bluuebunny/crossref_metadata_2025 huggingface dataset:
Apalutamide toxicity and tolerability: A real-world multicentre experience in metastatic hormone-sensitive prostate cancer (MHSPC) in the United Kingdom (UK).
Authors: Ramamurthy Sindhu , Elumalai Thiraviyam , Pearson Rachel , Bolnykh Iakov , Muhammad-Afzal Tehreem , Olukiran Gbenro , Arora Ananya , Bradley Gay , Taft Kate , Lin Myint Nayan , Htike Ei The , Ince Will , Jiang Xue Yan
Published: January 2024

107

Background: Apalutamide became available for mHSPC along with androgen deprivation treatment (ADT) in the UK in November 2021. We present here, to our best knowledge the first real world multicentre experience of Apalutamide use in mHSPC patients from three tertiary cancer centres from the UK. Our primary aim was to assess for toxicity and tolerability at this stage. Methods: We collected retrospective data from hospital prescription registries including all patients with mHSPC receiving Apalutamide between November 2021 and January 2023. Median period of follow up in our cohort was 14 months. Results: Two hundreds and ten patients received Apalutamide for mHSPC from three centres. The median age was 73 years. A total of 16.4% of the patients had recurrent mHSPC previously treated for localised PC and 83% were de novo metastatic. Of all patients, 43.3% had high-volume disease, and 56.7% had low-volume disease. The median presenting Prostate Specific Antigen (PSA) was 62 ng/l at diagnosis (range 0.87 to 5580). Undetectable PSA achieved in 43.3% of patient after starting Apalutamide and ADT. For those who have detectable PSA, median value was 0.22. Ninety percent of patients maintained their performance status (PS) at 0 or 1 on treatment. Most common side effects were fatigue (35.7%) and rash (11.4%). Cardiac adverse effects were recorded in 1.9% and thromboembolic events in 0.4%. Overall grade 3 and 4 toxicity was 5.2% across all symptoms assessed. To date, 83.3% patients continue on Apalutamide, 7.6 % discontinued due to toxicity and 9.1% had progressive disease (PD). Three deaths were recorded and all due to PD. Conclusions: In this multicentre retrospective analysis we found that Apalutamide and ADT is well tolerated in the real-world setting. Our patients are older and had lower volume metastasis compared with patients from the registry Trial (TITAN). Fatigue is more prevalent. Majority patients continue on Apalutamide with manageable side effects and good PS.
The frequency of use and enrollment impact of patient-centered outcomes in prostate cancer clinical trials.
Authors: Krischak Madison , Bank Merrick , Byrnes Mary , Stensland Kristian
Published: January 2024

115

Background: Cancer treatments should help patients live either longer or better by improving patient quantity or quality of life. However, some trial endpoints do not correlate with overall survival, and are not noticeable to patients. Selecting endpoints for clinical trials that reflect these goals could improve the discovery process by ensuring trial results are of direct interest to patients, and perhaps by improving enrollment rates to trials. However, how frequently prostate cancer clinical trials use patient-centered outcomes, and how outcome type impacts trial enrollment, is unknown. Methods: On October 23, 2022, we queried ClinicalTrials.gov for full text records of phase 2-3 prostate cancer trials started after January 1, 2007. We extracted primary outcomes and other trial characteristics using a custom Python script. Two reviewers categorized each outcome into categories (e.g., overall survival, response rate, patient reported measure). As previously studied, the only valid surrogate for overall survival is metastasis-free survival. We considered these two outcomes or any outcome directly noticeable to a patient to be a patient-centered outcome. For completed or terminated trials, we defined ‘sufficient accrual’ as attaining 85% of a trial’s goal enrollment. We identified associations between trial outcome types and sufficient trial enrollment with chi-square tests and logistic regression. Results: Of 1,717 prostate cancer trials, only 37% used a patient-centered outcome, with 6% using overall or metastasis-free survival. Among 318 Phase 3 trials, 49% used a patient-centered outcome and 26% used overall or metastasis-free survival. Of 731 completed or terminated prostate cancer trials, 55% of trials and 68% of phase 3 trials reached sufficient enrollment (85% of enrollment goal). On multivariable analysis, trials with an overall survival endpoint had higher odds of sufficient enrollment (OR 8.0 [95% CI 2.2-33.5], p < 0.01), but trials with any patient-centered outcome had lower odds of sufficient enrollment (OR 0.25 [95% CI 0.11-0.54], p < 0.01). Conclusions: Less than half of prostate cancer trials use an outcome that is clearly patient-centered (i.e., affecting overall survival or an outcome noticeable to a patient). Further work is needed to clarify the use, understanding, and effect of outcome selection in cancer trials. Realigning trial efforts with patient-centered goals could improve the efficiency, productivity, and applicability of clinical trials.
Outcomes, frailty status, and body composition of men with hormone-sensitive prostate cancer treated with bicalutamide and dutasteride.
Authors: Lebenthal Justin M , Hahn Andrew Warren , Tidwell Rebecca , Zhang Krystal , Aparicio Ana
Published: January 2024

122

Background: Prostate cancer is often a disease of the frail in which androgen withdrawal can further the risk of morbidity and mortality. This study aimed to describe a single institution experience with peripheral androgen blockade using bicalutamide and dutasteride (B+D) in men with hormone-sensitive prostate cancer (HSPC) in the context of body composition and frailty. Methods: Patients with HSPC treated with B+D at MD Anderson Cancer Center between 2010 and 2022 were retrospectively identified. Baseline and post-B+D frailty scores were calculated using the G8 geriatric score. Body composition was objectively measured from pre-treatment CT imaging. Differences in patient and disease characteristics between frail vs. not frail patients were compared with Kruskal Wallis tests or chi-square tests. Time on treatment (ToT), time to next treatment (TTnT) and overall survival (OS) were calculated by Kaplan-Meier methods, and comparisons by frailty status were made with the log rank test. Results: Forty-four patients were evaluable: median G8 frailty score was 13.5 with 22 patients classified as frail (G8 score ≤ 14) at baseline and after 6 months of B+D. ToT was shorter in frail individuals than non-frail (18.9 vs 38.2 months, p=0.03). TTNT was also shorter in frail individuals (20.9 vs 38.2 months, p=0.03). Only 3 patients have died, and 5-year OS is 81.3% for the entire cohort. Sarcopenia was found in 11 patients (52%) and sarcopenic obesity in 3 (14%). Conclusions: Bicalutamide and dutasteride was generally safe and feasible in a cohort of HSPC with increased pre-treatment frailty and sarcopenia. These findings suggest that peripheral androgen blockade is a eugonad treatment option that may warrant prospective study in at-risk populations and the application of frailty scores and measures of body composition can refine the relevant population. [Table: see text]
Dose modification in enzalutamide and abiraterone plus prednisolone for castration-resistant prostate cancer: Sub-analysis from ENABLE for PCa, a multicenter, randomized controlled trial.
Authors: Izumi Kouji , Mizokami Atsushi
Published: January 2024

127

Background: Head-to-head comparison between enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) demonstrated similar survival benefit for castration-resistant prostate cancer (CRPC) in ENABLE study for PCa. As it is previously reported that reduced dose of ENZ and ABI can maintain sufficient inhibitory ability of androgen receptor signaling, we analyzed the efficacy of modified dose in ENABLE study for PCa. Methods: ENABLE study for PCa is an investigator-initiated, multicenter, randomized controlled trial conducted in Japan. We analyzed survivals, prostate-specific antigen (PSA) response rate (≥50% decline from baseline), and safety assessment in patients treated with modified dose (ENZ ≤120 mg/day, ABI ≤750 mg/day) compared to those treated with standard dose (ENZ 160 mg/day, ABI 1000 mg/day) as a starting dose. Results: In total 92 patients in each arm treated and analyzed, the number of modified dose patients in the ENZ and the ABI arm was 16 and 16, respectively. Total 32 modified dose patients showed significantly better time to PSA progression (TTPP) and overall survival than 152 standard dose patients (HR 0.47, 95%CI 0.27-0.83, p=0.0379 and HR 0.35, 95%CI 0.19-0.63, p=0.0162). Although there was significantly longer TTPP in modified ABI group than standard ABI group (HR 0.29, 95%CI 0.14-0.62, p=0.0248), no significant difference was observed in TTPP between modified ENZ group and standard ENZ group (p=0.5366). There was significant difference in PSA response rate between modified ABI and standard ABI group (79% and 53%, respectively; P=0.0036). Similar adverse event rates and grades were observed in each treatment group. Conclusions: Modified ABI showed better outcomes than standard ABI and may be a potential treatment option for CRPC patients; however, all patients were of Japanese and patients in other countries were not included. Further study should be conducted including other ethnic backgrounds and focusing on different constitutions. Clinical trial information: UMIN000015529 .
Real-life data on [177Lu]Lu-PSMA-617: Descriptive analysis on the largest metastatic castration-resistant prostate cancer (mCRPC) cohort treated in France.
Authors: Roubaud Guilhem , Somme François , Barthelemy Philippe , Olivier Pierre , Massard Vincent , Giraudet Anne Laure , Flechon Aude , Girault Sylvie , Abadie Lacourtoisie Sophie , Bailly Clément , Viala Caroline , Godbert Yann
Published: January 2024

129

Background: VISION study showed that [177Lu]Lu-PSMA-617 added to BSoC prolonged imaging-based progression-free survival and overall survival in patients (pts) with PSMA-positive mCRPC. French Health Authorities has granted a "cohort" early access for [177Lu]Lu-PSMA-617 in this indication. Methods: PSMA positive mCRPC pts pretreated with at least 1 taxane-based chemotherapy regimen and ≥1 androgen receptor pathway inhibitor (ARPI) were included. [177Lu]Lu-PSMA-617 (7.4 GBq) was administered up to 6 cycles every 6 weeks. Pts’ characteristics and safety data are described for the entire population. Efficacy was analyzed within a sub-population with 6 months follow-up min after 1st [177Lu]Lu-PSMA-617 injection. Adverse events (AE) grading was not evaluated. Results: From 12/1/2021 to 6/30/2023, 945 pts were included, and 535 pts were analyzed for efficacy. At data cut-off, 474 were still under treatment, and 471 stopped treatment due to disease progression (50.1%), AE (7.2%) or death (7.4%). 124 pts (26.3%) completed all 6 injections. Pts baseline characteristics: median age 73.2 (44-92) years; ECOG 0-1: 86.3%; median PSA level 70.9 (0.1 -6972) ng/ml; metastatic sites: bone 93.8%, lymph node 62.4%, liver 10.7%; previous taxane regimen: 97.1% of which 61.6% have received 2; prior ARPI treatment: 100% and 66.6% received 2 or more (median: 2). Concomitant treatment with ARPI was observed in 26.8%. In terms of efficacy results, the best imaging response was assessed by investigators (by RECIST 1.1 and PCWG3 on CT/bone scan and/or metabolic responses PET PSMA): 1.2% CR, 35.7% PR, 26.7% SD. 68.1% pts had a decrease in PSA level at any time point. Median time to PSA decrease was 1.22 (0.1–9.6) months. 12.8% (n= 121) of pts experienced >1 treatment-related (TR) AE, including 99 pts with ≥1 serious AE. 3 fatal cases related to treatment have been reported. The most reported TRAEs were thrombocytopenia (5.4% of pts) and anemia (5.0% of pts). Conclusions: In this large real-life cohort of mCRPC treated with [177Lu]Lu-PSMA-617 pts are heavily pretreated, received less concomitant ARPI treatment and higher incidence of 2 prior taxane regimens compared to VISION study. Safety profile of [177Lu]Lu-PSMA-617 remains favorable. Since the cohort is still ongoing, updated results will be presented at ASCO GU congress, including longer follow-up period and higher number of pts who completed treatment.
ARTO trial: Overall survival analysis from a randomized phase II trial testing the benefit of adding stereotactic body radiotherapy to abiraterone acetate in patients with oligometastatic castrate-resistant prostate cancer.
Authors: Francolini Giulio , Di Cataldo Vanessa , Garlatti Pietro , Detti Beatrice , Caini Saverio , Bruni Alessio , Ingrosso Gianluca , D'Angelillo Rolando Maria , Alitto Anna Rita , Augugliaro Matteo , Triggiani Luca , Parisi Silvana , Facchini Gaetano , Banini Marco , Simontacchi Gabriele , Desideri Isacco , Meattini Icro , Valicenti Richard K. , Livi Lorenzo
Published: January 2024

132

Background: ARTO (NCT03449719) is a multicentre, randomized phase II trial testing the benefit of stereotactic body radiation therapy (SBRT) addition to abiraterone acetate (AA) in oligometastatic Castrate Resistant Prostate Cancer (CRPC) patients. Trial ended in October 2022. Results already showed significant benefit in terms of biochemical response and Progression Free Survival (PFS) in the experimental arm, the trial was positive for its primary endpoint. Here we present an updated overall survival (OS) analysis. Methods: Patients affected by oligometastatic CRPC (< 3 non-visceral metastatic lesions) were enrolled in the trial and randomized 1:1 to receive either AA alone (control arm) or associated with concomitant SBRT on all sites of disease (treatment arm). Kaplan-Meier survival analysis was performed to compare OS in the different arms of treatment. Results: One hundred fifty-seven patients were enrolled in ARTO trial. After a median follow up of 27 months, 29 patients died (9 vs 20 in the experimental vs control arm, respectively). Median OS was not reached in neither of the two arms of treatment, with a non-significant trend in favour of the experimental arm (p=0.07). Conclusions: After an updated follow up analysis, results confirmed good prognosis for this population of oligo-metastatic CRPC patients. First line abiraterone acetate conferred long term OS in a selected cohort of patients affected by oligometastatic disease. A positive, nonsignificant trend was found in favour of experimental arm. Considering the low number of events detected, longer follow up is needed to explore impact of upfront SBRT on OS within this randomized phase II trial. Clinical trial information: NCT03449719 .
Association of initial adjustment dose of apalutamide with progression to castration-resistant prostate cancer and skin-adverse events in men with metastatic castration-sensitive prostate cancer: A multicenter retrospective study of CsJUC cohort.
Authors: Tohi Yoichiro , Kato Takuma , Kobayashi Keita , Daizumoto Kei , Fukuhara Hideo , Ohira Shin , Katayama Satoshi , Shimizu Ryutaro , Takamoto Atsushi , Nishimura Kenichi , Ikeda Kenichiro , Nagami Taichi , Sugimoto Mikio ,   Chu-shikoku Japan Urological Consortium
Published: January 2024

137

Background: Japanese patients with prostate cancer (PC) treated with apalutamide often encounter skin-adverse events (AE), which might lead to adjust the initial-dose of apalutamide. However, concerns have emerged regarding the potential impact of these dose adjustments on the overall efficacy of apalutamide in real-world clinical practice. We aimed to evaluate the association between adjustment of apalutamide dose and clinical outcome in Japanese men with metastatic castration-sensitive PC (mCSPC). Methods: We retrospectively evaluated 108 mCSPC patients treated with apalutamide. We divided patients into two groups: initial full-dose and reduced-dose recipients. The primary outcome was the impact of apalutamide dose adjustment on progression to castration-resistant prostate cancer (CRPC) and PSA response. The secondary outcomes were the impact of apalutamide dose adjustment on the incidence of the skin-AE. Results: Initial reduced-dose recipients of apalutamide were observed in 16.7%. There were no differences in cancer characteristics, such as CHAARTED criteria between the groups. Initial full-dose recipients were significantly associated with a longer time to CRPC than initial reduced-dose recipients [median NA (NA - NA) vs. 19 months (95% CI, 10 - NA), P=0.0161], although the percentages of the initial full-dose recipients who reduced apalutamide dose were 30%, 44.4%, 60%, and 63.3% at 3, 6, 9, and 12 months, respectively. The percentage of PSA <0.2 decline at 3 months did not differ between the groups (59.1% vs 50%, P=0.602), but overall PSA 90% decline was higher in the initial full-dose recipients (88.8% vs 66.7%, P=0.027). Skin-AE occurred 50% in initial reduced-dose recipients and 51.1% in initial full-dose recipients, with no difference between the groups (P>0.999). Furthermore, time to skin-AE was not different between the groups (74 days vs. 69 days, P=0.992). Conclusions: Our study suggested the potential negative implications of initial apalutamide dose adjustments on clinical outcomes in Japanese men with mCSPC.
Real-world effects of novel androgen receptor axis-targeted agents on oncological outcomes in non-metastatic castration-resistant prostate cancer: A multi-institutional retrospective study.
Authors: Fujita Naoki , Hatakeyama Shingo , Tabata Ryuji , Yoneyama Takahiro , Hashimoto Yasuhiro , Sato Satoshi , Ohyama Chikara
Published: January 2024

142

Background: The benefits of novel androgen receptor axis-targeted agents (ARATs) on oncological outcomes in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in real-world settings are unclear. Methods: This multi-institutional retrospective study included 178 patients with nmCRPC treated between September 2003 and August 2022. Patients were divided into two groups: those who were treated with any novel ARATs, including apalutamide, enzalutamide, darolutamide, and abiraterone acetate, during any line of nmCRPC treatment (novel ARATs group) and those who were not (control group). Multivariable Cox proportional hazards regression analyses were performed to evaluate the effects of novel ARATs on metastasis-free survival (MFS) and overall survival (OS). Results: The median age and follow-up period after nmCRPC diagnosis were 76 years and 37 months, respectively. Of the 178 patients, 122 (69%) were treated with novel ARATs after nmCRPC diagnosis. The MFS and OS in the novel ARATs group were significantly longer than those in the control group ( P < 0.001 and P = 0.020, respectively). In multivariable analyses, a prostate-specific antigen doubling time (PSADT) of < 3 months and novel ARATs were independently and significantly associated with MFS and OS (Table). The effects of novel ARATs on MFS were consistently observed across subgroups stratified by age (< 75 years or ≥ 75 years), history of radical treatment (no or yes), biopsy Gleason score (< 9 or ≥ 9), clinical stage (≤ cT3 and cN0, or cT4 or cN1), and PSADT (≥ 3 months or < 3 months). Conclusions: Novel ARATs were significantly associated with improved oncological outcomes in patients with nmCRPC in a real-world setting, regardless of tumor aggressiveness. [Table: see text]
Characteristics and outcomes of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with lutetium-177–PSMA-617 (PSMA-RLT) in a real-world setting.
Authors: Kersting David , Kim Moon-Sung , Puellen Lukas , Seidl-Rathkopf Kathi , Schinwald Nicole , Mpofu Philani , Altomare Ivy , Sujenthiran Arun , Royce Trevor Joseph , Buhl Christoph , Grünwald Viktor , Herrmann Ken , Kleesiek Jens , Hadaschik Boris A.
Published: January 2024

143

Background: The VISION trial demonstrated a survival benefit of PSMA-RLT treatment (tx) for pts with PSMA-positive mCRPC. However, outcomes in a real-world setting are unknown. PSMA-RLT has been used at Essen University Hospital (UKE) in Germany since 2017. This retrospective cohort study describes characteristics and real-world overall survival (rwOS) of pts with mCRPC treated with PSMA-RLT. We contextualize these findings with results from a US-based mCRPC cohort that did not receive this novel tx. Methods: The UKE cohort included mCRPC pts treated with ≥ 1 cycle of PSMA-RLT from 11/2017 to 10/2022. Data comprised structured and unstructured data from UKE’s electronic health record (EHR). The US cohort was selected from the nationwide EHR-derived Flatiron Health database. It included pts with mCRPC diagnosis (dx) from 01/2014 to 09/2021 who received tx (=index tx) following ≥ 1 taxane and ≥ 1 androgen receptor pathway inhibitor (ARPI). Results: In the UKE cohort (N = 219, median (med) age: 73, interquartile range (IQR): 67, 78) med time from initial dx and mCRPC dx to the initiation of PSMA-RLT was 69 mos (IQR: 42, 128) and 23 mos (IQR: 13, 40), respectively. Pts were heavily pre-treated (1 taxane: 55.5%, ≥ 2 taxanes: 27.8%; 1 ARPI: 37.3 %, ≥ 2 ARPIs: 58.9%). Disease burden at the time of tx start was extensive, as indicated by sites of metastases (for tumor patterns see table). Median OS (mOS) from the start of PSMA-RLT was 9.8 mos (95% CI: 8.6, 11.3). In the US cohort (N = 857, med age = 71, IQR: 65, 78) med time from initial dx and mCRPC dx to index tx was 49 mos (IQR: 27, 99) and 16 mos (IQR: 10, 25), respectively. 88.9% of pts received prior tx with 1 taxane and 11.1% with ≥2 taxanes, 65% with 1 ARPI and 35% with ≥ 2 ARPIs. Med OS for US patients was 8.5 mos (95% CI:7.6, 9.1). Conclusions: This study provided the unique opportunity to describe real-world outcomes for late stage mCRPC patients treated with PSMA-RLT. The study design did not allow for a direct comparison between the two cohorts. Qualitatively, UKE patients were heavily pre-treated with extensive disease burden at the start of PSMA-RLT. Nevertheless, the study demonstrated promising rw outcomes for patients with mCRPC under PSMA-RLT. Future work, including the direct comparison of PSMA-RLT versus other tx in a similar disease setting, will help further characterize the benefit of this novel tx in practice. [Table: see text]
Analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with carboplatin-paclitaxel after multiple lines of treatment.
Authors: Fernández Pérez Elisa María , Beltrán Guerra Isabel , Sánchez Vegas Adrian , Robles Carlos Enrique , Lourenzo Aguilera Gloria , Fernández Carcaño Marta , Ayala De Miguel Carlos , Díaz López Sebastián , García González Guillermo , Bachurin Leonid , Rico López Javier , Fuentes Pradera Jose , Jimenez Castro Jeronimo , Rodríguez de la Borbolla María , López Álvarez Pilar , Gómez Reina María José , Chaves Conde Manuel , Fernández Parra Eva
Published: January 2024

144

Background: Metastatic castration-resistant prostate cancer (mCRPC) occurs in men with advanced disease progressing to androgen deprivation therapy, with serum testosterone < 50 ng/dL. In this setting, several active therapies are available, such as chemotherapy and androgen receptor-targeted agents. We analyzed the efficacy of the carboplatin - paclitaxel (C-P) combination in mCRPC patients after several lines of treatment. Methods: In this retrospective observational study, we analyzed the clinical data of 43 patients with mCRPC who received treatment with biweekly C-P between 2015-2022 at the Hospital Universitario Virgen de Valme. The data collected refer to the baseline characteristics of the patients at the start of treatment (age, functional status), stage at diagnosis and treatments received in first and successive lines, among others. The response variables analyzed were both overall survival (OS) and progression-free survival (PFS). Treatment-derived toxicity was collected. The data were processed with IBM-SPSS Statistics v. 25. The information was collected from Diraya Estación Clínica v 4.0.80 and Farmis-Oncofarm. Results: As of September 2022, data had been collected for 43 men with mCRPC. Histology was adenocarcinoma in all cases. At the start of C-P treatment: 48.9% of patients were in good functional status (ECOG ≤ 1), median age was 71 years and 62.8% had received at least 3 lines of treatment. Patients received C-P for a median of 12 weeks: 76.7% showed clinical improvement and 44.2% had PSA decline, with PSA decline ≥ 30% in 27.5% of patients. The median OS (mOS) was 8 months (95% CI 6.46-9.54) and the median PFS was 14 weeks. By Kaplan-Meier survival analysis, we compared mOS as a function of PSA: response/non-response, the differences being statistically significant: 11 (95% CI=6.22-15.78) vs. 6 (95% CI=4.21-7.79) months, respectively (Log Rank 0.001). The main toxicity was hematological. Conclusions: The C-P combination may be an effective treatment option in patients with mCRPC refractory to various lines of therapy, with PSA being a good marker of response to treatment.
Real-world (RW) survival and outcomes with androgen receptor pathway inhibitor (ARPI) –doublet therapy in patients (pts) with de novo metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Parrish Joshua , Polascik Thomas J. , Hong Agnes , El-Chaar Nader N. , De Hoedt Amanda Marie , Kim Janet , Trustram Eve Claire , Touya Maelys , Ramaswamy Krishnan , Gu Lin , Freedland Stephen J.
Published: January 2024

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Background: With multiple phase 3 trials showing improved overall survival (OS) with doublet therapy (androgen-deprivation therapy [ADT]+ARPI), it has become the standard of care for pts with mCSPC. However, data on RW effectiveness of ARPI doublets are limited. This study assessed OS, time to progression to metastatic castration-resistant prostate cancer (mCRPC), and PSA decline to <0.2 ng/mL in pts with de novo mCSPC on ADT alone vs ADT+ARPI doublets or ADT+first-generation nonsteroidal antiandrogens (NSAAs). Methods: Men in the Veteran’s Health Administration with ≥1 ICD code for PC and de novo mCSPC diagnosis confirmed by clinical chart review were identified and categorized into first-line (1L) ADT alone, ADT+NSAA, or ADT+ARPI cohorts (study period: Feb 2018−Mar 2023). Target recruitment quotas ensured representation of each treatment (Tx) regimen. Index date was the ADT initiation date. OS and time to mCRPC were calculated using inverse probability of Tx weighting (IPTW)-adjusted Cox regression. IPTW-adjusted incidence rate ratios (IRR) of the proportion of pts with PSA decline to <0.2 ng/mL at any time during 1L Tx were estimated using Poisson regression. Results: 384 men with de novo mCSPC were identified (Table). Median follow-up range was 34.8–38.1 mo. 1L Tx duration for ADT+ARPI was over twice as long as ADT alone (Table). Importantly, pts on ADT+ARPI had a 39% lower risk of death vs ADT alone (HR: 0.61, 95% CI: 0.43–0.87); while OS was similar between ADT+NSAA vs. ADT alone (HR: 1.09, 95% CI: 0.79–1.49). Consistent with the improved OS, ADT+ARPI showed a 54% lower risk of progression to mCRPC (HR: 0.46, 95% CI: 0.33–0.66) and significant superiority in achieving PSA <0.2 ng/mL (57% vs 17%; Table) than ADT alone. Conclusions: This is one of the first RW studies to validate clinical trial findings of the effectiveness of ARPI-doublets for de novo mCSPC as evidenced by significantly improved OS, time to mCRPC, and PSA response. ADT+NSAA may have limited value vs ADT alone, and ARPI-doublet is an effective Tx for de novo mCSPC. [Table: see text]
Efficacy and safety between first-line therapies in metastatic castration-resistant prostate cancer in combination in the PARPi and ARSI era: A systematic review and network meta-analysis.
Authors: Guo Xuanjun , Li Yixin , Wang Mengying , Peng Hexiang , Guo Huangda , Hou Tianjiao , Zhang Hanyu , Jiang Jin , Sheng Tao , Fan Yu , Wu Tao , He Zhisong
Published: January 2024

146

Background: The treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved tremendously, while little is known about the efficacy and safety comparison between current first-line mCRPC systemic therapies in the overall patient population and in the context of clinically relevant subgroups. Methods: We conducted a systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs). Multiple databases (PubMed, Embase, and Cochrane Library), ClinicalTrials.gov, and major congress abstracts were searched in the first-line treatment of mCRPC. The primary efficacy outcomes were radiographic progression-free survival (rPFS) and overall survival (OS). The safety outcomes were adverse events (AEs), serious AEs (sAEs), and grade ≥3 AEs. Two separate pairwise meta-analyses were conducted since there were no common arms between therapies with and without docetaxel (Doc) when considering OS and safety outcomes, while only trials without Doc assessed rPFS. Moreover, we performed subgroup analyses according to treatment regimens and homologous recombination repair (HRR) gene alteration status. Results: The analysis included data from 35 clinical trials (38 references) published as of June 6, 2023, comprising a total of 24,400 patients. For the non-Doc group, analysis of treatment ranking revealed that PARPi doublet, especially talazoparib plus enzalutamide, had the highest likelihood of improving rPFS and OS compared with ARSI doublet, ARSI monotherapy, and immunotherapy, mainly in the HRR-deficient patients while raising some concerns about safety profiles. Regarding therapies based on Doc, most Doc doublet regimens demonstrated subtle improvement in OS compared to Doc monotherapy with tolerable toxicity. Conclusions: This systematic review and meta-analysis provided a comprehensive analysis of the therapeutic effects and safety profiles of various first-line mCRPC systemic therapies. Our findings may provide decision-making guidance to clinicians and help inform mCRPC patients-centered treatment regimens. In an era of PARPi combination with ARSI, unfortunately, because of the lack of common arm delivery of Doc, we cannot estimate the relative value of Doc versus non-Doc as first-line mCRPC therapies.
Final study analysis of PRINT: Prostate cancer intensive, non–cross-reactive therapy for CRPC.
Authors: Liaw Bobby Chi-Hung , Joshi Himanshu , Sheng Tianxiang , Tsao Che-Kai , Galsky Matt D. , Bakst Richard Lorne , Stewart Robert , Stock Richard , Oh William K.
Published: January 2024

147

Background: The long-standing approach to mCRPC management has been to treat sequentially with one agent until resistance is met. PRINT explores the efficacy of treating mCRPC with a rapidly-cycling, non–cross-reactive regimen as a way to more effectively treat an intrinsic heterogeneous disease, delay or prevent drug resistance, and minimize treatment toxicity. Methods: All patients receive treatment with 3 consecutive treatment modules, each lasting 12 weeks: 1. abiraterone acetate 1000 mg PO daily + prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV + carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily + radium-223 55 kBq/kg IV q4 weeks. Upon completion of regimen, patients are followed on ADT alone. Primary endpoint for the study is time to progression (TTP), either by PSA or imaging. Secondary endpoints are PSA response rate with each module, changes to alkaline phosphatase levels, and safety. Results: From 3/2017 to 11/2020, 40 men with mCRPC were enrolled, with 33 completing the 9-month study regimen and evaluable for endpoint analysis. With median follow up of 139 weeks, median TTP after regimen completion was 15.9 weeks (95% CI 10.6-25.0 weeks), which did not meet prespecified TTP of 20 weeks to be considered a significant improvement over standard management. PSA response rates showed successive improvement with each sequential treatment module (Table). 77.8% of patients with elevated baseline alkaline phosphatase levels had normalization post-treatment. Previously reported, the treatment regimen was well-tolerated, with few grade 3/4 AE’s attributable by the investigator to the study regimen. Five patients (15.2%) were able to remain on post-study surveillance with ADT alone without the addition of a mCRPC agent for over a year, with one patient subsequently discontinuing ADT with PSA remaining undetectable in setting of recovering testosterone levels. Conclusions: Treatment of mCRPC with a rapidly cycling non–cross-reactive regimen did not significantly improve time to disease progression as compared to standard management. However, it is associated with significant antitumor response, with potential for long-term suppression of disease. Additional analysis into clinicopathologic and genomic factors that may predict for prolonged disease control is ongoing. Clinical trial information: NCT02903160 . [Table: see text]
PSA flare in patients with metastatic castration-resistant prostate cancer undergoing 177Lu-PSMA treatment.
Authors: Li Haoran , Wulff-Burchfield Elizabeth Marie , Abbasi Saqib , Narang Arshit , Dal Emre , Donald Joseph , Yap Wendell Y , Shen Xinglei , Chen Ronald C. , Parikh Rahul Atul
Published: January 2024

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Background: 177Lu-PSMA (Lu-177) is an FDA-approved radiopharmaceutical agent for metastatic castration-resistant prostate cancer (mCRPC) progressed on prior chemotherapy and androgen receptor pathway inhibitor. The chronology, frequency and association PSA flare with Lu-177 on overall treatment outcome is unclear. Our retrospective study evaluates the association of PSA flare with clinical outcomes in mCRPC patients undergoing Lu-177 therapy. Methods: A retrospective study was conducted from 4/2022-8/2023 for patients treated with Lu-177 at the University of Kansas Cancer Center. PSA flare was defined as an initial rise in PSA levels that subsequently declined. A bone flare is defined as increased radiotracer uptake in bone scans. The primary outcome was progression-free survival (PFS). The secondary outcomes included overall survival (OS), PSA response, disease control rate (DCR) and safety. Results: A total of 46 patients were included in this study. The median age was 73 years (range: 52-100). Of these, 14 patients (30.4%) had completed 6 cycles of treatment. The median number Lu-177 cycles received was 3 (range: 1-6). PSA flare was observed in 7 patients (15.2%), and all of the PSA flare occurred in the first cycle. The median time from the start of treatment to the onset of PSA flare was 2 weeks (range: 1-4). The median change in PSA from baseline to flare increased by 41% (range: 22-1133%). The median time from PSA flare to PSA nadir was 12 weeks (range: 9-30). The median change in PSA from flare to nadir decreased by 73% (range: 57-95%). Bone flare was seen in 4 patients (13.8%) and the median onset time is 12 weeks (range: 10-17). There was no significant difference in PFS and OS between patients with or without PSA flare [median PFS: 7.1 vs. not reached (NR), p=0.11; median OS: NR vs. NR, p=0.27). A total of 22 patients (56.4%) exhibited a 50% PSA decrease (PSA 50). The proportion of patients with PSA 50 response was similar in both the PSA flare group (57.1%) and the non-PSA flare group (56.3%) (p=0.97). Among the patients who underwent radiographic assessment (n=29), the DCR was achieved in 66.7% vs. 60.9% of patients with or without PSA flare (p=0.79). The most common side effects in patients with or without flare included fatigue (71.4% vs. 66.7%, p=0.81), arthralgia (0% vs. 26.7, p=0.31), nausea (14.3% vs. 20%, p=0.73), diarrhea (28.6% vs. 10%, p=0.20), and anorexia (28.6% vs. 10%, p=0.20). Conclusions: PSA flare in patients treated with Lu-177 is not uncommon. Our study suggests the clinical response appears consistent regardless of the flare. Further studies and additional long-term follow-up are needed to validate our findings.
Characteristics and outcomes of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) showing a primary resistance (PR) to docetaxel (DOC): Results from a large real-world database.
Authors: Caffo Orazio , ButtIgliero Consuelo , Ermacora Paola , Sorarù Mariella , Di Girolamo Stefania , Sabbatini Roberto , Gori Stefania , Facchini Gaetano , Cattrini Carlo , Marchetti Andrea , Valcamonico Francesca , Vignani Francesca , Conteduca Vincenza , Sartori Donata , Barile Carmen , Naglieri Emanuele , Calvani Nicola , Cavo Alessia , Biasini Claudia , Bimbatti Davide ,   on behalf of ECHOS trial group
Published: January 2024

158

Background: ECHOS trial is a large real-world study, which is collecting data on mCSPC patients treated in the daily clinical practice in Italy from 2015. To date, > 1500 pts were included in the study, most of them treated with DOC, according to the availability of the active agents over the time in Italy. In the present analysis, we assessed the characteristics and outcomes of mCSPC pts progressing within 6 mos from the start of DOC. Methods: We retrospectively and prospectively reviewed the clinical records of a consecutive series of mCSPC pts treated with DOC in the daily clinical practice in 69 Italian Hospitals. The treatment mostly consisted of DOC at the standard dose of 75 mg/sqm every 3 wks for six courses. For each pt we recorded the pre and post-DOC clinical history, the baseline characteristics of the pts, the treatment details and clinical outcomes. For the purpose of the present study, we considered only pts who ended chemotherapy by September 2022. PR was defined as the onset of progressive disease within 6 mos from the DOC start. Results: Among 920 mCSPC pts treated with DOC, 122 (14.3%) were PR. Most of them (95.6%) presented a de novo (DN) disease, which showed mostly high volume (HV) features (82.3%). Compared to the pts without PR, those showing PR presented more frequently a visceral involvement (26.2% vs 18.2%; p = 0.038), had lower baseline levels of hemoglobin (12.8 g/dl vs 13.4 g/dl; p < 0.0001), and higher baseline levels of lactate dehydrogenase (266 U/L vs 220,5 U/L; p < 0.002). No other significant differences were observed in terms of baseline PSA and alkaline phosphatase levels, symptoms degree, disease volume and timing of mets presentation between PR e no-PR pts. The median number of life prolonging agents administered after DOC progression was 1 in pts with PR as well as in pts without PR. The median overall survival was 11.9 mos and 44.9 mos in PR and no-PR pts, respectively (p < 0.0001). Conclusions: Our data suggest that PR led a significant worsening of prognosis with a relevant shortening of life expectancy in pts who receive DOC for mCSPC.
Comparative survival in metastatic castration-sensitive prostate cancer (mCSPC) by prognostic subgroups: A living network meta-analysis.
Authors: Naqvi Syed Arsalan Ahmed , Riaz Irbaz Bin , Khakwani Kaneez Zahra Rubab , Bibi Arifa , Andrews Jack R. , Childs Daniel S , Ravi Praful , Orme Jacob , Singh Parminder , Sweeney Christopher , Bryce Alan Haruo
Published: January 2024

171

Background: Treatment effects vary by volume of disease and timing of metastatic presentation in patients with mCSPC. Therefore, we updated the existing body of evidence to assess the comparative efficacy of systemic therapy in mCSPC by prognostic subgroups to inform clinical practice guidelines. Methods: This living systematic review was conducted using the living interactive evidence (LIvE) synthesis framework. Phase III clinical trials assessing contemporary systemic therapy in mCSPC and reporting overall survival (OS) by four prognostic subgroups were included. Prognostic subgroups included synchronous high volume (SHV), synchronous low volume (SLV), metachronous high volume (MHV), and metachronous low volume (MLV) disease. Mixed treatment comparisons were made using a network-meta-analytic approach in each subgroup. P-scores were used to assess relative treatment rankings in congruency with pairwise estimates. Higher scores indicated better efficacy. Results: This study included a total of nine trials with eight unique treatment options. In patients with SHV disease, darolutamide+docetaxel+ADT (DARO+D+ADT) significantly improved OS when compared to D+ADT (HR: 0.69; 0.57-0.85), enzalutamide (E)+ADT (HR: 0.67; 95% CI: 0.46-0.99), and apalutamide (APA)+ADT (HR: 0.65; 95% CI: 0.43-0.96). In patients with SLV disease, E+ADT (HR: 0.62; 95% CI: 0.42-0.91) and AAP+ADT (HR: 0.66; 95% CI: 0.49-0.89) significantly improved OS when compared to ADT. Although E+D+ADT trended toward improvement compared to other treatments, the results were not statistically significant. In patients withMHV disease, no statistically significant differences were observed among mixed treatment comparisons. However, OS with DARO+D+ADT trended toward improvement when compared to D+ADT (HR: 0.69; 95% CI: 0.39-1.23), APA+ADT (HR: 0.72; 95% CI: 0.23-2.33), E+ADT (HR: 0.67; 95% CI: 0.24-1.86), and E+D+ADT (HR: 0.59; 95% CI: 0.26-1.34). In patients with MLV disease, E+ADT significantly improved OS compared to ADT (HR: 0.51; 95% CI: 0.32-0.79), and D+ADT (HR: 0.48; 95% CI: 0.27-0.85). APA+ADT significant improved OS compared to ADT (HR: 0.22; 95% CI: 0.09-0.54), and D+ADT (HR: 0.21; 95% CI: 0.08-0.55). No other statistically significant differences were observed among mixed treatment comparisons. Conclusions: Current evidence suggests that triplet systemic therapy may be preferred in SHV, E systemic triplet and E hormonal doublet in SLV, DARO systemic triplet and APA hormonal doublet in MHV, and APA or E hormonal doublets in MLV mCSPC. [Table: see text]
The prognostic value of circulating miRNAs in patients with localized/locally advanced prostate cancer after radical prostatectomy and radiotherapy.
Authors: Zedan Ahmed H. , Hansen Torben , Madsen Jonna Skov , Osther Palle Jörn Sloth
Published: January 2024

184

Background: The outcome after curative intended management of local prostate cancer (PC) is promising. However, there is still a risk of biochemical relapse (BR) after either radical prostatectomy (RP) or radiotherapy (RT). MicroRNAs (miRNAs) have showed encouraging results as alternative biomarkers in different settings of PCa. The aim of this study was to investigate the prognostic value of circulating miRNAs after management of local PCa. Methods: In total 107 newly diagnosed patients with local or locally advanced PCa were included in the study. The cohort was divided into an interventional group with 59 patients (RP (39 patients) or RT (20 patients)) and an observational group with 48 patients (active surveillance (AS)). Both baseline samples at time of diagnosis and follow-up samples six months after treatment were collected. The relative expression of four miRNAs (miRNA-21, -93, -125b, and miRNA-221) was assessed in plasma using real-time polymerase chain reaction. Results: In the interventional cohort, the decrease in miRNA-125b after RT was significantly associated with a longer time to biochemical recurrence (BR) (HR= 0.17, p=0.03), and a higher level of miRNA-125b at baseline samples showed a tendency to higher risk for BR in the same population (HR= 2.82, p=0.09). On the other hand, lower levels of miRNA-221 at both baseline and follow-up samples tended to be associated with lower risk of BR in patients managed by RT (HR=0.14, p=0.07, and HR=0.13, p=0.07, respectively). None of these four miRNAs was associated with a significant risk of progression in patients managed by AS. Conclusions: Both baseline and the dynamics of miRNA-125b was informative as to the risk of BR in patients with PCa treated by RP. Validation in independent cohorts is called for.
Tumor suppressor genes (TSG), treatment, and survival in de novo metastatic hormone-sensitive prostate cancer.
Authors: Schoen Martin W. , Montgomery Robert Bruce , Knoche Eric Marshall
Published: January 2024

187

Background: The standard of care for metastatic hormone sensitive prostate cancer (mHSPC) has changed substantially in less than a decade. For patients with suitable functional status, combination therapy is recommended. A diverse molecular landscape of mHSPC exists, however molecular findings have yet to inform treatment in mHSPC. Outcomes for patients vary according to baseline molecular features and patients with mutations of tumor suppressor genes (TSG) have worse survival. We sought to examine the impact of TSG alterations on overall survival (OS) for men with de novo mHSPC. Methods: We identified patients diagnosed with de-novo mHSPC from July 2017-December 2021 within the Veterans Health Affairs. Alterations in TSG including TP53, PTEN, and RB1 were determined from National Precision Oncology Program (NPOP) testing collected at any time and all alterations were included. Only patients who survived 4 months and treated within 4 months of diagnosis were included. Treatments included androgen deprivation therapy (ADT) alone, docetaxel, or androgen receptor pathway inhibitors (ARPI). Kaplan-Meier and Cox proportional hazard models to assess the association between TSG and age, BMI, weight change in the year prior to mHSPC, Charlson comorbidity index, PSA at diagnosis, Black race, treatments for mHSPC, and OS. Results: We identified 2808 veterans with de novo mHSPC and 915 (32.6%) had NPOP data available. Patients with NPOP data were younger (mean age 71.4 vs. 75.2 years, p<0.001) and had longer OS than veterans without testing (43.7 months vs. 31.0, p<0.001). TSG alterations were found in 475 of 915 veterans (51.9%) and included 344 TP53 (37.6%), 206 PTEN (22.5%) and 50 RB1 (5.5%). Veterans with TSG had shorter OS compared to no TSG, median OS 48.5 months without TSG vs 37.7 with 1 or more TSG (p<0.001). Each TSG alteration was associated with mortality, TP53 adjusted Hazard Ratio (aHR) and 95% confidence interval 1.68 (1.35-2.09), PTEN aHR 1.33 (1.02-1.73), RB1 aHR 1.51 (1.01-2.26). ADT alone was given in 354 veterans (38.7%), docetaxel in 139 (15.2%), and ARPI in 422 (46.1%). In veterans with one or more TSG neither docetaxel nor ARPI therapy was associated with OS in unadjusted or adjusted analyses compared to ADT alone (Table). Conclusions: TSG alterations were associated with shorter survival in de novo mHSPC in veterans with molecular testing. In this real-world observational study, treatment intensification with docetaxel or ARPI in veterans with TSG was not associated with improved overall survival. [Table: see text]