bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world (RW) prevalence of adverse events (AEs) among patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Swami Umang , Xie Bin , Ramaswamy Krishnan , El-Chaar Nader N. , Gao Wei , Yang Hongbo , Wang Yao , Young Christopher , Mucha Lisa
Published: March 2023

109

Background: Treatment options for mCSPC patients include adding novel hormonal therapy (NHT) with/without docetaxel (DOC) to androgen deprivation therapy (ADT). Uptake of these agents has been slow, and safety concerns may contribute to therapeutic inertia. This study aims to understand the RW occurrence of prespecified AEs among pts with mCSPC in the US. Methods: Claims from the PharMetrics Plus database (IQVIA, Durham, NC) were used to retrospectively estimate the proportion of pts with AEs among those with mCSPC from Jan 2014 through Jun 2021. Common AEs (≥10%) specified in FDA labels of treatments of interest or clinical trials ≥2% more prevalent than ADT alone were included in the study. Results of four clinically important AEs (fatigue, hot flash, sexual function and gastrointestinal [GI] AEs) are reported here. The proportions of pts with each of these AEs at specific timepoints plus 95% confidence intervals (CI) were estimated from cumulative hazard plots. Results were adjusted using inverse probability of treatment weighting across ADT alone, ADT+ nonsteroidal antiandrogen (NSAA), ADT+DOC and ADT+NHT. Results: The mean age of the overall study population (N=4145) was 66 years. At baseline, common sites of metastasis were bone only (n=1886, 45.5%) and node only (n=1237, 29.8%); the most common medications used were for pain (n=2182, 52.6%) and corticosteroids (n=1213, 29.3%). The reference group for all comparisons of AEs was ADT alone. For the entire study period, GI AEs and fatigue were significantly higher only in the ADT+DOC group ( P<0.001). Hot flash was higher in ADT+NHT ( P=0.05) and the ADT+DOC groups ( P<0.001). No statistically significant differences in sexual function AEs in the groups was noted. The table shows the proportions of pts with specified AEs. Conclusions: In this large RW study, all groups, including ADT alone, showed an increase in AE reporting over time. Most AE rates with ADT+NHT were comparable to ADT alone and ADT+NSAA, while ADT+DOC showed an increase in GI AEs, fatigue and hot flash. [Table: see text]
Financial toxicity and coping mechanisms in patients with metastatic prostate cancer: A pilot study.
Authors: Joyce Daniel D , Schulte Phillip J. , Kwon Eugene D. , Dusetzina Stacie B , Penson David F. , Tilburt Jon Charles , Boorjian Stephen A.
Published: March 2023

125

Background: Assessments of financial toxicity among patients with metastatic prostate cancer are lacking. We sought to describe the prevalence and severity of financial toxicity, identify coping mechanisms, and assess characteristics that may be protective of financial toxicity among such patients at our institution. Methods: All patients evaluated in the advanced prostate cancer clinic at Mayo Clinic, Rochester, MN, were approached to complete a survey between February and May 2022. The survey consisted of three parts: 1) demographic, cancer, and treatment characteristics; 2) a coping mechanism questionnaire; and 3) The Comprehensive Score for Financial Toxicity (COST-FACIT) questionnaire. COST-FACIT scores range from 0-44, with lower scores signifying higher financial toxicity. Patients were defined as having either high (COST-FACIT score >24) or low (COST-FACIT score ≤24) financial toxicity. Coping mechanisms were compared between patients with low and high financial toxicity using Fisher’s exact test. Multivariable linear regression was used to evaluate patient characteristics associated with high COST-FACIT scores. Results: Of the 786 patients approached, 417 (53.1%) completed the survey and 281 met inclusion criteria. The median COST-FACIT score was 30 (IQR 24-36). On multivariable analysis, characteristics associated with lower financial toxicity included older age, (estimate:0.36, 95%CI 0.21-0.52), applying for patient assistance programs (estimate:4.42, 95%CI 1.72-7.11), and an annual income of at least $100,000 (estimate:7.81, 95%CI 0.97,14.66). Patients with high financial toxicity were more likely to decrease spending on basic goods (34.6% vs. 2.5%, p<0.001) and leisure activities (61.5% vs. 16.9%, p>0.001), as well as use savings (61.5% vs. 16.9%, p<0.001) to pay for their treatment. However, few patients stopped or partially filled their prostate cancer treatments due to cost. Conclusions: In this cross-sectional study of patients with metastatic prostate cancer, older age, higher income, and applying for patient assistance programs were associated with lower financial toxicity. Greater self-reported financial toxicity was associated with decreased spending on basic goods, leisure activities, and tapping into savings. On rare occasion they delayed or skipped treatment. These findings are important to inform treatment shared decision-making and supportive interventions to mitigate financial toxicity in metastatic prostate cancer.
Contemporary use of wearable activity monitors in prostate cancer survivors: A scoping review.
Authors: Noorvash Brandon , Raines Carolina , Posadas Edwin Melencio , Sandler Howard M. , Freedland Stephen J. , Gresham Gillian
Published: March 2023

127

Background: Remote monitoring of daily activity using wearable activity monitors (“wearables”) (e.g., Fitbits) provides an unintrusive method to obtain continuous, objective physical activity (PA) and sleep data outside the clinical setting. Despite their potential for improving PA assessment for cancer survivors, there is currently limited information on how wearables are being used in PCa survivors. Thus, we reviewed the literature to understand how wearables are being integrated into research and interventional studies conducted in PCa survivors. Methods: We searched PubMed, CENTRAL, and Clinicaltrials.gov for randomized controlled trials (RCTs) and observational studies that involve commercially available wearables in PCa survivors, published between 2012 and 2022. Upon screening and full-text review by two independent reviewers, data were extracted from eligible studies, including study and patient characteristics, details on study interventions and outcomes, and purpose of device use. Baseline PA data were abstracted from articles with available quantitative data, including step counts, time spent in moderate-to-vigorous physical activity (MVPA), and sleep duration, and included in a quantitative analysis. Results: Eighty studies were screened and 17 studies met eligibility criteria and were included in this review (8 RCTs; 9 observational), with a total sample size of 1,148 PCa survivors (median age 66 years, range 39-84). Wearables used included: Fitbit: (47%), pedometer (18%), smartphone (6%), Jawbone (6%), and heart rate monitor (6%). Most studies (71%) involved individual or group-based exercise interventions that were either gym-based supervised by an exercise physiologist or home-based (online web-based delivery or written recommendations), as well as remotely delivered behavioral interventions. One study compared objective (actigraphy) and subjective sleep quality measures and one was a validation study comparing Fitbit to the ActiGraph accelerometer. Study durations ranged from 1-48 weeks with median reported adherence to wearing the device of 79.5% (range 63-100%). PA data, as measured with wearables, were available in 13 studies and summarized. Conclusions: Wearables are increasingly being used to assess daily activity and monitor adherence to exercise interventions in PCa survivors. Findings suggest wearables are feasible for use in this population with high levels of adherence. Wearables can provide added value to PA and functional assessment, although more research is needed to understand how wearables can be integrated into routine patient care or used as means to track or deliver tailored interventions for PCa survivors. [Table: see text]
Differences in concomitant medication prescribing before and after novel hormonal therapy (NHT) in men with prostate cancer: A population-based study.
Authors: Yang Amy , Mei Chuchu , Banks Joshua , Nikita Nikita , Shaver Amy L , Keith Scott W. , Lu-Yao Grace L.
Published: March 2023

138

Background: Prostate cancer (PCa) is the most common non-skin cancer affecting American men. Two common NHTs used to treat PCa are enzalutamide and abiraterone. Due to the different mechanisms of these two NHTs, we hypothesized that the concomitant medications prescribed might be related to therapy-related adverse effects. The purpose of this study was to examine whether changes in concomitant medications depended on the NHT prescribed. Methods: Medicare patients with a prescription of either enzalutamide or abiraterone in the Surveillance, Epidemiology, and End Results (SEER)–Medicare database diagnosed with prostate cancer from January 01, 2004 to December 31, 2015 were included. Medications were classified by Lexicomp’s pharmacologic category. Only oral prescriptions were included. McNemar’s test was used to compare the drug use prevalence of each category prior to and after initiation of NHT. Generalized logistic regression was used to evaluate whether changes in prescription drug class during the 6 months post-NHT initiation periods depended on the type of NHT. Results: Among the 1067 patients included, 354 were prescribed enzalutamide and 713 were prescribed abiraterone. We found statistically significant interactions between NHT (enzalutamide vs. abiraterone) and period (post vs. preinitiation NHT). Patients prescribed enzalutamide were more likely to discontinue prescriptions for steroids (p<0.01) as expected. The odds of fluoroquinolones, non-steroidal anti-inflammatory drugs (NSAIDs), and loop diuretics prescriptions were similar pre-NHT initiation for both enzalutamide and abiraterone patients; however, patients treated with enzalutamide were significantly less likely than abiraterone patients to have post-NHT initiation prescriptions for fluoroquinolones (Odds ratio (OR) 0.69 p=0.01) or loop diuretics (OR: 0.57 p<0.01). Conclusions: To our knowledge, this is the first population-based study to describe concurrent medication prescribing before and after NHT. Further studies are warranted to better understand the underlying reasons for the observed patterns.
Long-term safety and tolerability of darolutamide and duration of treatment in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) from the ARAMIS Rollover Study.
Authors: Shore Neal D. , Luz Murilo de Almeida , Ulys Albertas , Ortiz Jorge A. , Srinivasan Shankar , Kurland Etah , Fizazi Karim
Published: March 2023

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Background: Darolutamide (DARO) significantly improved metastasis-free survival by ~2 y and reduced the risk of death by 31% vs placebo, with a favorable safety profile in patients (pts) with nmCRPC (ARAMIS study; NCT02200614). We report long-term safety and tolerability with continued DARO treatment in the ARAMIS Rollover Study (ROS; NCT04464226). Methods: Following the primary analysis of double-blind (DB) treatment, the ARAMIS study was unblinded, and all pts were permitted to continue on open-label (OL) DARO. After study completion, pts could continue DARO in the ROS if they had no evidence of metastases and were benefitting clinically. Of 955 pts initially randomized to DARO, 954 pts started DB DARO, 466 continued to OL DARO, and 294 entered the ROS. Pts received DARO 600 mg orally twice daily. DARO safety and treatment duration are described for the 954 pts over the DB, DB+OL, and DB+OL+ROS periods, with a data cutoff of Jan 31, 2022. Results: The median (range) treatment duration was 1.5 y (0.0–4.0) for DB DARO, 2.1 y (0.0–4.9) for DB+OL DARO, and 2.8 y (0.0–6.8) for DB+OL+ROS DARO. By the data cutoff date, 62.4% of the 954 pts had received DARO for ≥2 years, 30.1% for ≥4 years, and 12.8% for ≥5 yrs; 24.0% were still receiving DARO at data cutoff. Incidences of treatment-emergent adverse events (TEAEs) increased slightly as expected with longer observation time: any grade (DB 85.7%; DB+OL 89.8%; DB+OL+ROS 91.5%), grade 3/4 (26.3%; 31.8%; 35.5%), serious (26.1%; 32.1%; 38.5%), and leading to treatment discontinuation (8.9%; 10.5%; 12.9%). Increases in incidences of TEAEs of special interest across the DB, DB+OL, and DB+OL+ROS periods were mostly minimal. Conclusions: Approximately 30% of pts with nmCRPC remained on DARO for ≥4 y, suggesting long-term clinical benefit. The favorable safety profile of DARO was maintained with long-term exposure. No new safety concerns were observed with longer DARO treatment in the ROS. Clinical trial information: NCT04464226 . [Table: see text]
Efficacy of subsequent treatments in patients who progressed to mCRPC following treatment with apalutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC): A post-hoc analysis of the SPARTAN phase III trial.
Authors: Oudard Stephane , Hadaschik Boris A. , Antoni Laurent , Diels Joris , Luccarini Irene , Thilakarathne Pushpike , Smith Matthew Raymond , Small Eric Jay
Published: March 2023

157

Background: Apalutamide (Apa) delays the onset of metastases and extends survival in nmCRPC. However, the benefit of subsequent therapy for metastatic castration resistant prostate cancer (mCRPC) following progression on Apa remains inadequately explored. Methods: A post-hoc analysis of SPARTAN, a randomized phase III (NCT01946204), double-blind, placebo-controlled trial with Apa for the treatment of men with nmCRPC was undertaken in order to assess the impact of post-protocol treatment. Patients included in this analysis were SPARTAN patients who developed mCRPC while on Apa and received a first subsequent therapy for mCRPC (the “Next Cohort”). The index date of the analysis was the initiation of first subsequent treatment for mCRPC. The baseline characteristics of the Next Cohort (reported from the time of initial randomization because updated characteristics at the index date could not be derived) were compared to those of the ITT Apa arm in SPARTAN. Subsequent overall survival (sOS) and subsequent progression-free survival per physician assessment (sPFS) were calculated from the index date using Kaplan-Meier method. Results: At study completion, 237 patients remained on Apa without progression, while 311 were included in the Next Cohort. Of these, 241 (77.5%) received abiraterone acetate plus prednisone (AAP) provided by the sponsor as an option as first subsequent treatment, 29 (9.3%) received docetaxel; 20 (6.4%) enzalutamide and 21 other treatments (6.8%). Compared to the ITT Apa arm in SPARTAN, a higher proportion of the Next Cohort had PSA doubling time ≤6 months (79.1% vs 71.5%) and a PSA value above median at baseline, and experienced poorer PSA response (51% PSA90 overall response rate vs 62%) whilst on apalutamide treatment. The median sPFS and sOS were 6.8 months (95% confidence interval, CI, 5.8-7.9) and 20.0 months (95% CI, 17.0-22.6), respectively. Choice of subsequent next treatment did not appear to have an impact on sPFS and sOS. Conclusions: Limitations of this analysis include its retrospective nature and the lack of randomization to first line mCRPC therapy and related potential confounding, and the inclusion of patients who had progressed at SPARTAN study completion with associated poorer prognosis. Nevertheless, the analysis suggests comparable efficacy of selected first line mCRPC therapies, following progression on Apa for nmCRPC. Clinical trial information: NCT01946204 . [Table: see text]
Intra-individual dose escalation of abiraterone (ABI) according to its plasma exposure in patients (pts) with progressive metastatic castration-resistant prostate cancer (mRCPC): Results of the OPTIMABI trial.
Authors: Alexandre Jerome , Oudard Stephane , Campedel Luca , Golmard Lisa , Ladoire Sylvain , Khalil Ahmed , Maillet Denis , Tournigand Christophe , Goirand Françoise , Guitton Jerome , Dariane Charles , Joly Florence , Xylinas Evanguelos , Golmard Jean Louis , Abdoul Hendy , Khoudour Nihel , Puskiel Alicja , Carton Edith , Huillard Olivier , Blanchet Benoit
Published: March 2023

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Background: Abiraterone acetate (ABI) improves survival in mCRPC. In a previous observational study, worse PSA response and shorter progression-free survival (PFS) were associated with mean ABI plasma through concentration (ABI Cmin) < 8.5 ng/mL within the first three months (ms) of treatment (Carton E et al. Eur J Cancer 2017). The OPTIMABI study, a multicenter non-randomized study (NCT 03458247), aimed to investigate whether a dose escalation of ABI improve PFS in underexposed progressive mCRPC pts. Methods: In step 1, pts with docetaxel-naive progressive mCRPC received ABI at the standard dose of 1000 mg/d + Prednisone 10 mg/d. Mean ABI Cmin was calculated from three monthly dosages. Pts experiencing progression within the first 6 ms and for whom mean ABI Cmin was < 8.5 ng/mL were included in step 2 and received 1000 mg twice daily (2000 mg/d) of ABI. ABI Cmin was assessed every month. The primary endpoint was the non-progression rate at 12 weeks in step 2. Identification of risk factors of 6 ms-PFS was done using Cox regression analysis. Results: From 06/2018 to 09/2021, 81 of 93 pts (median age: 72 yrs) included in step 1 were evaluable for statistical analysis. The median ABI Cmin was 10.0 (IQR: 4.5-15. 0) ng/mL over the first three ms. Inter-individual variability was 59%. The 6 ms-PFS was 68% (IC 95%: 56% - 80%) with no statistical difference between pts with mean ABI Cmin ≥ or < 8.5 ng/mL (log-rank test, p= 0.24). In multivariate analysis, liver metastasis (Hazard ratio, HR = 5.95, CI95% = 1.22–28.92; p=0.027) and creatinine clearance < 60 mL/min (HR = 3.51, CI95% = 1.12–10.99; p=0.031) were independently associated with 6 ms-PFS. Among 21 pts (25.9%), with mean ABI Cmin < 8.5 ng/mL, 8 pts (38.1%) experienced tumor progression within the first 6 ms; four of them could be included in step 2. None of them fulfilled the primary endpoint despite a significant increase in plasma ABI Cmin (p <0.036 by paired t-test). Conclusions: Despite high inter-individual variability of mean ABI Cmin, the OPTIMABI study does not support the strategy of intra-individual dose escalation according to plasma concentration of ABI in mCRPC. Underexposure to ABI (ABI Cmin < 8.5 ng/mL) was not statistically associated with shorter PFS. Clinical trial information: NCT03458247 .
Comparison of prognostic characteristics between vintage and novel androgen receptor-axis-targeted drug among Japanese patients with non-metastatic castration-resistant prostate cancer: A multi-institutional study of Japanese Urological Oncology Group (JUOG).
Authors: Sakamoto Shinichi , Sato Kodai , Kimura Takahiro , Matsui Yasuyuki , Shiraishi Yusuke , Hashimoto Kohei , Miyake Hideaki , Narita Shintaro , Miki Jun , Nishiyama Naotaka , Ichikawa Tomohiko , Kitamura Hiroshi ,   pan Urological Oncology Group (JUOG)
Published: March 2023

163

Background: We conducted a multicenter study, 1) to verify the prognostic difference between novel androgen receptor-axis–targeted (ARAT) drug and vintage drug (Vintage) and, 2) to identify the prognostic PSA doubling time (PSADT) among Japanese non-metastatic castration-resistant prostate cancer (nmCRPC) patients. Methods: Of 515 patients diagnosed and treated for nmCRPC at 25 JUOG participating centers, including Chiba University Hospital, 489 patients with complete clinical characteristics were included. The association between each clinical factor, including drug types, PSADT, progression-free survival (PFS), and overall survival (OS) were analyzed, retrospectively. Results: The median age at nmCRPC diagnosis was 72 years, PSA was 3.24 ng/ml, and the observation period was 980 days. nmCRPC PFS and OS were 22 and 95 months, respectively. nmCRPC first-line therapy included Vintage + LH-RH alone: 197 cases/ARAT: 285 cases /Docetaxel (DOC): 7 cases. In the search for optimal PSADT (3-12M), PFS and OS correlated best at 10M (HR 1.64, p=0.005) and 4M (HR 2.63, p<.0001), respectively. ARAT(DOC) significantly prolonged PFS (HR 3.15, p<.0001) compared to Vintage, however, did not affect OS (HR 1.09, p=0.697) nor combined PFS (HR 0.94, p=0.733). The result was consistent, even after adjustment of the patient`s background by the propensity score matched analysis (n=145 in each arm), such as PFS (HR 0.35, p<.0001), OS (HR 1.16, p=0.598) and Combined PFS (HR 0.66, p=0.133). Multivariate analysis showed that PSADT was an independent prognostic factor for PFS (PSADT 10M: HR 3.1 p<.0001) and OS (PSADT 4M: HR 2.8, p=0.002). Conclusions: ARAT(DOC) prolonged PFS, but not OS, compared to Vintage in Japanese nmCRPC patients. PSADT (4-10M) may represent a useful tool in predicting prognosis and constructing treatment strategies for Japanese nmCRPC patients. [Table: see text]
Niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations: Second interim analysis (IA2) of MAGNITUDE.
Authors: Efstathiou Eleni , Smith Matthew Raymond , Sandhu Shahneen , Attard Gerhardt , Saad Marniza , Olmos David , Castro Elena , Roubaud Guilhem , Gomes Andrea Juliana , Small Eric Jay , Rathkopf Dana E. , Gurney Howard , Jung Wonho , Mason Gary , Francis Peter St. John , Wang George C. , Wu Daphne , Diorio Brooke , Lopez- Gitlitz Angela Mennicke , Chi Kim N.
Published: March 2023

170

Background: In the primary analysis of the phase 3 MAGNITUDE study, NIRA/AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations. Here, we report results from IA2 of secondary endpoints in MAGNITUDE. Methods: 423 eligible pts with mCRPC and HRR alterations (HRR+ cohort) were randomized 1:1 to receive NIRA/AAP (n = 212) or placebo (PBO)/AAP (n = 211). At the prespecified IA2, secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]) were formally assessed and the primary rPFS endpoint was updated in the HRR+ cohort, with sensitivity analysis performed for the subgroup of pts with BRCA alterations. Results: Updated descriptive rPFS results at IA2 (cutoff: June 17, 2022) were consistent with the primary analysis in the HRR+ cohort. In the BRCA subgroup, NIRA/AAP extended median rPFS to 19.5 mos vs 10.9 mos with PBO/AAP. NIRA/AAP led to statistically significant benefit in TSP in the HRR+ cohort with consistent benefit in the BRCA subgroup. Continued consistent improvement of TCC was seen with NIRA/AAP in the HRR+ cohort and in the BRCA subgroup. There was a trend towards improved OS with NIRA/AAP in the BRCA subgroup in the primary stratified analysis and the multivariate analysis (MVA), accounting for imbalances in key baseline characteristics. BRCA pts treated with NIRA/AAP experienced delayed time to worst pain intensity (HR, 0.70; 95% CI, 0.44, 1.12; nominal P = 0.1338) and pain interference (HR, 0.67; 95% CI, 0.40, 1.12; nominal P = 0.1275) compared to PBO/AAP. The safety profile at IA2 was consistent with that of the primary analysis, with no new safety signals observed. Conclusions: With 26.8 months of median follow-up, there was a statistically significant and meaningful clinical benefit in TSP and meaningful clinical benefit in TCC. Additionally, updated rPFS results from MAGNITUDE IA2 were consistent with the primary analysis; OS benefit was not conclusive due to immaturity and will be followed through to final analysis. Taken together, these data continue to support the use of NIRA/AAP in pts with mCRPC and BRCA alterations or select other HRR gene alterations. Clinical trial information: NCT03748641 . [Table: see text]
Impact of run-in treatment with abiraterone acetate and prednisone (AAP) in the MAGNITUDE study of niraparib (NIRA) and AAP in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Authors: Castro Elena , Chi Kim N. , Sandhu Shahneen , Olmos David , Attard Gerhardt , Saad Marniza , Gomes Andrea Juliana , Rathkopf Dana E. , Smith Matthew Raymond , Kang Taek Won , Cruz Felipe Melo , Basso Umberto , Mason Gary , del Corral Adam , Dibaj Shiva , Wu Daphne , Diorio Brooke , Lopez- Gitlitz Angela Mennicke , Tural Deniz , Small Eric Jay
Published: March 2023

172

Background: NIRA/AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations, particularly in BRCA, in the phase 3 MAGNITUDE study. As a practical measure, pts were permitted to receive up to 4 mos of AAP (in 1L mCRPC) prior to randomization to allow time for genomic testing. We evaluated the impact of AAP run-in treatment on the efficacy of NIRA/AAP. Methods: 423 pts with mCRPC and HRR gene alterations were randomized 1:1 to receive NIRA/AAP or placebo (PBO)/AAP. At the prespecified second interim analysis, a sensitivity analysis based on the duration of AAP run-in was conducted. Pts with BRCA alterations were also analyzed separately. Results: Median duration of prior AAP treatment received was 1.9 (range, 0.3–4.1) mos. Pts receiving AAP ≤2 mos had similar benefit (radiographic progression-free survival [rPFS] hazard ratio [HR], 0.69 [95% confidence interval [CI], 0.36-1.30]; time to cytotoxic chemotherapy [TCC] HR, 0.52 [95% CI, 0.24-1.11]; time to symptomatic progression [TSP] HR, 0.32 [95% CI, 0.13-0.79]; Table) to pts not receiving any prior AAP. rPFS benefit was not demonstrated in pts who had previously received AAP >2 – 4 mos: HR, 1.47 (95% CI, 0.66-3.30). Findings were consistent in the BRCA population. Conclusions: Pts receiving a short run-in (≤2 mos) of AAP alone obtained similar benefit from NIRA/AAP as those who received both NIRA/AAP together for initial treatment of mCRPC. While interpretation of data is limited by the small sample size and event numbers, for pts where NIRA/AAP is being considered as therapy, AAP may be initiated during HRR testing and combination treatment should be initiated expeditiously once HRR positivity is established to attain maximal treatment benefit. Clinical trial information: NCT03748641 . [Table: see text]
Oral EPI-7386 in patients with metastatic castration-resistant prostate cancer.
Authors: Pachynski Russell Kent , Iannotti Nicholas , Laccetti Andrew Leonard , Carthon Bradley Curtis , Chi Kim N. , Smith Matthew Raymond , Vogelzang Nicholas J. , Tu Wilson , Kwan Edmond Michael , Wyatt Alexander William , Villaluna Karen , Younginger Brett , Cesano Alessandra
Published: March 2023

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Background: EPI-7386 is a next generation aniten, a novel class of compounds designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain. Preclinical data supports disruption of AR regulated gene transcription even in the presence of resistance mechanisms including ligand-binding domain point mutations and truncated splice variants. Here we report results of the Part 1a first-in-human trial of EPI-7386 in mCRPC (NCT04421222). Methods: This Phase 1, open-label, multicenter, dose escalation (Part 1a) and expansion (Part 1b) trial was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of EPI-7386 in mCRPC patients (pts) progressing on standard of care treatment, including next generation antiandrogen(s) and chemotherapy. Originally designed to assess up to 5 doses of EPI-7386 (200, 400, 600, 800, and 1000 mg QD), two additional cohorts were added examining 400 and 600 mg BID due to 600 mg QD showing exposure saturation while demonstrating a favorable safety profile. Results: 31 pts were enrolled in the QD cohorts and 8 in the BID cohorts. Pts had a median of 4 lines of prior therapy for mCRPC: 83% received abiraterone and at least one next generation AR inhibitor, and 58% had at least one line of prior chemotherapy. No DLTs were observed; EPI-7386 was safe and well tolerated at all doses/schedules evaluated. All related adverse events (AEs) were Grade 1 and 2 and consistent with AEs associated with second-generation antiandrogens. For doses above 400 mg QD, exposures were at or above those associated with antitumor activity in animal models. Evidence of antitumor activity (including significant and durable PSA responses and/or decreases in ctDNA, and/or radiographically documented tumor shrinkage) were observed in pts with fewer than 3 lines of treatment for mCRPC, no visceral metastases and no prior chemotherapy (9/31 pts). Conclusions: Part 1a treatment with EPI-7386 monotherapy was safe, well tolerated up to a daily dose of 1200 mg (600 mg BID), achieved target clinical exposures and showed preliminary signals of antitumor activity in heavily-pretreated mCRPC. Part 1b is open with enrollment focused on pre-chemotherapy, post-second generation antiandrogen treated mCRPC pts in one cohort, and treatment-naïve non-mCRPC pts in a window of opportunity proof-of-concept second cohort. Two doses will be evaluated (600 mg BID and QD) based on FDA Project Optimus recommendations. Clinical trial information: NCT04421222 .
Rucaparib for metastatic castration-resistant prostate cancer (mCRPC): TRITON3 interim overall survival and efficacy of rucaparib vs docetaxel or second-generation androgen pathway inhibitor therapy.
Authors: Bryce Alan Haruo , Piulats Josep M. , Reaume M. Neil , Ostler Peter James , McDermott Raymond S. , Gingerich Joel Roger , Pintus Elias , Sridhar Srikala S. , Abida Wassim , Daugaard Gedske , Heidenreich Axel , Krieger Laurence E. M. , Sautois Brieuc , Loehr Andrea , Despain Darrin , Go Jowell , Watkins Simon Paul , Chowdhury Simon , Ryan Charles J. , Fizazi Karim
Published: March 2023

18

Background: TRITON3 (NCT02975934) is a randomized, multicenter, open-label, phase 3 study of rucaparib vs physician’s choice (docetaxel [DTX], abiraterone [ABI] or enzalutamide [ENZ]) in patients (pts) with chemotherapy-naïve mCRPC with BRCA1/2 (BRCA) or ATM alterations. It was previously reported that rucaparib significantly improved the primary endpoint of radiographic progression-free survival (rPFS) vs physician’s choice in pts with BRCA or ATM alterations. We report here the interim overall survival (OS) and also report on efficacy of rucaparib compared individually with either DTX or ABI/ENZ. Methods: Pts had disease progression after 1 prior second-generation androgen pathway inhibitor therapy in any setting and were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX, ABI or ENZ. An ordered step-down multiple comparisons procedure was used to control the overall error rate. OS was a key secondary endpoint with rPFS as the primary endpoint tested first in the BRCA subgroup, then the intent-to-treat (ITT) population. Subgroup analyses based on physician’s choice were exploratory. Results: As of August 25, 2022, 302 pts with BRCA and 103 pts with ATM alterations were randomized. OS maturity was 54% in the BRCA subgroup and 59% in the ITT population. rPFS and OS are shown. The most frequent treatment-emergent adverse event (TEAE) in the rucaparib, DTX and ABI/ENZ groups was asthenia/fatigue (61.1%, 67.6% and 57.6%, respectively). The most frequent grade ≥3 TEAE in the rucaparib, DTX and ABI/ENZ groups was anemia (23.7%), neutropenia (14.1%), and hypertension (10.2%), respectively. Conclusions: Rucaparib significantly improved rPFS vs either DTX or ABI/ENZ; safety was consistent with prior reports. Interim OS results suggest a trend towards improvement for rucaparib vs DTX or ABI/ENZ in pts with mCRPC and BRCA alterations. Clinical trial information: NCT02975934 . [Table: see text]
RIPK2 as a prognostic biomarker and predictor of aggressive prostate cancer.
Authors: Hammudi Mustafa , Aldhahri Walaa , Kalola Akshar , McCullum Catherine , Motoni Caddie , Martha Antonio , Rajendran Rithika , Nava Victor , Estephan Fayez , Byrne Morgan , Diao Guoqing , Jain Maneesh Rajiv
Published: March 2023

211

Background: Receptor-Interacting Protein Kinase 2 (RIPK2) has been known to play a significant role in inflammation and anti-microbial response via the NF-KB pathway. Recently, RIPK2 was also shown to stabilize and activate c-Myc, a molecule implicated in the progression of various malignancies including prostate cancer (PCa). Our study aims to determine the prognostic value of RIPK2 expression in PCa using immunohistochemistry (IHC) analysis of biopsy specimens with special focus on a predominantly African American (AA) cohort. Methods: Eligible patients aged ≥18 years diagnosed with PCa at the Washington DC VA Medical Center were randomly selected and retrospectively grouped into indolent, locally advanced, and metastatic disease categories and stratified by age, ethnicity, AJCC stage, PSA and Gleason score at diagnosis. Representative tissue from prostate core biopsy, transurethral resection, or radical prostatectomy was analyzed for each patient. RIPK2 expression and intensity were assessed by IHC and graded by two independent pathologists by the following scale: 0 (no cytoplasmic staining), 1+ (weak cytoplasmic staining similar to benign prostatic tissue), 2+ (moderate cytoplasmic staining), and 3+ (strong cytoplasmic staining). The primary endpoint was RIPK2 expression by disease group, and key secondary outcomes were RIPK2 association with Gleason score, PSA at diagnosis, age and race. Fisher’s exact test was used to evaluate statistical significance of the association between RIPK2 expression level and disease category. Results: A total of 89 patients were selected for analysis, of which 75 (84.3%) were AA. All tumors had at least 1+ level RIPK2 expression and there was a highly significant difference in RIPK2 expression according to disease severity (p < 0.001). Stratified RIPK2 expression was 1.53, 1.83, and 2.28 in the indolent, locally advanced, and metastatic groups respectively. We observed a significant directly proportional correlation between RIPK2 expression and a higher PSA level (p= 0.0021), Gleason score (p< 0.001), higher age (p= 0.0276), and AJCC stage (p< 0.001) at the time of diagnosis. Mean RIPK2 expression was 1.81 in AA patients and 2.15 in White patients (p= 0.0332). Conclusions: PCa is the most prevalent cancer in US males and there is an urgent need for more accurate biomarkers that can predict disease severity and suggest actionable targeted therapy. In this retrospective analysis, we confirm that higher RIPK2 expression is associated with more advanced PCa. We extend these findings to a predominantly AA cohort, which may promote improvements in personalized medicine for this population at higher risk for PCa if RIPK2-targeting drugs such as Ponatinib can be utilized.
Using microfluidic models to evaluate whether monocyte preconditioning plays a role in tumor-associated macrophage mediated resistance to hormone therapy in men with prostate cancer.
Authors: Kosoff David , Bootsma Matthew L , Zhao Shuang , Recchia Emma , Breneman Matthew T
Published: March 2023

228

Background: While men with metastatic castrate-resistant prostate cancer benefit greatly from 2nd generation androgen targeted therapies (ATTs), the utility of these therapies is inevitably limited by the development of resistance. Tumor associated macrophages (TAMs) are a myeloid immune cell population within the prostate tumor microenvironment (TME) that have been shown to play an integral role in development of ATT-resistance. However, the pathways that underlie TAM-mediated ATT resistance remain under investigation. In particular, many TAMs within the TME are derived from circulating monocytes and it is not yet clear whether the pathways driving TAM-mediated resistance are activated exclusively within the TME or if the activation of critical resistance pathways begins while the cells are circulating as monocytes. In this study, we utilized novel microscale technologies to investigate the transcriptome of monocytes and macrophages derived from patients progressing and responding to ATTs as well as the degree to which the macrophages promote ATT resistance in prostate tumor models. Methods: Primary monocytes were isolated from 22 men with prostate cancer who were either progressing or responding to 2ndgeneration ATTs. A portion of the monocytes from each patient were isolated for transcriptome analysis and the rest were differentiated into monocyte-derived macrophages (MDMs). MDMs were then cultured in monoculture or in co-culture with androgen-independent prostate tumor cells (22Rv1 and C42B). Each culture was then left untreated or treated with enzalutamide therapy. Following culture/treatment, each macrophage condition was isolated for transcriptome analysis and tumor cell populations from each condition were evaluated for treatment cytotoxicity. Results: Viability data from MDM-C42B co-culture demonstrated a 20% increase in tumor cell viability following enzalutamide treatment when C42B cells were cultured with primary MDMs from castrate-sensitive patients as compared to MDMs from castrate-resistant patients. Subsequent transcriptome analysis demonstrated key signatures in monocyte/macrophage populations that were associated ATT response. Conclusions: Leveraging a novel microfluidic culture platform known as Stacks, we were able to utilize primary, patient-derived cells to demonstrate that the role of TAMs in ATT resistance within the prostate TME is dependent, at least in part, on factors that are present prior to extravasation into the TME. Transcriptome analysis identified candidate pathways, which may be driving TAM-mediated differences in ATT response. These findings have the potential to lead to future use of circulating monocytes as a predictive biomarker as well as lead to the identification and targeting of ATT resistance pathways in patients.
Genomic determinants of patterns of failure in metachronous oligometastatic castration-sensitive prostate cancer.
Authors: Sutera Philip , Van der Eecken Kim , Shetty Amol , Song Yang , Hodges Theresa , Verbeke Sofie , Van Dorpe Jo , Fonteyne Valerie , De Laere Bram , Mishra Mark V. , Rana Zaker Hamid , Molitoris Jason K. , Ferris Matthew J. , Roberts Nicholas J , Song Daniel Y. , DeWeese Theodore L. , Pienta Kenneth J. , Deek Matthew , Ost Piet , Tran Phuoc T.
Published: March 2023

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Background: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state along the progression of metastatic disease in which patients experience improved outcomes compared to those with higher disease burden. Despite the generally more indolent nature, much heterogeneity still exists with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Here we correlate tumor genomics with modes of progression (MOP) and patterns of failure (POF) following treatment for omCSPC. Methods: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC, who underwent tumor next generation sequencing (NGS) with at least 1 year of follow-up. Descriptive POF and MOP were reported with respect to presence of genomic alterations in pathways of interest. Genomic pathways of interest included TP53, SPOP, WNT ( APC, CTNNB1, RNF43), DNA double strand break repair, cell cycle genes ( Rb1, CCND1–3, CDKN1B, and CDKN2A), and PI3K/AKT/mTOR. MOP were defined as oligoprogression (1-3 lesions), polyprogression (≥4 lesions), or long-term control (LTC, no radiographic progression at last follow-up). POF included location of lesions at first failure. Overall survival (OS) was calculated by the Kaplan-Meier method. Genomic associations with patterns/modes of failure were compared with chi-square test. Results: 221 patients were included for analysis with the majority having either 1 (47.5%) or 2 (27.3%) metastatic lesions at oligometastasis. 5-yr OS was associated with MOP 92% vs 89% vs 69% (p<0.01) for LTC, oligo- and polyprogression respectively. TP53 mutations were associated with significantly lower rates of LTC (24.4% vs 46%, p<0.01) and cell cycle mutations associated with high rates of polyprogression (36.7% vs 15.7%, p<0.01). With respect to POF, bone failure was significantly more common within tumors harboring mutations in TP53 (41.2% vs 23.1%, p=0.01) and less common with SPOP mutations (4.2% vs 27.8%, p=0.02). Finally, visceral failures were more common in tumors harboring either WNT pathway (20% vs 5.1%, p<0.01) or SPOP (17.4% vs 5.2%, p=0.04) mutations. Notably, SPOP and WNT pathway mutations cluster together (p<0.01). Conclusions: Tumor genomics provides novel insight into patterns of failure and modes of progression following treatment for metachronous omCSPC. Patients with TP53 and cell cycle mutations have a higher likelihood of progression and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism.
Survival trends in de novo metastatic prostate cancer: SEER and Veterans Affairs comparison.
Authors: Schoen Martin W. , Owens Lukas , Luo Suhong , Montgomery Robert Bruce , Sanfilippo Kristen Marie , Etzioni Ruth Douglas
Published: March 2023

28

Background: Advances in treatment for metastatic prostate cancer (mPC) have improved overall survival (OS) in clinical trials for mPC over the last 20 years. It is unclear whether these changes from trials have translated to improvements in survival in the real world. We sought to characterize trends in OS among patients with newly diagnosed mPC in two large national registries. Methods: Patients diagnosed from 2000-2019 were included. Patients from SEER-17 were included if stage at diagnosis was distant. For years prior to 2004, SEER Historic Stage A was used. Patients in the Veterans Affairs Prostate Cancer data core (VA) were included if the SEER summary stage variable was distant in the first record of prostate cancer in VA or oncology registry data for veterans diagnosed after 2018. Results: 55,661 patients were identified in SEER and 14,904 patients were identified in VA. Median age at presentation was 72 years in both datasets, with 16.6% identified as Black in SEER and 28.5% Black in VA. Median OS from 2000-2004 to 2015-2019 in SEER increased from 25 to 31 months, corresponding to a hazard ratio (HR) of 0.82 (p <0.001); median OS in VA increased from 25.8 to 30.9 months, corresponding to a HR of 0.912 (p=0.003). Patients <70 years of age had median OS that increased from 31 to 41 months (HR 0.78, p <0.001) in SEER and 34.4 to 42.2 months (HR 0.87, p=0.003) in VA compared to patients 70+ in SEER (21 to 26 months, HR=0.84, p<0.001) and in VA (21.6 to 25.6 months, HR=0.935, p=0.03). In SEER, black patients had worse survival compared to white patients (HR 1.10, p<0.001). Survival improvement over time in SEER was seen for both black (HR 0.81, p<0.001) and white (HR 0.83, p<0.001) patients. In VA, black patients had better OS compared to white patients (HR 0.96, p=0.0475). Survival improvement over time in VA was seen in black (HR 0.84, p<0.001), but was not significant in white (HR 0.94, p=0.052) patients. Conclusions: This real-world analysis demonstrates that median OS in de novo mPC has improved over the last 20 years, particularly in patients <70 years of age. However, these improvements are less than what has been observed in clinical trials. Black patients had inferior OS in SEER compared to white patients but in the VA black patients had better OS and an improvement in OS over time, potentially reflecting more equal access to care in the VA system. [Table: see text]
Patterns of failure with 18F-DCFPyL PSMA PET/CT in the post-prostatectomy setting: A regional cohort analysis.
Authors: Sigurdson Samantha S. , al Salman Khalid , Mesci Aruz , Tsakiridis Theodoros , Dayes Ian S. , Quan Kimmen , Goldberg Mira , Schnarr Kara , Kapoor Anil , Shayegan Bobby , Bauman Glenn , Zukotynski Katherine , Lukka Himu
Published: March 2023

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Background: The participants are patients enrolled in the PSMA-PET Registry for Recurrent Prostate Cancer (PREP) who were referred for [18F]-DCFPyL PET/CT at our institution in Hamilton, Canada. The Registry is the only funded access to PSMA PET/CT for patients in Ontario. Methods: Our analysis includes all men who had a PSMA PET/CT on the Registry between April 2019 and December 2021 and are either node positive, or persistently detectable PSA after initial radical prostatectomy (RP), or biochemical failure after initial RP. Results: In total 177 men were enrolled on the Registry who met the above criteria. 170 men had complete pathological information available and were included. The pre-PSMA PET/CT median PSA was 0.27 ng/mL. Overall, the probability of a positive PSMA PET/CT result was 59.4%, and the incidence increased with increasing PSA. Lymph node (LN) and distant metastases (DM) were detected more frequently in patients with Grade groups 3-5 and higher pathologic tumor (pT) and nodal (pN1) disease. Across all 170 patients the most common site for LN recurrence was in the internal iliac chain (15.9%), followed by the external iliac (14.7%), obturator (11.8%), common iliac (10.0%), pre-sacral (8.8%), para-aortic (7.7%), and peri-rectal (5.9%) chains. The PSMA PET/CT recurrence rate, PSA, and pathological tumor stage is reported, with the location of the recurrence indicated. Conclusions: Our prospective study elucidates patterns of failure for prostate cancer patients with biochemical recurrence after RP and could impact management at diagnosis and after RP. There is a significant risk of pelvic LN positivity on PSMA PET/CT, which emphasizes the importance of including pelvic LNs within salvage radiation volumes. [Table: see text]
“It just makes sense to me”: Patient experiences with prostate MRI during prostate cancer active surveillance.
Authors: Sutherland Ryan , Gross Cary Philip , Ma Xiaomei , Jeong Farah , Seibert Tyler M , Cooperberg Matthew R. , Catalona William , Loeb Stacy , Schulman-Green Dena , Leapman Michael
Published: March 2023

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Background: Although prostate MRI is commonly used in the diagnosis, staging and active surveillance of prostate cancer, little is known about patient perspectives on MRI imaging. Methods: We performed a qualitative descriptive study consisting of in-depth, semi-structured interviews of patients with low and intermediate risk prostate cancer managed with active surveillance. Interviews focused on experiences with prostate MRI and MRI-ultrasound fusion biopsy during active surveillance monitoring. We purposively sampled patients who received prostate MRI as part of their clinical care, over-sampling Black and Latino men, and conducted interviews until thematic saturation. We performed conventional content analysis to analyze data. Results: The mean sample (n=20) age was 68 years (range 51-79). Fourteen (70%) participants identified as White, 5(25%) as Black, and 2(10%) as Hispanic/Latino. At diagnosis, 17 (85%) had a Gleason grade group 1, and 3 (15%) had a grade group 2 tumor. Overall, participants viewed prostate MRI as a valuable tool that accurately localizes and monitors prostate cancer over time. Prostate MRI was seen as central to active surveillance monitoring. We identified five thematic categories: (1) the experiential aspects of undergoing an MRI scan; (2) the experience of visualizing one’s own prostate and prostate cancer; (3) adequacy of provider explanations of MRI results; (4) confidence in prostate MRI in decision-making; and (5) the role of prostate MRI in longitudinal follow-up during active surveillance, including an interest using MRI to modify the timing of, or replace, prostate biopsy. Conclusions: These findings reveal that patients highly value prostate MRI as a tool that enhances the confidence in the initial diagnosis and monitoring of prostate cancer. This work can inform future studies to optimize the patient experience, education and counseling during active surveillance for prostate cancer.