute myelosuppression maintained a higher incidence, confirming relationship with 177Lu-PSMA-617 treatment. Conclusions: The adjusted safety analysis, accounting for a longer safety observation due to longer rPFS in patients receiving 177Lu-PSMA-617, reveals a comparable incidence of TEAEs between arms. This confirms a favorable risk/benefit profile of 177Lu-PSMA-617 added to SoC in this patient population. Clinical trial information: NCT03511664. [Table: see text]
Long-term safety of darolutamide in patients with metastatic castration-resistant prostate cancer.
Authors: Vjaters Egils , Fizazi Karim , James Nicholas D. , Tammela Teuvo , Matsubara Nobuaki , Priou Frank , Lesimple Thierry , Bono Petri , Kataja Vesa V , Garcia Jorge A. , Protheroe Andrew , Aspegren John , Joensuu Heikki , Kuss Iris , Thiele Silke , Fiala-Buskies Sabine , Jones Robert Hugh
Published: February 2022

90

Background: Darolutamide, a structurally distinct and highly potent androgen receptor inhibitor, had a consistently favorable safety and tolerability profile in patients with nonmetastatic castration-resistant prostate cancer in ARAMIS, and discontinuation rates due to adverse events (AEs) remained consistently low after longer follow-up. In previously reported phase 1/2 studies in patients with metastatic castration-resistant prostate cancer (mCRPC), darolutamide was well tolerated for up to 25 months. We report the safety and tolerability of extended treatment with darolutamide in these mCRPC studies. Methods: Data from three phase 1/2 studies (NCT02363855, NCT01317641/NCT01429064, and NCT01784757) in patients with mCRPC were pooled for analysis of long-term safety. Results are summarized descriptively. Results: Of 173 patients with mCRPC evaluable for safety in the 3 studies, 13 patients received > 2 years of darolutamide treatment; median duration of treatment was 38 months (range 24–90). Six patients received > 4 years of darolutamide treatment. Nine of 13 patients with > 2 years of darolutamide therapy initially received 600 mg BID; others received 200 mg (n = 1), 300 mg (n = 1), or 700 mg (n = 2) BID. Median age was 68 years in the > 2-years group, and most patients were white. Patients were enrolled from France (n = 4), Latvia (n = 3), United Kingdom (n = 3), Finland (n = 2), and Japan (n = 1). Most patients had normal renal function (n = 10) and hepatic function (n = 10), 12 patients had Eastern Cooperative Oncology Group performance status of 0, and 9 patients had a Gleason score ≥7. Prior systemic anticancer treatments taken by more than 1 patient were bicalutamide (n = 10); cyproterone (n = 3); and triptorelin and leuprorelin (n = 2 each). No patient received prior chemotherapy. All 13 patients reported AEs, most grade 1 or 2; 6 reported grade 3 AEs. Treatment-related AEs were reported in 5 patients, and all were grade 1 in severity. Serious AEs were reported in 6 patients, and all were judged not related to darolutamide. One patient treated with darolutamide for > 2 years had an AE (new neoplasm; not related to darolutamide) that led to treatment discontinuation. Conclusions: Extended darolutamide treatment > 2 years in this small group of patients with mCRPC was generally well tolerated, with safety and tolerability consistent with that previously reported. Clinical trial information: NCT02363855, NCT01317641/NCT01429064, and NCT01784757.
Clinical utility of next-generation sequencing for prostate cancer in the context of a changing treatment landscape.
Authors: Griffin Jacqueline R. , Jun Tomi , Liaw Bobby Chi-Hung , Guin Sunny , Tsao Che-Kai , Patel Vaibhav G. , Rossi Michael , Zhou Xiang , Hantash Feras , Chen Rong , Oh William K.
Published: February 2022

112

Background: Next-generation sequencing (NGS) is increasingly common in clinical practice, but its clinical utility may depend on the availability of sequencing-directed therapies (SDT). There were no FDA-approved SDTs in prostate cancer (PCa) until 2020, when PARP inhibitors olaparib and rucaparib were approved for tumors bearing alterations in certain homologous recombination repair (HRR) genes. We assessed the clinical utility of NGS in PCa before and after the approval of these agents in a single academic medical center. Methods: This was a retrospective single-center study including all PCa patients seen at Mount Sinai Hospital (New York, NY) between 2018–2021 who received NGS via the 161-gene Sema4 Signal Solid Tumor Panel. Clinical data were extracted from the Mount Sinai electronic medical record using a proprietary automated pipeline with limited manual curation (Sema4 PRODB). The primary outcome was clinical utility in metastatic PCa, defined as the proportion of metastatic PCa patients who received SDT. Secondary outcomes included time-to-next-treatment (TTNT, defined as time from SDT start to the start of next systemic therapy) and the proportion of patients with clinically actionable (as of 9/2021) alterations, defined as either Tier 1 (associated with FDA-approved treatments in prostate cancer) or Tier 2 (associated with either off-label or investigational agents). Results: The cohort consisted of 332 PCa patients; 51% (N = 170) were sequenced in 2020 or later. The median age at diagnosis was 65 (IQR 12). The most advanced stage documented was localized for 39% (N = 129) and metastatic for 61% (N = 203). Overall, 167 actionable alterations were identified in 125 patients (38% of cohort). Of the actionable alterations, 31% (N = 51) were Tier 1 and 69% (N = 116) were Tier 2. Of the 44 patients with Tier 1 alterations, 8 (18%) received SDT (all received olaparib). The proportion of metastatic patients receiving olaparib increased from 1% (2/145) before 2020 to 10% (6/58) during or after 2020 (p = 0.008). Of the 36 patients not receiving olaparib: 20 were sequenced before FDA approval and were treated with an alternative systemic therapy; 8 had localized disease and were not eligible; 8 had limited follow-up or unknown treatment status. For those who received olaparib, median TTNT was 5 months. Conclusions: In this single-center retrospective cohort, clinical utility of NGS was linked to treatment landscape. Increases in NGS test volume and olaparib use coincided with the approval of PARP inhibitors for patients with HRR-mutated prostate cancers. Notably, NGS was used to match patients to off-label/ investigational olaparib before its FDA approval.[Table: see text]
Updated biomarker results from a phase 1/2 study of olaparib and radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases (COMRADE).
Authors: McKay Rana R. , Xie Wanling , Ajmera Archana , Saraiya Biren , Parikh Mamta , Folefac Edmund , Olson Adam C. , Heath Elisabeth I. , Parikh Rahul Atul , Ivy S. Percy , Van Allen Eliezer Mendel , Lindeman Neal Ian , Shapiro Geoffrey
Published: February 2022

119

Background: Radium-223 is an α-emitting radioisotope that induces DNA double-strand breaks leading to cell death. In preclinical models, PARP inhibitors have shown efficacy as radiosensitizing agents. We designed a phase 1/2 trial to test the safety and efficacy of radium-223 + olaparib. Tissue based studies investigated homologous recombination repair (HRR) gene status. Methods: This was an open-label, multi-center, phase 1/2 study (NCT03317392) evaluating the dosing, safety and efficacy of radium-223 + olaparib. Eligible patients (pts) had mCRPC with ≥2 bone metastases without visceral metastases or lymphadenopathy > 4 cm. There was no limit on prior therapy. All pts had a baseline biopsy and archival tissue was collected when available. The phase 1 used a 3+3 dose escalation design with fixed dose radium-223 (55 kBq/kg IV every 4 weeks x 6). Dose level 1 (DL1) was olaparib 200 mg PO BID; DL2 was olaparib 300 mg PO BID. The primary objective was to determine the recommended phase 2 dose (RP2D). Secondary objectives included radiographic progression-free survival (rPFS) (PCWG3 criteria), PSA response (50% decline from baseline), and alkaline phosphatase response (30% decline from baseline). HRR gene status was determined using Oncopanel tissue profiling. Results: 12 pts were enrolled on the phase 1. Median age was 68 (range 59-81) years. Median prior lines of CRPC therapies was 2 (1-5), including 3 (25%) who had received prior chemotherapy and 12 (100%) a prior novel hormone therapy. The RP2D of olaparib was 200 mg BID when combined with radium-223. Overall, PSA response and alkaline phosphatase response were 16.7% (n=2) and 67% (n=8), respectively. Median follow-up was 6.5 (range 2.8, 11.8) months, and 6-month rPFS was 57% (95% CI: 25%, 80%). 9 patients had available tissue for Oncopanel testing (7 from baseline metastasis biopsy; 2 from archival prostate tissue). Two patients were identified to have pathogenic HRR gene alterations: 1 patient with a BRCA2 mutation with rPFS of 11.63 months, 1 patient with CDK12 mutation with rPFS 2.60 months (Table). Conclusions: We demonstrate that olaparib can be safety combined with radium-223 with RP2D of 200 mg BID. Though limited by sample size, we demonstrate prolonged disease control in a pt with a BRCA2 mutation receiving radium-223 + olaparib. Additional profiling from the currently accruing phase 2 study of radium-223 +/- olaparib will further elucidate biomarkers of response. Clinical trial information: NCT03317392. [Table: see text]
Triplet therapy in metastatic castration-sensitive prostate cancer: A systematic review and meta-analysis.
Authors: Naqvi Syed Arsalan Ahmed , Riaz Zaryab Bin , Riaz Anum , Islam Mahnoor , Siddiqi Rabbia , Ikram Waleed , Jafar Muhammad Ali , Singh Parminder , Ravi Praful Kumar , Riaz Irbaz Bin , Bryce Alan Haruo
Published: February 2022

136

Background: Intensification of initial treatment of in patients with metastatic castration-sensitive prostate cancer (mCSPC) with androgen pathway inhibition (API) in addition to docetaxel (DOC) and androgen deprivation therapy (ADT) has shown promise to improve clinical outcomes. Thus, we synthesize the data from modern clinical trials to estimate overall estimates of progression and survival outcomes. Methods: A systematic search of electronic databases (MEDLINE and EMBASE) was conducted to include phase III randomized controlled trials (RCTs) evaluating triplet therapy (API+DOC+ADT) against doublet therapy (DOC+ADT) in mCSPC. Outcomes of interest included overall survival (OS) and radiographic progression-free survival (rPFS). A DerSimonian-Laird random-effects meta-analysis was performed to pool precomputed hazard ratios (HRs) and confidence intervals (CIs) after logarithmic transformation using inverse-variance weighting approach. Cochran’s Q statistical test was used to assess statistically significant heterogeneity not explained by chance, while I2 statistical test was used to quantify the total observed variability, due to between-study heterogeneity. I2 values >50% indicated substantial heterogeneity. A summary of findings table was constructed to translate relative estimates to absolute risks. Results: A total of 1,531 patients in four RCTs with direct comparative data between triplet and doublet therapies, were included in this meta-analysis. PEACE-1 was the only RCT directly assessing this question (AAP+DOC+ADT). ENZA+DOC+ADT was evaluated as a subgroup in two RCTs (ENZAMET; ARCHES), APA+DOC+ADT was evaluated as a subgroup in one (TITAN). To be able to pool studies, the relative efficacy of control arm in ENZAMET (first generation bicalutamide + ADT) was considered equivalent to ADT based on prior literature. A total of 672 rPFS events were observed (34%; 261 events in triplet therapy, 54%; 411 events in doublet therapy). The difference was statistically significant (HR: 0.49; 95% CI: 0.42-0.58; I2: 0%). Similarly, 469 OS events were observed (28%; 217 events in triplet therapy, 33%; 252 events in doublet therapy). The difference was statistically significant (HR: 0.80; 95% CI: 0.67-0.96; I2: 0%). The summary of findings is outlined in the table. Conclusions: The results of this meta-analysis support an improvement in rPFS and OS in favor of triplet therapy over doublet therapy for mCRPC. However, comparative effectiveness of different triplet regimens may be different and needs further exploration.[Table: see text]
PRIMERA trial (NCT04188275), early survival results from a prospective trial exploring impact of circulating tumor cell detection in castrate resistant prostate cancer patients undergoing abiraterone or enzalutamide I line treatment.
Authors: Francolini Giulio , Loi Mauro , Ciccone Lucia Pia , Mangoni Monica , Detti Beatrice , Di Cataldo Vanessa , Aquilano Michele , Allegra Andrea , Pinzani Pamela , Salvianti Francesca , Cerbai Cecilia , Burchini Luca , Frosini Giulio , Mattioli Chiara , Salvestrini Viola , Guerrieri Barbara , Salvatore Giulia , Sottili Mariangela , Desideri Isacco , Livi Lorenzo
Published: February 2022

137

Background: Circulating tumor cells (CTC) detection and androgen receptor splice variant 7 (ARV7) expression have been shown to be associated with worse clinical outcomes in metastatic castration resistant prostate cancer (mCRPC) patients undergoing androgen receptor targeted agents (ARTA) treatment, paving the way for alternative treatment options for patients with negative predictive factors. Full-length androgen receptor (ARFL), prostate specific membrane antigen and prostate specific antigen (PSA) may further help to refine prognostic models. In our institution, a prospective observational trial testing CTC detection in mCRPC undergoing ARTA treatment (PRIMERA trial, NCT04188275) terminated the planned enrollment in 2020. Here we present early results of the overall cohort. Methods: PRIMERA (NCT04188275) is a prospective, observational trial enrolling mCRPC patients undergoing ARTA treatment. All patients were treated with either abiraterone or enzalutamide in I line setting. Blood samples to detect CTCs were taken before starting ARTA treatment. Reverse transcription - quantitative real-time PCR (RT-qPCR) was used to determine the CTC expression of PSA, PSMA, AR and ARV7. PSA drop (defined as difference between baseline PSA at ARTA treatment start and PSA at nadir under treatment), progression free and overall survival (PFS and OS) and their correlation with CTC detection were reported. Explorative analysis about AR, PSA and PSMA expression in CTC+ patients were conducted. Results: Overall, 44 patients were included. CTC were detected at treatment start in 19 patients (43,2%), of whom 3(15,78%), 9(63,15%), 15(78,94%) and 14 (73.68%) patients expressed ARV7, ARFL, PSA and PSMA, respectively. Biochemical response was significantly improved in CTC+ vs. CTC- patients, with median PSA drop values of 18.5 vs 2.5 ng/ml (p=0.03). After a median follow up of 18 months, 22 (50%) patients progressed. PFS was significantly longer in CTC- patients (not reached vs 16 months, respectively, p=0.02). Eight (18.2%) patients died, a non-significant trend in terms of overall survival was detected in favor of CTC- patients (not reached vs 29 months, respectively, p=0.05). AR, PSA and PSMA expression in CTC+ had no significant impact on PSA drop, PFS or OS. Conclusions: PRIMERA trial confirmed the CTC detection predictive importance in mCRPC patients. Adequately powered studies will be needed to further explore CTC profiling in this setting. Clinical trial information: NCT04188275.