bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of exposure to clinical trials and standard-of-care therapy in metastatic or recurrent prostate cancer: An update.
Authors: Kim Grace G , Mohamed Heba , Bhuiyan Ishmam , Macphail Corin , Sidhu Taylor , Emami Amir , Huang Longlong , Sun Shaun Zheng , Tyldesley Scott , Ko Jenny J.
Published: January 2024

76

Background: Treatment (tx) options for metastatic prostate cancer (mPC) have advanced significantly. Literature shows that access to, and uptake of, clinical trials or standard intensified tx in mPC may be low. Methods: We conducted further survival analysis on all consecutive patients (pts) diagnosed with any stage of PC between 2016-2017 in British Columbia, and only included pts with de novo metastasis or later recurrence. We performed descriptive statistics, univariate and multivariate analysis to examine overall survival (OS). Results: This study included 796 pts with either de novo metastatic (n=554, 69.6%) or recurrent PC (N=242; 30.4%); 743 (93.3%) had metastasis by time of cutoff (Sep 1, 2022). Median age at diagnosis of mPC in all patients was 73 (range 45-98). 790 (99.2%) started androgen deprivation tx (ADT). 263 (35.4%) had additional line of tx started with ADT at hormone sensitive mPC (mHSPC); 309 (38.8%) had 1st line tx started at castrate resistant mPC (mCRPC). Radiotherapy (RT) to prostate for mPC were given to 93 (11.6%). 307 (38.6%) received 1 line of tx; 181 (22.7%), 2; 128 (16.1%), 3 or more. 432 (54.3%) received ≥1 androgen receptor pathway inhibitors (ARPI). At cutoff, 474 (59.5%) died; most (n=400; 84.4%) died of prostate cancer. 35 pts who went on trial had longer mOS than those who did not go on trial (63.6 vs 39.5m, p=0.025). Pts with 5 or 6 lines of therapy had numerically longer but statistically similar mOS than those who had 1 (51.7m vs. 63.7m vs. 38.1m, p=0.47). Pts who got 1 line of ARPI had statistically similar mOS than those not exposed to ARPI (43.3m vs. 39.5m, p=0.89). In pts with de novo mPC, more than 1 line (44.3m) or 1 line of ARPI (42.1m) were associated with numerically longer but statistically similar mOS compared to no ARPI (30.1m, p=0.47); pts with recurrent mPC showed an opposite trend (22.5 vs 48.5m vs. not reached, p=0.009). In multivariable analysis, RT to prostate for mPC was associated with better mOS in mHSPC (HR 0.409, 95% CI 0.180 – 0.92, p=0.032) but not mCRPC. None of age, PSA at metastasis, Gleason score, or ADT type was identified as an independent factor affecting mOS. No significant differences in mOS was seen with varying years of mPC diagnosis (2015-2022). Conclusions: Our multicentre data suggest that access to clinical trials and timely RT to prostate in appropriate pts with mPC are associated with longer mOS and should be considered standard of care. Access to clinical trials may be challenging for a significant proportion of pts. Exposure to as many lines of tx/ARPI as possible may potentially help in pts with de novo mPC, but more data are required to determine benefit in all subgroups.
Impact of TP53, RB1, and PTEN mutations on overall survival in metastatic prostate cancer: A multi-center study via the Guardian Research Network.
Authors: Ganiyani Mohammad Arfat , Prabhakar Pushan , Khosla Atulya Aman , Bellur Shreyas S , Pon Avudaiappan Arjun , Bond Liz , Marada Suresh , McCracken Andrea , Hurmiz Charlie , Bastos Bruno R. , Garje Rohan
Published: January 2024

82

Background: The treatment paradigm for metastatic prostate cancer has significantly improved in the past decade. Nevertheless, there remains an unmet need for novel biomarker-driven risk stratification. Studies have shown that genetic alterations in any of the PTEN, RB1, and TP53 genes influence the prognosis, potential for androgen independence and overall survival of individuals diagnosed with advanced prostate cancer. Based on these findings, we compared survival rates by contrasting patients with any of these mutations to those lacking them, using an extensive real-world sample from community oncology centers across the Guardian Research network (GRN). Methods: All patients diagnosed with metastatic prostate cancer who had undergone Next-Generation Sequencing (NGS) were included across an oncology-focused hospital consortium network database (GRN). Study participants were classified into two cohorts based on the presence or absence of biomarkers. Patients harboring at least one of the following genomic alterations— TP53, Rb, or PTEN—were categorized as "biomarker-positive." Those without these mutations were designated as "biomarker negative." Overall survival (OS) was compared between the two cohorts by Kaplan-Meier Curve analysis. Results: We identified 350 patients with metastatic prostate cancer, of which 140 were biomarker positive and 210 were biomarker negative. The biomarker-positive cohort had a lower overall survival (p=0.002) when compared to the biomarker-negative cohort. For the sub-group with a minimum follow up of four years, median survival was 35.8 months vs 67.2 months for biomarker marker positive and negative cohorts, respectively. Furthermore, the biomarker-positive cohort was associated with significantly higher number of patients with bone and liver metastases. Conclusions: Our study indicates poor overall survival in patients with TP53, RB1, and PTEN mutated prostate cancer, underscoring the need for novel treatment strategies for this aggressive disease genotype. Future studies based on genomic risk stratification are needed to customize therapies through appropriate intensification or de-intensification based on individual genomic profiles. [Table: see text]
Quality of treatment with targeted agents for advanced prostate cancer by treating specialist.
Authors: Faraj Kassem S , Oerline Mary , Kaufman Samuel , Caram Megan Veresh , Shahinian Vahakn B. , Hollenbeck Brent K.
Published: January 2024

88

Background: Urologists are increasingly prescribing oral targeted agents to men with advanced prostate cancer, who traditionally have been cared for by medical oncologists. These agents require close monitoring, since they mechanistically affect androgen biosynthesis and can lead to cardiovascular and metabolic adverse events. It is unclear whether patients treated by urologists—whose practice scope typically does not involve systemic therapies—experience more frequent therapy-related adverse events. Further, these medications are expensive, often subjecting patients to high out-of-pocket costs, which can lead to coping strategies like treatment non-adherence. Urologists may have less experience discussing these costs and exploring cheaper alternatives. Methods: A 20% sample of National Medicare claims was used to perform a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer between 2012-2020 who were treated with a targeted agent (abiraterone or androgen receptor blocker). The primary outcome was the composite of any hospital or emergency department visit for a cardiometabolic event within 1 year of starting a targeted agent. Secondary outcomes included monthly out-of-pocket costs in those without low-income subsidies and adherence to treatment in first 6 months after initiating treatment. Multivariable regression models were fitted to assess the association between prescribing specialist (urologist or medical oncologist) and each outcome. Results: There were 1,462 (25%) and 4,501 (75%) patients who were prescribed a targeted agent by a urologist and medical oncologist. Men who were managed by urologists were more often started on an androgen receptor blocker, compared to those managed by medical oncologists (67% vs 36%, p<0.001).There were no differences in the adjusted frequencies of composite adverse events of patients managed by urologists and medical oncologists in those who were started on abiraterone (7.7 % vs 8.1%, P=0.79) or an androgen receptor blocker (6.4% vs 6.2%, p=0.91). Out-of-pocket costs did not vary between patients who were managed by urologists vs medical oncologists in those who were started on abiraterone ($748 % vs $778%, P=0.48) or an androgen receptor blocker ($795 vs $834, p=0.33). Adherence to treatment was similar between the specialties in those prescribed abiraterone (67% vs 64%, P=0.15), but the likelihood of adherence was higher in men prescribed an androgen receptor blocker by a urologist (65% vs 61%, p=0.04). Conclusions: Although urologists may be less accustomed to primarily managing advanced prostate cancer than medical oncologists, patients fared no worse when assessing adverse events, out-of-pocket costs, or adherence to treatment. This study provides further support for urologists’ increased role in managing advanced prostate cancer.
Nonadherence to medications for chronic conditions and risk of nonadherence to androgen receptor signaling inhibitors (ARSIs) in patients with prostate cancer.
Authors: Lichtenstein Morgan RL , Raghunathan Rohit R. , Wei Alexander Z , Gershman Boris , Stein Mark N. , Hershman Dawn L.
Published: January 2024

92

Background: While ARSIs have become a cornerstone in treatment for prostate cancer, nonadherence to these oral medications is common. We investigated the association between patterns of prior nonadherence to medications for chronic conditions with ARSI nonadherence. Methods: In this retrospective cohort study, the MarketScan database was searched for patients >18 years old with a prostate cancer claim between 1/1/2014 and 12/31/2019 and who filled >2 ARSI prescriptions between 9/1/2013 and 12/31/2020. Nonadherence to medications for 4 chronic conditions (hypertension, hyperlipidemia, diabetes, benign prostatic hypertrophy (BPH)) in the 12 months before diagnosis was defined as a medication possession ratio (MPR) <80%. Nonadherence to ARSIs was defined as an MPR <80% between the first and last ARSI prescription up to 1 year. We used logistic regression to examine the relationship between nonadherence to prior medications and nonadherence to ARSIs. Results: Among 4,898 patients, 967 (19.7%) were nonadherent to ARSIs. Regarding prior medication nonadherence, of the patients prescribed hypertension medications (n=2602), 15.4% (n=402) were nonadherent to hypertension medications, of those prescribed hyperlipidemia medications (n=2234), 18.8% (n=419) were nonadherent to hyperlipidemia medications, of those prescribed diabetes mediations (n=826), 19.1% (n=158) were nonadherent to diabetes mediations, and of those prescribed BPH medications (n=1827), 13.4% (n=245) were nonadherent to BPH medications. Among those without prior medications (n=1031 [21.1%]), 21.3% of patients were nonadherent to ARSIs. Compared to those without prior medications, those who used at least 1 medication prior to ARSI and were adherent to all of them (n=2919 [59.6%]) had a 17.2% nonadherence rate to ARSI treatment (OR: 0.77; 95% CI: 0.64, 0.91; p: 0.003). Those who used at least 1 medication prior to ARSI and were nonadherent to 1 of them (n=722 [14.7%]) had a 24.0% nonadherence rate to ARSI (OR: 1.16; 95% CI: 0.93,1.46; p: 0.195), while those who used at least 1 medication prior to ARSI and were nonadherent to >2 (n=226 [4.6%]) had a 30.5% nonadherence rate to ARSI (OR: 1.62; 95% CI: 1.18,2.23; p: 0.003). Conclusions: Nonadherence to medications for chronic conditions prior to ARSI treatment is common and associated with greater nonadherence to ARSIs in patients with prostate cancer. History of medication nonadherence could serve a marker to target a high-risk population for adherence interventions. [Table: see text]
A cost-effectiveness analysis assessing systemic treatments in metastatic castration-sensitive prostate cancer (mCSPC) by volume of disease.
Authors: Naqvi Syed Arsalan Ahmed , Faisal Kunwer Sufyan , Khan Muhammad Ali , Khakwani Kaneez Zahra Rubab , Van Houten Holly K. , Moriarty James P. , Borah Bijan J. , Singh Parminder , Childs Daniel S , Sharma Vidit , Boorjian Stephen A. , Humphreys Mitchell R. , Sartor Oliver , Cobran Ewan Kemar , Riaz Irbaz Bin , Bryce Alan Haruo
Published: January 2024

93

Background: The treatment paradigm for mCSPC patients has rapidly evolved over the last few years with the emergence of triplet therapy and prognostication by volume of disease. However, the health economic implications of triplet therapy by disease volume remain unclear. Methods: A Markov model where patients transitioned between the progression-free, progression and death states was developed. State utilities were derived from the LATITUDE trial. Point probabilities for overall survival, progression-free survival, grade ≥ 3 and 5 toxicities were obtained from the eligible mCSPC phase III clinical trials. Medicare Advantage and commercial total paid amounts (2022 US$) of treatments were obtained from OptumLabs Data Warehouse. Costs and disutilities of adverse events were derived from published literature. Half-cycle corrected costs and utilities were accrued monthly over a 20-year lifetime horizon and were discounted at 3%. Monte Carlo simulation was used to calculate incremental cost-effectiveness ratios (ICERs). A willingness-to-pay (WTP) threshold of US$100,000 was used. Results: In terms of Medicare Advantage payer’s perspective (Table), docetaxel (D)+ADT was observed to provide additional 0.068 QALYs compared to ADT at an ICER of US$16,544 per QALY in high volume disease. Compared to D+ADT, abiraterone (AAP) triplet provided additional 1.03 QALYs at US$56,641 per QALY. Compared to AAP triplet, apalutamide (APA)+ADT provided additional 0.048 QALYs at US$5,846,248 per QALY in high volume disease. In low volume disease, D+ADT provided 0.45 more QALYs at US$20,690 per QALY compared to ADT alone. Compared to D+ADT, AAP triplet provided an additional 1.51 QALYS at US$44,267 per QALY. In terms of total paid commercial costs, AAP triplet provided an additional 1.19 QALYs compared to ADT at US$91,952 per QALY in high volume disease. In low volume, D+ADT provided additional 0.38 QALYs at US$22,058 per QALY compared to ADT. Compared to D+ADT, AAP triplet provided a 0.97 QALY gain at US$105,958 per QALY. Compared to AAP triplet, darolutamide (DARO) triplet provided a 0.47 QALY at US$689,196 per QALY. Compared to DARO triplet, APA+ADT provided an additional 0.49 QALYs at an ICER of US$971,389 per QALY. All other treatments (not reported here) were dominated. Conclusions: At the selected WTP of US$100,000 per QALY, AAP triplet therapy was most likely the cost-effective strategy in overall mCSPC population particularly in patients with high volume disease. However, these results should be interpreted with careful accounting for timing of metastases. [Table: see text]
Impact of combined novel hormonal agents on testosterone levels of patients with prostate cancer undergoing treatment with leuprorelin.
Authors: Lages Dr. Paulo Sergio , Vargas Pivato de Almeida Daniel , Bergerot Paulo Gustavo , Barbosa Michelle , Lages Luciana , Morbeck Igor Alexandre Protzner , Zulli Guilherme Augusto
Published: January 2024

95

Background: Novel hormonal agents (NHA) are part of the management of prostate cancer (PCa) since from the high-risk localized disease throughout the disease continuum, while sustained androgen deprivation therapy (ADT), through the utilization of gonadotropin-releasing hormone (GnRH) agonists or antagonists, stands as the cornerstone of this combined treatment regimen. Although deeper and earlier PSA response rates were demonstrated with these combinations, there is a lack of information on the testosterone levels during the treatment with this doublet. In this retrospective real-world study, we meticulously analyzed data on testosterone tests obtained from a prominent Brazilian institution to comprehensively assess the clinical efficacy of leuprorelin either in monotherapy or in combinations on the management of PCa. Methods: We conducted a retrospective analysis by gathering data from the medical records of pts diagnosed with PCa who were undergoing treatment with leuprorelin alone or in combination with a novel hormonal agent (NHA). Descriptive statistics was assessed by medians and comparison between groups was assessed by chi-square test. This data collection spanned a nine-year period from 2014 to 2023. Results: A total of 1,744 tests were collected from 240 individual pts. Median baseline testosterone level was 373.9 ng/mL among those treated with leuprorelin monotherapy and 368 ng/mL for those receiving leuprorelin + NHA. Testosterone levels < 50 ng/mL were achieved in 776/786 tests (98.7%) of pts receiving leuprorelin and 945/958 tests (98.6%) in pts receiving leuprorelin + NHA (p=0.9). Testosterone levels < 20 ng/mL were found in 633/786 tests (80.5%) of pts receiving leuprorelin and 842/958 tests (87.9%) in pts receiving leuprorelin + NHA (p < 0.0001). Conclusions: In this robust institutional database analysis, we demonstrated that leuprorelin demonstrated similar levels of testosterone suppression (< 50 ng/mL) both in monotherapy or combined with NHA. However, when analyzing deeper testosterone suppression levels, the addition of NHA was associated with statistically significant difference in the rate of patients with testosterone < 20 ng/mL. These results reinforce the importance of intense hormonal treatment in pts with PCa receiving leuprorelin.
Association of body-mass index (BMI) with age, PSA, and survival in metastatic prostate cancer.
Authors: Schoen Martin W. , Montgomery Robert Bruce , Khan Saira , Eaton Daniel B. , Fedele Nicholas , Sachdeva Ashwin , Hahn Andrew Warren , Etzioni Ruth Douglas
Published: January 2024

96

Background: Increased body-mass index (BMI) is associated with increased prostate cancer incidence and death. However, an ‘obesity paradox’ exists where patients with BMI have longer survival once diagnosed with cancer. We investigated the influence of BMI on overall survival of veterans with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Methods: Two cohorts were identified in the US Veterans Health Affairs. The mHSPC cohort included patients diagnosed with de-novo mHSPC from 2011-2021. The mCRPC cohort was treated with abiraterone or enzalutamide from May 2011 to June 2017. We determined BMI at time of treatment and weight loss during the one year prior. BMI was categorized as ≤20, >20-25, >25-30 or >30 kg/m2. We used Kruskal-Wallis testing for ordinal variables and Cox hazard models to assess the association between BMI, age, Charlson comorbidity index, PSA level at diagnosis, Black race, weight loss, and survival. Results: We identified 5019 veterans with mHSPC and 8159 with mCRPC. Mean BMI was 27.2 (SD 5.9) in mHSPC and 28.2 (SD 5.8) in mCRPC. Mean age was 75.7 years (SD 9.8) in mHSPC and mean age of 74.6 (SD 9.3) in mCRPC. Median overall survival was 25.6 months (95% CI 24.6-26.6) in mHSPC and 20.5 months (95% CI 19.9-21.1) in mCRPC. There were significant differences in age, Black race, and PSA at diagnosis across BMI strata with BMI>30 having the youngest age, lowest percentage of Black race, lowest PSA, and longest survival in mHSPC and mCRPC (see Table). In unadjusted analyses, veterans with BMI>30 had lowest risk of death with Hazard Ratio (HR) 0.66 (95% CI 0.60-0.71) in mHSPC and 0.60 (95% CI 0.56-0.64) in mCRPC compared to BMI>20-25. In adjusted analyses, veterans with BMI>30 had lowest risk of death with adjusted hazard ratio (HR) 0.89 (95% CI 0.81-0.97) in mHSPC and HR 0.77 (95% CI 0.72-0.83) in mCRPC compared to BMI>20-25. Conclusions: Increased BMI is associated with younger age at diagnosis, lower PSA, and longer survival in both mHSPC and mCRPC. Further studies between BMI and prostate cancer are warranted to understand these complex interactions. [Table: see text]
Measuring oncological value of exercise and statin: Can we improve the prognosis of patients with cancer and change the microenvironment in different tumor types with exercise and statins (MOVES study)?
Authors: Sormunen Jorma T.J , Hakulinen Annastiina , Kemppainen Jukka , Tiainen Leena , Staff Synnöve , Kankaanranta Krista , Murtola Teemu
Published: January 2024

TPS234

Background: Hypoxia is an important mechanism in cancer cells, which protects them from body’s immune reactions. Exercise improves circulation thus reducing hypoxia. Therefore, we study the effect of exercise and statins on prognosis of cancer patients. Lipid metabolism is an important energy source during hypoxia. We expect to see that patients who participate in regular physical exercise and use lipid-lowering medicine atorvastatin have longer survival than patients without such intervention. Methods: The MOVES study is an open-label single-centre randomised controlled phase 3 pilot trial. A total of 240 adult patients with stage IV cancer (prostate, renal cell, breast or ovarian) and starting 1st line oncological treatment are randomised 1:1:1 into one of three groups: 1) Supervised exercise for 3 months; 2) Supervised exercise with 40 mg atorvastatin daily for 3 months; and 3) Control group. Patients are followed at 3-month intervals for up to two years. Choice of oncological treatment is up to the clinician’s discretion according to the patient’s clinical need. Radiological, clinical and/or biochemical progression, death, side effects of the treatments and interruptions of the cancer treatments are registered. The primary outcome is progression-free survival, measured as time to 2nd line oncological treatment or death. The secondary outcomes are overall survival, quality of life, levels of hypoxia markers and cancer metabolites in blood and urine and treatment tolerability. A substudy will implement EF5-PET and FDG-PET scans to evaluate tumor hypoxia and metabolic activity before and after the trial intervention. The Ethics Committee of Tampere University Hospital has approved the study protocol. Results will be published after completion of the study in international peer viewed journals. Clinical trial information: NCT05796973 .
A phase I, open-label, dose-finding study of fatty acid synthase (FASN) inhibitor TVB-2640 administered in combination with enzalutamide (Enza) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Nuzzo Pier Vitale , Ribeiro Caroline Fidalgo , Rodrigues Silvia , Fernandez Escarleth , Molina Ana M. , Nauseef Jones , Sternberg Cora N. , Tagawa Scott T. , Loda Massimo , Nanus David M.
Published: January 2024

TPS248

Background: Recent studies have shown that targeting lipid synthesis is a novel therapeutic strategy to overcome androgen resistance in mCRPC. TVB-2640 is a first-in-class FASN inhibitor, a key enzyme in de novo lipogenesis that is overexpressed and androgen-regulated in CRPC. FASN promotes the synthesis of palmitate that can be elongated and desaturated to produce saturated fatty acids (SFAs) and monounsaturated FA (MUFAs) that can support membrane synthesis and energy production, protect against free radicals and chemotherapeutics, and regulate post-translational modifications of major oncogenic pathways. Our preliminary in vitro and in vivo data show that TVB-2640 co-administered with enza to CRPC cells significantly reduced cell growth, increased apoptosis, and promoted cell cycle arrest, as well as down-regulating full-length androgen receptor (AR) and its splice variant, AR-V7. Methods: This is an open-label, single-arm, Phase I dose-escalation study that enrolls pts with mCRPC who are candidates to receive enza. The primary objective is to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of TVB-2640 in combination with enza. Secondary objectives include safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Exploratory objectives include the effects of FASN inhibition on metabolites, genetics, and lipids in human blood and tumor tissue, to identify potential predictive and prognostic markers of response. Pts with a confirmed histological or cytological diagnosis of PC, evidence of metastatic PC on imaging (bone scan and/or CT/MRI scan), serum testosterone <50 ng/dl, who had progressed on androgen-depletion therapy (ADT), with documented progressive metastatic castration-resistant prostate cancer (mCRPC) based on Prostate Cancer Working Group 3 (PCWG3) criteria a are eligible. Enrolled pts will receive enza at a daily dose of 160 mg for 36 days to reach a steady state, followed by the addition of oral TVB-2640 starting at 100 mg/daily. The dose escalation will follow the Bayesian optimal interval (BOIN) design with additional dose levels of 150 mg, 200 mg, 250 mg, and 300 mg daily. The maximum sample size for this study is 30 pts, with a target dose-limiting toxicity (DLT) rate of 25% or less and a maximum of 15 pts at any given dose level. This is the first clinical trial to evaluate the targeting of the AR pathway through inhibition of lipid synthesis as a new approach to treating mCRPC. Enrollment of Cohort 1 began in August 2023. Clinical trial information: NCT05743621 .
A phase Ib trial of enzalutamide with oral decitabine/cedazuridine in metastatic castration-resistant prostate cancer (CRPC).
Authors: Roy Arya Mariam , Gopalakrishnan Dharmesh , Jatwani Karan , Green Kelly , Farmer Bailey , Jaiswal Neha , Attwood Kristopher , Levine Ellis Glenn , Beltran Himisha , Goodrich David , Chatta Gurkamal S.
Published: January 2024

TPS252

Background: Exposure to androgen receptor (AR)-pathway inhibitors like enzalutamide (Enza) is associated with the emergence of ARlow subclones that coexist with ARhigh subclones in CRPC. These ARlow cells, including those in neuroendocrine prostate cancer (NEPC), are not critically dependent on AR signaling for survival and proliferation. Alterations in RB1, TP53, and PTEN tend to co-occur in human ARlow CRPC and NEPC. These as well as tumors from triple knockout mouse models demonstrate altered expression of epigenetic reprogramming factors, including consistent upregulation of DNA methyltransferase 1 (DNMT1).1 DNA methylation in CpG islands is increased in human CRPC/NEPC as well as CRPC xenograft models indicating that elevated DNMT activity may correlate with resistance to AR-targeted therapies.2 Treatment with decitabine (Dec), a DNMT inhibitor, delays the development of ARlow NEPC and increases Enza sensitivity in murine models of prostate cancer.2 Cedazuridine (Ced), an inhibitor of cytidine deaminase which degrades Dec, increases its oral bioavailability. We hypothesize that the combination of Enza with oral Dec/Ced will reverse acquired therapeutic resistance in ARlow CRPC/NEPC tumors where DNMT activity is aberrantly elevated by RB1 and/or TP53 loss. Methods: This is a single-center, open-label, non-randomized, dose escalation/de-escalation phase Ib study of fixed drug combination (FDC) oral Dec/Ced [ASTX727, FDC 35mg/100mg] with Enza (160mg/day) in patients with Enza-refractory mCRPC. Three dose levels of ASTX727 will be evaluated using a 3+3 study design - FDC of ASTX727 will be administered on either 4 (cohort 1), 3 (cohort -1) or 5 (cohort 2) consecutive days of a 28-day cycle. The primary endpoint will be safety with determination of the maximum tolerated dose (MTD) and recommended phase II dosing (RP2D). We plan to include an expansion cohort of 10 patients at the MTD, eligibility for which will be restricted to patients with genomic alterations in RB1 and/or TP53. Correlative studies will be aimed at 1) Evaluation of DNMT1 levels and DNA methylation patterns, 2) Analysis of circulating tumor DNA to monitor changes in DNA methylation and emergence of ARlow CRPC/NEPC, 3) Evaluation for tissue markers of neuroendocrine lineage, RB1 loss and/or TP53 mutations to examine for treatment emergent ARlow CRPC/NEPC and its correlation with RB1 and/or TP53 loss. The study is currently open with 6 patients enrolled. 1) McCabe MT et al. Cancer Res. 2005;65(9):3624-32. 2) Ku SY et al. Science. 2017;355(6320):78-83. 3) Zorn CS et al. Clin Cancer Res. 2007;13(7):2136-43. Clinical trial information: NCT05037500 .
Safety, tolerability, and dosimetry of 177Lu-TLX591 with best standard of care in patients with PSMA-expressing metastatic castration-resistant prostate cancer (ProstAct-SELECT).
Authors: Lenzo Nat , O'Byrne Ken , Ngai Stanley , Meyrick Danielle , Patel Neel , Hayward Colin
Published: January 2024

TPS253

Background: Prostate-specific membrane antigen (PSMA) has proven to be an ideal therapeutic target in prostate cancer (PC) as it is highly expressed by malignant prostate cells. Based on previous clinical evidence of its favorable safety profile and specificity for PC tumors, 177Lu-DOTA-HuJ591-CHO (hereafter referred to as 177Lu-TLX591) may be a potential radioimmunotherapy for the treatment of PC. ProstACT-SELECT (NCT04786847) is a phase 1 study designed to evaluate the safety, tolerability, biodistribution and dosimetry of 177Lu-TLX591 administered with standard of care (SoC) for patients with PSMA-expressing, metastatic castration-resistant prostate cancer progressing despite prior treatment with a novel androgen axis drug. We previously reported positive interim results, and primary analysis of safety and dosimetry data is currently underway and expected to be available in mid-October 2023. Methods: Approximately 30 participants were to be enrolled in 2 cohorts. Cohort 1: 5 patients received a single (27 mCi) intravenous infusion of 177Lu-TLX591. SPECT images and pharmacokinetic blood samples will be acquired at several time points until Day 13 after dosing. Dosimetry analysis and qualitative comparison of biodistribution of tracer level of 177Lu-TLX591, as demonstrated by SPECT, with 68Ga-PSMA-11 on PET imaging were performed to ensure equivalent (or improved) radiopharmaceutical tumour targeting. Patients were to receive a second administration of 177Lu-TLX591, at a full therapeutic dose of 76 mCi, 14 days following the initial dose after safety confirmed by independent review board. SoC was to continue according to standard practice. Cohort 2: Subsequent patients were to receive 2 administrations of 76 mCi 177Lu-TLX591, with SPECT dosimetry and pharmacokinetics as in cohort 1. The primary endpoints include the absorbed radiation dose of administered 177Lu-TLX591 to kidneys, liver, lungs, spleen, bone/red marrow, and salivary glands; tumour-to-healthy tissue ratios and residence times; and type, frequency, and severity of TEAEs. Clinical trial information: NCT04786847 .
A phase II single-arm trial of niraparib in platinum-sensitive metastatic castration-resistant prostate cancer with DNA repair defects (PLATPARP).
Authors: Welch Erin Catherine , Torres Alexandra , Miller Joann , Louie Jennifer , Lee Daniel , Haas Naomi B. , Takvorian Samuel U , Maxwell Kara Noelle , Domchek Susan M. , Narayan Vivek
Published: January 2024

TPS255

Background: The optimal use of PARP inhibitor (PARPi) therapy is evolving for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring germline and/or somatic homologous recombination repair gene mutations (HRRm). The sensitivity to platinum-based chemotherapy may predict improved clinical outcomes with PARPi. ‘Maintenance’ PARPi strategies are routinely used in patients with advanced ovarian and pancreatic malignancies with HRRm following an initial clinical response to platinum-based chemotherapy. Platinum-based chemotherapy is increasingly used in patients with mCRPC and HRRm as either a monotherapy or in combination with taxanes, but yields clinical responses of limited duration and is hindered by cumulative toxicities. We hypothesize that maintenance niraparib, a PARPi with demonstrated activity in mCRPC with HRRm, will prolong clinical responses to platinum-based chemotherapy with manageable 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 ≥4 weeks since completion of chemotherapy, subjects without evidence of clinical or radiographic disease progression receive investigational treatment with maintenance niraparib (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. Eleven of a planned total of 18 subjects have enrolled (N=4 germline BRCA2; N=1 germline BRCA1; N=3 somatic BRCA2; N=1 germline PALB2; N=1 germline ATM; N=1 germline CHEK2). This investigator-initiated study incorporates a novel, combined genetic and clinical patient-selection approach for PARPi therapy to optimize clinical outcomes. Clinical trial information: NCT04288687 .
Rezvilutamide in combination with androgen-deprivation therapy, with or without salvage radiotherapy, for patients experiencing biochemical recurrence following radical prostatectomy: A multi-center, open-label, two-cohort study.
Authors: Zhang Shun , Xu Linfeng , Qiu Xuefeng , Zhuang Junlong , Zou Qing , Wang Junqi , Guo Hongqian
Published: January 2024

TPS355

Background: Rezvilutamide, a novel androgen-receptor inhibitor exhibiting minimal blood-brain barrier penetration, has demonstrated robust antitumor efficacy in metastatic castration-resistant prostate cancer and high-volume, metastatic, hormone-sensitive prostate cancer, which received approval from the Chinese National Medical Products Administration in 2022. The standard management for biochemical recurrence (BCR) post-prostatectomy typically involves androgen-deprivation therapy (ADT) alone or in combination with salvage radiotherapy (SRT). This study aims to evaluate the efficacy and safety of rezvilutamide plus ADT, with or without SRT for patients with BCR post-prostatectomy. Methods: In this multi-center, open-label, two-cohort study, patients with postoperative pathology-confirmed pN0 or pNx prostate adenocarcinoma who manifested BCR subsequent to radical prostatectomy (evidenced by two successive elevated serum prostate-specific antigen [PSA] measurements between 0.2-2 ng/ml, without identifiable local or metastatic recurrence on computed tomography and bone scans) would be enrolled. Cohort 1 participants will undergo 6 months of ADT, 6 cycles of rezvilutamide (240 mg/day, spanning 28 days per cycle), and SRT. Those in Cohort 2, either declining or ineligible for SRT, will receive 12 months of ADT combined with 12 cycles of rezvilutamide. The choice of ADT regimens rests with the investigators. The primary endpoints are the 2-year biochemical progression-free survival (bPFS) rate for Cohort 1 and the 3-year bPFS rate for Cohort 2. Secondary endpoints encompass bPFS, radiographic PFS, metastasis-free survival, and rates of undetectable PSA (with PSA levels < 0.1 ng/ml). Additionally, safety profiles, overall quality of life, testosterone recovery rates post-treatment initiation, and the time to testosterone recovery post-treatment discontinuation will be appraised. The study acquired ethical approval on November 24th, 2022, and subsequently commenced recruitment. As of now, 22 out of the planned 96 patients have been enrolled. Clinical trial information: NCT05753566 .
Strategic treatment pause of first-line immune checkpoint inhibitor + VEGFR-tyrosine kinase inhibitor in patients with good or intermediate risk metastatic renal cell carcinoma (mRCC) in response at 1 year of treatment (SPICI-GETUG R05): A non-inferiority randomized clinical trial.
Authors: Gross-Goupil Marine , Lefort Felix , Larroquette Mathieu , Asselineau Julien , Frison Eric , Albiges Laurence , Ravaud Alain
Published: January 2024

TPS487

Background: Treatment of mRCC consists of combination of either Immune Checkpoint Inhibitor (ICI)-Tyrosine Kinase Inhibitor (TKI) for all IMDC prognosis group, or ICI-ICI for intermediate and unfavorable IMDC groups. Treatments are maintained until disease progression or toxicity for a total duration of 2 years for ICI, in routine. Acceptability and feasibility of treatment pause of the TKI, with no detrimental effect on efficacy were reported in the prospective STAR trial. The good-risk population is characterized by prolonged survival, close to that reported in the intermediate risk population group with a single adverse prognostic factor. Therefore, a pause of ICI-TKI could improve quality of life, safety, and total cost of care without detrimental impact on oncologic outcomes. Methods: This non-inferiority, randomized, open-label, multicenter, parallel-group trial (NCT05219318) aims to compare treatment pause versus treatment continuation in good or intermediate risk mRCC patients with only one prognostic factor and a confirmed objective response (complete or partial) at 12 months of treatment with ICI-TKI. 372 patients (186 in France) will be recruited in tertiary hospitals and randomized in a 1:1 ratio with stratification by center, prognostic group (good/intermediate) and response (complete/partial). The primary objective is to test the non-inferiority of treatment pause versus continuation, with the estimation of the difference in 12-month progression rate after randomization, and its one-sided 97.5% confidence interval. The non-inferiority margin is set at 15%. An interim safety data monitoring at 6 months after randomization of the first third of participants (i.e. 60 per arm) will check progression rate after treatment pause. A formal interim futility analysis will be performed when 50% of the study sample reaches the primary outcome time point, using a Bayesian predictive power stopping rule and a futility threshold set at 20%. Secondary objectives are overall safety and tolerability, health-related quality of life, anxiety and depression, quality-adjusted survival, 2-year overall and progression-free survival. Others objectives include progression patterns (site, known lesions, or/and new lesions), subsequent treatment (type, efficacy), in the experimental arm. In France, healthcare resource utilization and costs at 12 months will be compared. The first participant was randomized in January 2023. 27 centers in France were selected and are gradually/progressively opening. The opening of European centers is being planned. Health Ministry and National Cancer Institute Funds. Clinical trial information: NCT05219318 .
The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in immune-oncology era (SEVURO-CN): A study protocol for a multi-center, prospective, randomized trial.
Authors: Park Jee Soo , Kim Jongchan , Jeon Jinhyung , Lee Jongsoo , Jang Won Sik , Lee Seung Hwan , Han Woong Kyu , Choi Young Deuk , Koo Kyo Chul , Cho Kang Su , Chung Byung Ha , Ham Won Sik
Published: January 2024

TPS490

Background: The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear in the immuno-oncology (IO) era. The results of two randomized trials, CARMENA and SURTIME, questioned the role and timing of CN. However, despite the latest advances in the systemic treatment of mRCC, previous trials have only used targeted therapy, and no studies have fully investigated the role of CN in immune checkpoint inhibitor (CPI) settings, and there is an urgent need for future studies to better define the role and timing of CN. Methods: This study is an open-label, multi-center, parallel, prospective, randomized, interventional clinical study to evaluate the efficacy of CN in combination with CPIs in mRCC patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk. Synchronous mRCC patients with ≤3 IMDC risk features will be randomly allocated to three groups (1, upfront CN; 2, deferred CN; and 3, systemic therapy (ST) only). For ST, the nivolumab plus ipilimumab combination regimen, one of the standard regimens for intermediate- and poor-risk mRCC, is chosen. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, objective response rate, number of participants with treatment-related adverse events, and number of participants with surgical morbidity. We will analyze the genetic mutation profiles of the tumor tissue, circulating tumor DNA, urine tumor DNA, and tumor-infiltrating lymphocytes. The gut and urine microbial communities will be analyzed. The study will begin in 2023 and will enroll 40 patients. Clinical trial information: NCT05753839 .
Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).
Authors: Serzan Michael Thomas , Jegede Opeyemi , Bilen Mehmet Asim , Braun David A. , Einstein David Johnson , Haas Naomi B. , Hammers Hans J. , King Jennifer , Runcie Karie , Sosman Jeffrey A. , Sternberg Cora N. , Yang Yuanquan (Aaron) , Choueiri Toni K. , Signoretti Sabina , Atkins Michael B.
Published: January 2024

TPS492

Background: First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods: ARCITECT is a phase II, multicenter study evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC ( favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806 .
MAIN-CAV: Phase III randomized trial of maintenance cabozantinib (CABO) and avelumab (Av) vs Av after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001).
Authors: Gupta Shilpa , Ballman Karla V. , Apolo Andrea B. , Sridhar Srikala S. , Chen Ronald C. , Wen Yujia , Yen Aihua Edward , Grivas Petros , Tan Alan , Baghaie Shiva , Galsky Matt D. , Morris Michael J. , Rosenberg Jonathan E.
Published: January 2024

TPS714

Background: 1st-line induction platinum-based chemotherapy followed by switch maintenance Av is the current preferred standard of care in patients (pts) with aUC who do not progress after platinum-based chemotherapy. There is an significant need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitor. We hypothesized that CABO-Av combination would improve survival vs Av alone and have an acceptable safety profile as switch maintenance therapy in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for pts with locally advanced/metastatic UC (including cN3M0 only)) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adults are randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or Av and CABO 40 mg daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of anti-PD(L)1, no CNS metastases, no major surgery within 4 wks, no uncontrolled hypertension or cardiovascular disorders. Pts are stratified based on 1) best response to 1L chemotherapy: complete vs partial response vs stable disease and 2) presence vs absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of 1-sided alpha 0.025, power 80%, median OS 21 months (mo) with Av and hazard ratio 0.75, thus hypothesizing median OS 28 mo on CABO-Av. Key secondary endpoints include progression-free survival, safety, tolerability, and efficacy of CABO-Av vs Av alone based on RECIST 1.1 and iRECIST criteria (and PD-L1 status).Quality of life (QOL) are assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-Av vs Av alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test the correlation of established and new radiomic signatures with survival, adverse events and QOL and incorporate both radiologic and biologic features to assess their potential association with outcomes. This trial would be the first to systematically address whether adding the multitargeted TKI, CABO, to Av improves survival vs Av alone as 1L maintenance therapy. https://acknowledgments.alliancefound.org . Support: U10CA180821, U10CA180882; U24CA196171, U10CA180863 (CCTG); Clinical trial information: NCT05092958 .