bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline circulating soluble factors as predictors of immune-related adverse events (irAEs) in patients (pts) with metastatic clear cell renal carcinoma (mRCC) treated with nivolumab: A translational NIVOREN GETUG-AFU 26 study.
Authors: Carril-Ajuria Lucia , Naigeon Marie , Dalban Cécile , Desnoyer Aude , Rioux-Leclercq Nathalie , Sautès-Fridman Catherine , Meylan Maxime , Vano Yann-Alexandre , Beusenlick Benoit , Chouaib Salem , de Oliveira Caroline , Tantot Florence , Flippot Ronan , Escudier Bernard , Albiges Laurence , Chaput Nathalie
Published: March 2023

724

Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes and irAEs in mRCC pts treated with nivolumab. We previously identified (training-set = 80 pts, validation-set= 233 pts) several soluble factors associated with overall survival (IL-6, IL-8, VEGF, BAFF, and CXCL13) (Carril-Ajuria et al. ASCO. 2022). Our aim was to evaluate the association between baseline levels of circulating soluble factors and the presence of all grade and severe irAEs. Methods: 720 patients treated with nivolumab within the NIVOREN study and with available safety data were included in the study. The association between baseline levels of seven different circulating soluble factors (VEGF, VCAM-1, IL-6, IL-7, IL-8, BAFF, CXCL13) and the development of all grade and severe irAEs was evaluated in those pts who had previously undergone soluble factors quantification within the translational program. The association between other systemic inflammatory markers (the lung immune prognostic index (LIPI), LDH and the derived neutrophil to lymphocyte ratio (dNLR)) and irAEs was also evaluated. Results: Out of 720 pts, 456 (63%) and 143 (20%) pts presented all grade and severe irAEs respectively. Soluble factors quantification at baseline was available for 353 pts. Baseline characteristics were similar to the overall trial population. Lower levels of circulating IL-6 (cut-off: 8.7 pg/ml) at baseline were significantly associated with a higher risk of all grade irAEs (p=0.025). Lower dNLR levels (<3, p=0.003) at baseline and a good LIPI score (p=0.014) were also associated with a higher risk of all grade AEs. No other significant associations were found between circulating soluble factors and all grade irAEs. No significant associations were found between circulating solubles factors/systemic inflammatory markers and the presence of severe irAEs Conclusions: Using the cut-off values previously identified, we observed that lower baseline levels of circulating IL-6 were associated with an increased risk of all grade irAEs. Good LIPI patients and those with a lower dNLR also presented a higher risk of all grade irAEs. Baseline circulating soluble factors and systemic inflammatory markers failed to demonstrate a significant association with the development of severe irAEs.
Impact of cytoreductive nephrectomy (CRN) on overall survival (OS) in metastatic non–clear cell renal cancer (nccRCC).
Authors: Nelson Ariel Ann , Szabo Aniko , Kilari Deepak
Published: March 2023

730

Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for 25% of kidney cancer diagnoses and encompasses a diverse group of kidney tumors with distinct biology for which treatment in the metastatic setting is evolving. The role of CRN for nccRCC population in the current treatment landscape remains unclear. Methods: We retrospectively identified patients (pts) with nccRCC from The National Cancer Database (NCDB) participant user file (PUF) for Kidney and Renal Pelvis Tumors. Pts with de novo metastatic disease diagnosed between 2006 and 2017, received systemic treatment (trt) with immunotherapy (IO) or non-immunotherapy (NIO) and either underwent or could have undergone a CRN were selected. Demographic and disease characteristics were summarized using descriptive statistics. The cumulative incidence of CRN with death without CRN as a competing risk, was estimated using the Nelson-Aalen estimator. The association of each demographic and disease characteristic on the cumulative incidence of CRN was evaluated using univariate Fine-Gray regression. The effect of CRN on survival was visualized using a Simon-Makuch plot. P values were based on Mantel-Byar test. Cox regression with a time-dependent predictor was used to estimate the change in the hazard of death after CRN. Results: We identified 3644 pts, 72% male, mean age 61 ±13 years. Nearly 40% of pts (n=1453) had sarcomatoid histology, followed by 30% with papillary (n=1075). Most pts, 96% (n=3489) received NIO systemic trt and only 9% were treated with IO (n=319). Nearly half of the study population (45%) underwent CRN (n=1642). Of these, 95% received NIO trt (n=1564) and 9% received IO (n=152). Pts who underwent CRN were younger and less likely to have bone, brain or liver metastases. Minority pts were less likely to undergo CRN. Mean time from dx to surgery was 1.1 ±1.7 months. For all pts, mOS was 9 months (95% CI: 8.6-9.4). OS was improved for pts who underwent CRN vs those who did not (11.3 vs 7.5 months, p<0.0001). In multivariate analysis, cytoreductive nephrectomy was associated with a reduction in the risk of death, HR 0.73 (95% CI: 0.68, 0.80, p<.0001). Conclusions: For pts with de novo metastatic nccRCC, CRN is associated with improved outcomes. Further analysis regarding the effect of treatment regimens on survival outcomes is warranted and planned. Prospective randomized trials in the modern treatment era are needed to further assess the timing and impact of CRN on outcomes in pts with metastatic nccRCC. [Table: see text]
Histopathological upstage, recurrence, and survival in a population-based cohort of surgically treated patients with clinical T1b renal cell carcinoma.
Authors: Lundstam Sven , Karlsson Rosenblad Andreas , Ljungberg Borje
Published: March 2023

731

Background: T1 renal cell carcinoma (RCC) is considered to have a low malignant potential. Partial nephrectomy (PN) is recommended for nephron sparing whenever technically feasible also for T1b RCC. Despite a favorable prognosis there remains a risk for upstaging and recurrence, and the place for PN in clinical T1b tumors is questionable. Therefore, we have characterized these variables and overall survival (OS) in a real-world population-based cohort of patients with clinical T1b RCC. Methods: Patients without metastases registered in the National Swedish Kidney Cancer Register (99% of RCCs diagnosed in Sweden) 2005-2014 with clinical T1b (> 4-7 cm), surgically treated and with a follow-up of ≥ 5 years were included. Results: There were 2137 patients (1300 males, 837 females) with a mean age of 66 years; 82% had clear cell (ccRCC), 11% papillary (pRCC) and 6% chromophobe (chRCC) RCC. Radical nephrectomy (RN) was performed in 1836 patients and PN in 301 patients. After histopathological examination 435 (20%) were upstaged to pathological (p) T3: 21% of ccRCCs, 13% of pRCC and 20% of chRCCs. Recurrent disease after ≥ 5-years follow-up was diagnosed in 127 (29%) pT3 patients and in 238 (14%) with pT1b, 322 (18%) in ccRCC, 127 (11%) in pRCC and 6(5%) in chRCC. Lung metastases occurred in 52% of patients with recurrencies and 144 (39%) of these had two or more metastatic sites. Patients with pT3RCC had a 67% five-year OS compared to 83% in pT1b patients (Log-rank test, p<0.001). Regardless of other factors, patients treated with PN had a higher 5-year OS of 86% compared to 79% in patients treated with RN (Log-rank test, p=0.006). In multivariable analyses, lower age, female sex, smaller tumors, N0, pRCC and chRCC, and pT1b stage were significantly associated with longer survival. A hazard ratio of 0.93 [95% CI 0.65-1.32] for PN indicated that PN was non-inferior to the treatment with RN in patients with clinical T1bRCC. Conclusions: Clinical T1bRCC is a malignant disease with risk for upstaging and tumor recurrence. Nonetheless, the results indicate that PN is non-inferior to the treatment with RN in clinical T1bRCC and support the recommendation to offer PN also in these patients.
Efficacy of systemic therapy following [177Lu] Lu-PSMA in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kostos Louise Kathleen , Lai William Yu Ching , Lambroglou Peter , Medhurst Elizabeth , Buteau James Patrick , Sandhu Shahneen , Tran Ben , Spain Lavinia Anne , Conduit Ciara , Wallace Roslyn , Alipour Ramin , Akhurst Timothy J. , Kong Grace , Cardin Anthony , Saghebi Javad , Ravi Kumar Aravind , Hofman Michael S , Azad Arun
Published: March 2023

77

Background: [177Lu]Lu-PSMA (LuPSMA) is currently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Little is known about the efficacy of treatment in pts with subsequent progression after LuPSMA. In this single-centre retrospective analysis, we evaluated efficacy of first subsequent therapy following LuPSMA. Methods: 234 mCRPC pts who received LuPSMA at the Peter MacCallum Cancer Centre from 2015-2022 were analysed. Pts were excluded if they did not receive any subsequent treatment (n=136), if they received the initial course of LuPSMA in combination with another therapy (n=10), or if insufficient follow-up data were available (n=15).Retreatment withLuPSMA was considered a subsequent line of therapy. Data collected included 50% PSA response rate (PSA-RR), PSA-progression free survival (PSA-PFS) and overall survival (OS). Survival outcomes were calculated using Kaplan-Meier analysis. Results: Of 73 evaluable pts, 32 were retreated with LuPSMA (median 2 cycles); and 41 commenced a new line of systemic therapy. In the LuPSMA retreatment group, the PSA-RR was 44%, median PSA-PFS was 3.8 months and median OS 14.8 months. In pts who changed to a new line of treatment, cabazitaxel was the most commonly prescribed therapy (n=25), followed by docetaxel (n=7), and single-agent carboplatin (n=4), in addition to carboplatin/etoposide, mitoxantrone, olaparib, capecitabine and a clinical trial (n=1 for each). PSA-RR was 12%, median PSA-PFS was 3.5 months and median OS 6.6 months. Conclusions: This retrospective data demonstrates that retreatment with LuPSMA is associated with benefit, though this is reduced compared to initial treatment. In our cohort of pts who commenced a new line of therapy, most were not suitable for retreatment with LuPSMA, potentially reflecting de-differentiated and more aggressive disease phenotypes. In those not suitable for LuPSMA retreatment, other systemic therapy appears to have limited benefit, highlighting the lack of effective salvage options and raising questions about treatment sequencing. [Table: see text]
Characterization and survival benefit of drugs approved for metastatic prostate cancer.
Authors: Benjamin David Joseph , Rezazadeh Arash
Published: March 2023

81

Background: The treatment landscape of metastatic prostate cancer (mPC) drastically changed with the approval of chemotherapy (docetaxel) in 2004, and novel hormonal therapy (NHT) abiraterone in 2011. Since then, several other therapies have been approved in the metastatic castrate-sensitive (mCSPC) and -resistant (mCRPC) settings. Despite multiple drug approvals, it remains unclear how much improvement in survival these therapies have provided. Methods: We reviewed the US Food and Drug Administration (FDA) website to evaluate all approvals for prostate cancer from 2004 to 2022. We collected progression-free survival (PFS) and overall survival (OS) from the approval notification or from the corresponding clinical trial cited for drug approval. Results: Between 2004 and 2022, there were 14 drug (single or combination) approvals for mPC. Most approvals (81.3%) were granted through regular approval. Average PFS benefit for mCSPC was 4.8 months and average OS benefit for mCSPC was not reached in ongoing trials. Average PFS benefit for mCRPC was 3.7 months (range 1.9-5.4) and average OS benefit for mCRPC was 3.67 months. Conclusions: Despite 14 drug (single or combination) approvals for mPC since 2004, the improvements in average PFS and OS were modest in both castrate-sensitive and -resistant settings. OS data for several NHTs continues to mature, and may alter average OS benefits once median OS is reached. Nonetheless, continued drug development for mPC is warranted. [Table: see text]
Association of intermittent or continuous androgen deprivation therapy with cardiovascular disease and endocrine/metabolic disorders in patients with nonmetastatic prostate cancer.
Authors: Morgans Alicia K. , Ebrahimi Ramin , Bobbili Priyanka J. , Nwokeji Esmond , Gandhi Raj , Desai Raj , Zhang Adina , Ryan Michael , Hanson Sarah , Duh Mei Sheng , Preston Mark A.
Published: March 2023

83

Background: Evidence on risks of cardiovascular disease (CVD) and endocrine/metabolic disorders associated with long-term intermittent and continuous androgen deprivation therapy (iADT and cADT, respectively) in patients (pts) with nonmetastatic prostate cancer (nmPC) is mixed. This real-world study examined these risks in pts with nmPC receiving iADT or cADT in the US. Methods: This was a retrospective cohort study of SEER-Medicare pts with nmPC initiating ADT (2010–2017), with ≥36 months of continuous insurance coverage, unless death occurred, and who did not receive chemotherapy or a second-generation anti-androgen during follow-up. iADT and cADT cohorts were defined by treatment patterns and gaps in therapy. Comorbidities and clinical events were identified using ICD-9/10-CM codes. Outcomes examined were major adverse cardiovascular events (MACE [myocardial infarction (MI), stroke, cardiomyopathy/heart failure (HF), pulmonary embolism (PE), ischemic heart disease (IHD), or all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, or osteoporosis). Inverse probability of treatment-weighted Cox regression models estimated the adjusted hazard ratio (aHR) of the outcomes. Subgroup analyses examined pts by CVD history. A sensitivity analysis restricted the definition of MACE to include CVD-related mortality as a component, i.e., MACESA (MI, stroke, cardiomyopathy/HF, PE, IHD, or CVD-related mortality). Results: 10,655 pts were included; 2095 (20%) received iADT and 8560 (80%) cADT; 63% of iADT pts and 66% of cADT pts had baseline CVD history. Median follow-up was 44 and 48 months and time on ADT (excluding gaps for iADT pts) was 23 and 17 months for the iADT and cADT cohorts, respectively. In adjusted analyses, pts receiving cADT had a lower risk of MACE vs iADT. No difference in risk of endocrine/metabolic events was observed. Results for MACE were similar in pts with prior CVD history; however, there was no difference in risk of MACE in those without CVD history. Sensitivity analysis results for MACESA were similar to the main results. Conclusions: Pts with nmPC receiving cADT had a lower risk of MACE, and no difference in risk of endocrine/metabolic events, compared with iADT. There was no difference in risk of MACE in pts without a prior history of CVD. [Table: see text]
First look at the baseline characteristics of participants in IRONMAN, the international registry for men with advanced prostate cancer.
Authors: Mucci Lorelei A , Vinson Jake , Gerke Travis A. , Hyslop Terry , Howard Lauren , Dreicer Robert , Rathkopf Dana E. , Chi Kim N. , Esteban Emilio , Enting Deborah , Bjartell Anders , Tagawa Scott T. , Nanus David M. , Ong Michael , Barata Pedro C. , Hotte Sebastien J. , Grant Marie , Villanti Paul , Kantoff Philip W. , George Daniel J.
Published: March 2023

85

Background: Patients with advanced prostate cancer (APC) experience high mortality and increasingly deteriorating quality of life due to the disease itself and the therapies they are treated with. Despite recent advances in the treatment landscape, disparities in outcomes have only worsened. There is an urgent need to identify disparities in treatment patterns and outcomes in advanced disease in diverse populations. The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is uniquely equipped to address these needs. Methods: IRONMAN is a prospective registry initiated in 2017 with a planned accrual of 5000 patients with newly diagnosed metastatic hormone-sensitive (mHSPC) and castration-resistant (CRPC) prostate cancer. As of 10/11/2022, 2890 patients have enrolled from 14 countries at 113 sites, with 2 more countries pending activation. Sites were selected to create a diverse cohort across race/ethnicity, geography and socioeconomic factors. Patients are followed for survival, clinically significant adverse events, changes in cancer treatments, biomarkers, and Patient-Reported Outcome Measures (PROMs). This analysis includes patients with treatment data reported from Baseline through Month 3 as of October 2021 (n=1931, 9 countries). Results: Patients were recruited across the USA (N=799), Australia (146), Canada (282), Spain (238), England (205), and all other countries (261). 61% had mHSPC, and 39% had CRPC at enrollment with little variation in these proportions across countries. Based on self-report, 87% of patients were White, 9% Black, 4% reported other races/ethnicities, and 353 did not report race. In the US, 18% of patients were Black. Globally, 22% of respondents reported current or former military service. The most common first systemic therapy on study was androgen receptor signaling inhibitors (ARSI) +/- ADT in 1039 (54%), ranging between 12% and 66% of patients by country. 19% received chemotherapy +/- ADT and 18% received ADT alone. ARSI use varied by age, race, and metastatic disease site. Conclusions: Our preliminary results highlight our ability to successfully enroll and follow APC patients from 113 sites across 14 countries, with 2890 of 5000 planned patients enrolled. Accrual is greater in de novo mHSPC patients than anticipated. Differences in treatment patterns are already emerging, with more ARSI use in the mHSPC setting in North America than other regions. Our data demonstrates that IRONMAN participating sites are rapidly adopting new treatment recommendations into clinical practice of real-world patients.
Utilization of metastatic hormone sensitive prostate cancer (mHSPC) treatment in a community oncology practice setting.
Authors: Conner Terri , Appukkuttan Sreevalsa , Kong Sheldon , Jhaveri Jay , Ko Gilbert , Kalayeh Bashir , He LiHong , Hauser Robert Sean , Loaiza-Bonilla Arturo
Published: March 2023

86

Background: Treatment options for mHSPC have continued to evolve. While androgen deprivation therapy (ADT) has been the backbone treatment, more recently early use of docetaxel and/or novel androgen receptor inhibitors (nARIs) has demonstrated improved clinical outcomes. This study assessed real-world treatment among mHSPC patients who received at least one line of therapy (LoT). Methods: A retrospective observational study utilizing de-identified health records from five Cancer Treatment Centers of America (CTCA) included patients with metastatic prostate cancer who were treated with ADT, docetaxel or nARIs at CTCA for 6+ months between 1/2015-3/2021. Treatment patterns were observed from first LoT to metastatic castration resistance, death, or lost-to-follow-up until 3/2022. LoT was defined as first to last date of active drug therapy, not including long-term hormone agonists. First LoT was defined as initial regimen with no new drugs added 30+ days after start date. Patient characteristics, proportion and duration of each LoT, and reasons for early discontinuation were gathered using structured data elements and chart abstraction. Results: The characteristics of the 523 patients in this study were as follows: mean (SD) age 62 (8) years, 60% white and 33% black, 53% with commercial insurance, 75% with ECOG 0-1, and 65% with bone metastasis at diagnosis. Median follow-up time was 2.9 years. The most common LoT 1 regimen was either ADT alone or ADT with first generation androgen receptor inhibitors (FGARI) (table below). 46% received a second and 15% received a third LoT. Mean (SD) duration of first and second active LoTs were 12 (11.8) and 10 (11.1) months, respectively. Among the 65% and 78% patients who discontinued therapy in LoT 1 and 2, respectively, the majority discontinued due to progression of disease (35% LoT 1 and 53% LoT 2) followed by patient choice (23% LoT 1 and 18% LoT 2). Conclusions: Despite recommendations from guidelines on early intensification of therapy in mHSPC, in this contemporary cohort we find that most patients received either ADT alone or ADT ± FGARI in LoT 1 while chemotherapy and nARIs were initiated predominantly in later lines. Most patients discontinued LoT 1 due to disease progression which may suggest undertreatment and need for improved outcomes. Further studies are needed to assess the factors associated with non-intensification of treatments. [Table: see text]
Real-world homologous recombination repair (HRR) mutation testing patterns in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in the United States (US).
Authors: Barata Pedro C. , Montgomery Rachel , Last Matthew , Gillespie-Akar Liane , Nazari Jonathan , Niyazov Alexander
Published: March 2023

99

Background: A subset of pts with metastatic prostate cancer have HRR mutations. These can be either germline or somatic mutations. Previous studies have established a prognostic and predictive role of HRR mutations and there are ongoing trials (e.g., TALAPRO-3, AMPLITUDE) exploring combination strategies of poly-ADP ribose polymerase inhibitors (PARPi) with novel hormonal therapies (NHT). Therefore, it is relevant to establish baseline HRR testing rates in the real-world setting. This study assessed real-world (rw) HRR testing patterns in pts with mCSPC in the US and described characteristics of tested vs untested pts. Methods: Data were drawn from the Adelphi Prostate Cancer Disease Specific Programme; a point-in-time questionnaire administered to oncologists and urologists in the US between January-August 2020. Physicians abstracted medical records for the next 4-9 pts receiving active drug treatment for mCSPC. Study variables included pt demographics, clinical factors, physician characteristics, and testing status for at least 1 of 12 HRR genes of interest ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C). Pt demographics and clinical characteristics were compared between groups using t-tests for continuous and chi-squared or Fisher’s exact test for categorical variables. A multiple logistic regression model was used to assess factors associated with odds of HRR testing. Results: A total of 71 physicians reported on 204 pts with mCSPC. The median age was 68.8. 57/204 (28%) pts were tested for HRR mutations using germline or tumor testing. Pts who were not HRR tested were older compared to HRR tested pts (69.6 vs 66.8, P = 0.038). More pts currently receiving care by an oncologist had a HRR mutation test vs. pts currently receiving care by a urologist [50/156 (32%) vs 7/48 (15%), P =0.02]. According to the multiple logistic regression model, having a known family history of prostate cancer [OR = 3.9 (95% CI: 1.1 – 13.6); P = 0.04], and having visceral metastases at mCSPC diagnosis [OR=4.9 (95% CI: 2.0 – 12.1); P = 0.001] were associated with a significantly higher odds of receiving a HRR mutation test. Conclusions: In this rw US study of adult patients with mCSPC, most patients did not receive HRR testing. Disparities in HRR mutation testing were observed, suggesting that clinical characteristics may influence decisions to test for HRR mutations. Focused efforts to increase HRR mutation testing should be implemented.
Circulating tumor DNA analysis of IMbassador250: Association of ctDNA fraction, AR alterations and therapy outcome in mCRPC.
Authors: Sweeney Christopher , Graf Ryon , Fabrizio David , Yuen Kobe , Wongchenko Matthew J. , Gupta Pratyush , Hegde Priti , Oxnard Geoffrey R. , Powles Thomas
Published: March 2023

LBA249

Background: IMbassador250 was a prospective phase III international trial which showed no overall survival (OS) benefit for adding atezolizumab to enzalutamide for men with mCRPC who had prior progression on abiraterone. We hypothesized that genomic biomarkers in ctDNA may identify patients who have poorer OS with 2nd generation novel hormonal therapy. Methods: Pre-treatment (but post-abiraterone progression) plasma samples from IMbassador250 were submitted for comprehensive genomic profiling using FoundationOne Liquid CDx. We detected elevated ctDNA tumor fraction (TF) using a novel algorithm that incorporates aneuploidy as well as tumor-derived short variant signal. A pre-specified TF cutoff of ≥ 2% was defined as high. A prospective-retrospective biomarker statistical analysis plan was developed in accordance with Simon Criteria, pre-specifying analyses, cutoffs, and power assessments. Results: 494 baseline plasma specimens were evaluable. The TF high group [371 (74%)] had significantly shorter OS than TF low (median 11.0 vs. 22.1 months, HR 4.3, 95% CI 3.0 – 6.1, p < 0.0001) (primary endpoint). Pre-specified supportive analyses compared the performance to prognosticate OS (concordance [std error]) of baseline PSA alone (0.65 [0.63 – 0.67]) to a model consisting of all evaluable baseline features including PSA, treatment arm, age, race, ECOG score, hemoglobin, alkaline phosphatase, albumin, number of metastatic sites, and sites of metastasis (0.71 [0.70 – 0.73]) to TF alone (0.72 [0.71 – 0.73]) to all features plus TF (0.76 [0.74 – 0.77]). Likelihood ratio test for improvement of OS prediction by adding TF to all available clinical features: p < 0.0001. Focusing on the patients with TF ≥ 2% (n = 371) exploratory analysis observed less favorable outcomes with detection of AR amplifications (n = 203 [55%], HR: 1.4, 95%CI: 1.1 – 1.8), while individual AR mutations were not as strongly associated with OS: L702 ([16%], HR: 1.2, 95%CI: 0.88 – 1.7), W742 ([4.3%], HR: 0.59, 95%CI: 0.30 – 1.2), H875 ([9.4%], HR: 0.71, 95%CI: 0.46 – 1.1), T878 ([25.3%], HR: 0.86, 95%CI: 0.65 – 1.1). Conclusions: In this cohort TF < 2% at baseline is strongly associated with favorable OS on enzalutamide after progression on abiraterone compared to TF ≥ 2%. TF alone has comparable discriminatory ability to anticipate overall survival compared to all available clinical features combined, and adds significant prognostic power when combined with clinical features in this setting. AR amplifications, but not mutations, further improve strengths of association. Clinical trial information: NCT03016312 .
VIOLET: A phase I/II trial evaluation of radioligand treatment in men with metastatic castration-resistant prostate cancer with [161Tb]Tb-PSMA-I&T.
Authors: Buteau James Patrick , Kostos Louise Kathleen , Alipour Ramin , Jackson Price , McIntosh Lachlan , Emmerson Brittany , Haskali Mohammad B , Yeung Theresa , Xie Sophia , Medhurst Elizabeth , Ravi Rajeev , Gonzalez Brian D. , Fettke Heidi , Ng Nicole , Docanto Maria , Bukczynska Patricia , Blyth Benjamin , Furic Luc , Azad Arun , Hofman Michael S
Published: March 2023

TPS281

Background: [177Lu]Lu-PSMA is an effective class of therapy for men with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response is partially explained by the presence of micrometastatic deposits. Single tumor cells and micrometastases are energy-sheltered deposits receiving low absorbed radiation, due to the ~0.7mm mean path-length of Lutetium-177 (177Lu). Terbium-161 (161Tb) has abundant emission of Auger electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161Tb has shown superior in-vitro and in-vivo results in comparison with 177Lu. We hypothesize that [161Tb]Tb-PSMA-I&T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 to 36 men with progressive mCRPC. The phase I dose-escalation is designed with a 3+3 model to establish the safest dose of [161Tb]Tb-PSMA-I&T (dose levels: 4.4, 5.5 and 7.4 GBq). The maximum tolerated dose (MTD) will be defined as the highest dose level at which a dose-limiting toxicity occurs in less than 1/3 or 2/6 participants. The phase II dose-expansion will include 24 participants at the MTD. Up to six cycles of [161Tb]Tb-PSMA-I&T will be administered intravenously every six weeks, with each subsequent dose for each patient reduced by 0.4GBq. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy and a second-generation anti-androgen, PSMA-positive disease on PSMA PET/CT (SUVmax ≥20), no sites of discordance on FDG PET/CT, adequate bone marrow, hepatic and renal function, ECOG performance status ≤2, and no prior treatment with another radioisotope. The co-primary objectives are to establish the MTD of [161Tb]Tb-PSMA-I&T, and safety profile [CTCAE v5.0]. Secondary objectives include measuring absorbed radiation dose [Gray], evaluating anti-tumour activity [PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective response rate], and evaluation of pain [BPI-SF] and health-related quality of life [FACT-P and FACT-RNT] over the first 12 months after treatment commences. Exploratory objectives include ctDNA analysis at baseline, during treatment and at progression, and optional tissue biopsies, to determine biomarkers of treatment response and resistance. Patient enrolment began in October 2022, with recruitment expected to continue for 24 months. Clinical trial information: NCT05521412 .
CAPItello-280: A phase III study of capivasertib and docetaxel versus placebo and docetaxel in metastatic castration-resistant prostate cancer.
Authors: Crabb Simon J. , Ye Ding-Wei , Uemura Hirotsugu , Morris Thomas , Gresty Christopher , Logan Jill , Rooney Claire , Foxley Andrew , Carducci Michael Anthony
Published: March 2023

TPS287

Background: Docetaxel is the standard first-line chemotherapy for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed on an androgen receptor-targeted agent (ARTA; typically, abiraterone, enzalutamide, apalutamide, or darolutamide). However, most patients develop chemotherapy resistance, and median overall survival (OS) remains under 3 years. Preclinical studies have associated phosphoinositide 3-kinase (PI3K)/protein kinase (AKT)/phosphatase and tensin homolog (PTEN) pathway signaling with the development of mCRPC and with resistance to taxane chemotherapy. The ProCAID Phase II trial (NCT02121639) examined whether adding capivasertib, a potent, selective inhibitor of all three AKT isoforms (AKT1/2/3), to docetaxel chemotherapy improved clinical outcomes. Although no difference in the primary endpoint (composite progression-free survival [PFS]) was detected, OS, a secondary endpoint, was extended in the capivasertib plus docetaxel treatment group. A subsequent follow-up analysis at advanced maturity suggested that the OS benefit in ProCAID was restricted to patients who had received prior treatment with an ARTA. Methods: CAPItello-280 is a Phase III study to confirm the efficacy and safety of capivasertib in combination with docetaxel compared with placebo and docetaxel in patients with mCRPC who have not previously received chemotherapy for mCRPC, but whose disease has progressed despite treatment with an ARTA in any setting. Approximately 790 patients will be randomized 1:1 to receive either capivasertib or matching placebo (320 mg orally, twice daily [BD], 4 days on, 3 days off) plus docetaxel (75 mg/m2 on day 1 of each 21-day cycle for 6–10 cycles, with prednisone or prednisolone 5 mg BD or 10 mg once daily) with a background of continued androgen deprivation therapy until disease progression, unacceptable toxicity, death, or withdrawal of consent. The primary endpoint is OS; secondary endpoints include radiographic PFS, time to pain progression, symptomatic skeletal events, safety, and tolerability. Recruitment began in March 2022 and is planned at 207 study sites in 20 countries, including the USA, Canada, Europe, South America, and Asia-Pacific. Clinical trial information: NCT05348577 .
A phase 2 expansion study of ARV-766, a PROTACandrogen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Petrylak Daniel P. , Stewart Tyler F. , Gao Xin , Berghorn Elmer , Lu Haolan , Chan Edward , Gedrich Richard , Lang Joshua Michael , McKean Meredith
Published: March 2023

TPS290

Background: Patients with mCRPC inevitably develop resistance to available therapies and lack curative options. In patients treated with novel hormonal agents (NHAs), mutations can develop in the ligand-binding domain (LBD) of the AR gene, some of which are associated with resistance to current therapies and disease progression. ARV-766 is a novel, potent, orally bioavailable proteolysis targeting chimera (PROTAC) protein degrader that degrades not only wild-type AR but also clinically relevant AR LBD mutants, including the most prevalent AR L702H, H875Y, and T878A mutations. Here we describe a phase 2 expansion study to evaluate the clinical activity and safety of ARV-766 in men with mCRPC who have experienced disease progression on prior NHA therapy. Methods: This phase 2 cohort expansion is part of an open-label, first-in-human, phase 1/2 clinical trial of ARV-766 in men (aged ≥18 years) with histologically, pathologically, or cytologically confirmed mCRPC and Eastern Cooperative Oncology Group performance status score of 0 or 1. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor or orchiectomy is required. Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Following completion of dose escalation in the phase 1 portion of the study, which is evaluating the safety and tolerability of ARV-766, 2 doses (100 mg and 300 mg administered orally once daily in 28-day cycles) were selected for the phase 2 cohort expansion. The primary objectives of the cohort expansion study are to evaluate the antitumor activity of ARV-766 based on the overall response rate (per Response Evaluation Criteria in Solid Tumors) and the rates of prostate-specific antigen (PSA) declines of 30% (PSA30) and 50% (PSA50). Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140 .
A phase II single-arm trial of niraparib in platinum-sensitive metastatic castration-resistant prostate cancer with DNA repair defects (PLATPARP).
Authors: Narayan Vivek , Torres Alexandra , Seger Philip , Aaron Megan , Louie Jennifer , Lee Daniel , Haas Naomi B. , Takvorian Samuel U , Maxwell Kara Noelle , Domchek Susan M.
Published: March 2023

TPS291

Background: Platinum-based chemotherapy, either as monotherapy or in combination with taxanes, is increasingly used for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring germline and/or somatic homologous recombination repair gene mutations (HRRm). However, clinical responses with platinum-based therapy are often of limited duration and limited by cumulative toxicities. The PARP inhibitor (PARPi) olaparib is approved for the treatment of mCRPC patients with pathogenic HRRm after progression on enzalutamide or abiraterone. Importantly, sensitivity to platinum-based chemotherapy may predict improved clinical outcomes with PARPi, and ‘maintenance’ PARPi strategies are routinely used in patients with advanced ovarian and pancreatic malignancies with HRRm with initial clinical response to platinum chemotherapy. We hypothesize that maintenance niraparib, a PARPi with demonstrated activity in mCRPC with HRRm, will prolong clinical responses to platinum-based chemotherapy with acceptable toxicity in mCRPC patients harboring germline and/or somatic HRRm. Methods: We are conducting an open-label, single-arm, phase II study to evaluate the clinical benefit of maintenance niraparib in biomarker-defined, platinum-sensitive mCRPC patients. Eligible subjects harbor a pathogenic germline and/or somatic mutation in BRCA1/2, ATM, FANCA, CDK12, RAD51B, RAD54L, PALB2, CHEK2, HDAC2, or BRIP1 and have received at least 3 cycles (or minimum 9 weeks) of platinum-based chemotherapy for the treatment of mCRPC per investigator discretion. Following ³4 weeks since completion of chemotherapy, subjects without evidence of clinical or radiographic disease progression receive investigational treatment with maintenance niraparib (starting dose 200 mg daily). The primary objective is an improvement in 6 month PFS rate (PFS6) (H0: PFS6 rate 25%; H1: PFS6 rate 50%; power 0.77 with one-sided α = 0.05). Serial plasma samples are obtained for correlative analyses of markers of response and/or resistance to maintenance niraparib. Eight of a planned total of 18 subjects have enrolled (N=3 germline BRCA2; N=2 somatic BRCA2; N=1 germline PALB2; N=1 germline ATM; N=1 germline CHEK2). This study incorporates a novel, combined genetic and clinical patient-selection approach for PARPi therapy to optimize clinical outcomes. Clinical trial information: NCT04288687 .
Neo-adjuvant PARP inhibition prior to prostatectomy: A phase II biomarker-driven trial for men with high-risk, localized prostate cancer and alterations in DNA repair genes.
Authors: Dall'era Marc , McPherson John , Evans Christopher P. , Parikh Mamta , Verma Rashmi , Lara Primo N
Published: March 2023

TPS401

Background: Many men with localized prostate cancer will experience recurrence and progression after radical prostatectomy. While radiation therapy for high-risk prostate cancer is routinely given with systemic androgen therapy, peri-operative systemic therapy is not part of the standard of care with prostatectomy. Defective DNA repair pathways represent a non-hormonal target for PARP inhibitors which have proven efficacy in the metastatic, castrate resistant setting. We designed a novel biomarker driven neoadjuvant trial with niraparib prior to prostatectomy for men with clinically localized high risk prostate cancer and alterations in DNA repair genes (NCT04030559). Methods: We instituted a phase II trial for men with NCCN high and very high-risk prostate cancer. All men who met inclusion by clinical variables underwent targeted genomic sequencing for somatic and/or germline alterations in genes involved in DNA repair pathways. Enrolled patients are treated with oral Niraparib 300mg/day for 90 days before surgery. The primary endpoint is pathologic response at prostatectomy defined as complete response or minimal residual disease (<0.5 cc3) of histological viable cancer. The secondary endpoint is biochemical free survival as well as molecular endpoints including disease responses stratified by mutational status. We have screened 37 men and 10 have met genomic criteria. We have enrolled 8 out of planned 30 men to date, 7 have undergone prostatectomy. Enrolled men have alterations in BRCA2 (germline), MSH6, ZMYM3, MUTYH, ATM, CDK12, ERCC3 and KMT2c. Clinical trial information: NCT04030559 .
A phase III randomized trial of eribulin (E) with or without gemcitabine vs standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.
Authors: Sadeghi Sarmad , Plets Melissa , Lara Primo N , Tangen Catherine , Bangs Rick , Lerner Seth P. , Flaig Thomas W. , Petrylak Daniel P. , Thompson Ian M
Published: March 2023

TPS581

Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab; received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Funding: National Institutes of Health/National Cancer Institute grants U10CA180888, U10CA180819. Clinical trial information: NCT04579224 .
Study of cabozantinib in second line under real-life setting in patients with advanced renal cell carcinoma (aRCC): Study design of a French retrospective, multicenter study (OCTOPUS).
Authors: Thiery-Vuillemin Antoine , Mourey Loic , Pasquier David , Thibault Constance , Bernhard Jean-Christophe , Zara Laetitia , Perrot Valérie , Albiges Laurence
Published: March 2023

TPS744

Background: Cabozantinib is a tyrosine kinase inhibitor (TKI) directed against VEGFR, MET and AXL. In the pivotal phase III METEOR study, cabozantinib demonstrated significantly improved progression-free survival (PFS), overall response rate (ORR) and overall survival (OS) versus everolimus in patients with previously treated aRCC with clear-cell component. Thus, cabozantinib received marketing authorization from the European Medicine Agency in September 2016 for the treatment of aRCC in patients previously treated with a VEGF-targeted therapy. Cabozantinib effectiveness and safety have been investigated in several real-world evidence studies such as CABOREAL or CASSIOPE. However, many questions arising during the routine care of patients with aRCC treated by cabozantinib remain unanswered by the current literature. Therefore, the aims of OCTOPUS study are to describe the effectiveness and safety of 2nd line cabozantinib in a real-life setting in France and to address these unanswered questions in certain patients subgroups. Methods: Octopus is a multicenter (25 centers), retrospective, non-comparative, non-interventional study in patients with aRCC initiating cabozantinib in 2nd line in France. The primary endpoint is the duration of treatment (DOT) with cabozantinib: median DOT will be estimated using Kaplan Meier method. Key secondary endpoints to be assessed are: best overall response (BOR), PFS, adverse events (AEs) and subsequent treatment. DOT, BOR, PFS, safety and all baseline characteristics for each of the following subgroups will be described as exploratory endpoints: sequencing post-cabozantinib, long-responders, non-responders, cabozantinib & rechallenge, cabozantinib & therapeutic schedules, cabozantinib & local treatment, cabozantinib & elderly patients. Data will be analyzed descriptively. Due to the observational nature of this study, no formal calculation of sample size and statistical power were performed. With a sample size of 300 participants who started cabozantinib in 2nd line between 1st March 2018 and 1st March 2021 and a median DOT of 7.6 months, the two-sided confidence interval of the median will be estimated with a width equal to 1.7 months (95% Confidence Interval [CI] [6.8; 8.6]) and a censoring probability near 0. All collected data will be in accordance with the daily practice of medical doctors, with a maximum follow-up of 12-months. Data collection started in Q3 2022 and the first patient was included on September 16th 2022. No interim analysis is planned. This study is funded by Ipsen Pharma. Clinical trial information: NCT05444933 .
Re-examination of radiative capture of deuteron 3He(d,γ)5Li at low energy
Authors: Sabeeh Syeda , Jawad Muhammad , Kabir Abdul , Nabi Jameel-Un
Published: March 2023

3He(d,γ)5Li is important in the Big Bang Nucleosynthesis (BBN), as it provides seeds for the 6Li formation. Within the framework of the potential model the 3He(d,γ)5Li is analyzed. In the present investigation the nuclear width

, nuclear cross-sections, astrophysical S-factor, and nuclear reaction rates have been computed. The present study is in better agreement with the observed data.
Approach to the Patient: Central Precocious Puberty
Authors: Kilberg Marissa J , Vogiatzi Maria G
Published: March 2023

Central precocious puberty (CPP) classically refers to premature activation of the hypothalamic–pituitary–gonadal axis with onset of sexual development before the age of 8 years in girls and 9 years in boys. A decrease in the age of thelarche has been reported over the past several decades; however, the tempo of pubertal progression can be slower and adult height may not be adversely affected in many of the girls who experience thelarche at 6-8 years. Outside of this secular trend in the development itself, the past several decades have also brought about advances in diagnosis and management. This includes the widespread use of an ultrasensitive luteinizing hormone assay, decreasing the need for stimulation testing and a better understanding of the genetics that govern the onset of puberty. Additionally, management of CPP using gonadotropin-releasing hormone analogs (GnRHas) has changed with the advent of new longer-acting formulations. Emerging long-term outcomes of GnRHa administration with regards to obesity, cardiovascular risk factors and fertility are reassuring. Despite these advancements, clinical care in CPP is hampered by the lack of well-designed controlled studies, and management decisions are frequently not supported by clear practice guidelines. Data in boys with CPP are limited and this article focuses on the diagnosis and management of CPP in girls, particularly, in those who present with thelarche at the age of 6-8 years.
The Use of Levothyroxine Absorption Tests in Clinical Practice
Authors: Caron Philippe , Declèves Xavier
Published: March 2023

Although levothyroxine (LT4) is a widely prescribed drug, more than 30% of LT4-treated patients fail to achieve the recommended serum level of thyrotropin with a body weight–based dose of LT4. An LT4 absorption test (LT4AT) is part of the workup for confirming normal LT4 absorption or diagnosing malabsorption. We searched PubMed with the terms levothyrox*, L-T4, LT4, TT4, FT4, FT3, TT3, test, loading, uptake, absorp*, “absorb*, bioavailab*, bioequiv* malabsorb*, and pseudomalabsorb*. A total of 43 full-text publications were analyzed. The published procedures for LT4AT differ markedly in the test dose, formulation, test duration, frequency of blood collection, analyte (total thyroxine [TT4] or free thyroxine [FT4]), metric (absolute or relative peak or increment, or area under the curve) and the threshold for normal absorption. In a standardized LT4AT for routine use, the physician could advise the patient to not consume food, beverages, or medications the morning of the test; administer 1000 µg of LT4 in the patient's usual formulation as the test dose; ensure that the patient is supervised throughout the LT4AT; perform a 4-hour test, with hourly blood samples; assay FT4; and consider that normal LT4 absorption corresponds to an FT4 increment of more than 0.40 ng/dL (5.14 pmol/L) or a TT4 increment of more than 6 μg/dL (77.23 nmol/L) for a test dose of at least 300 µg, or a percentage TT4 absorption of more than 60%. If the test indicates abnormal LT4 absorption, the physician can increase the LT4 dose, change the formulation or administration route, and/or refer the patient to a gastroenterologist.