tbuckley/cabot-search huggingface dataset:
Testosterone suppression and recovery in patients with advanced prostate cancer treated with intermittent androgen deprivation therapy (iADT) with relugolix.
Authors: Patrick Campbell, Georges Gebrael, Arshit Narang, Chadi Hage Chehade, Vinay Mathew Thomas, Gliceida Galarza Fortuna, Nicolas Sayegh, Nishita Tripathi, Clara Tandar, Emre Dal, Haoran Li, Umang Swami, Neeraj Agarwal, Benjamin L. Maughan
Journal: Journal of Clinical Oncology (2024)

70 Background: Many patients with advanced prostate cancer do not want to pursue continuous androgen deprivation therapy (cADT) because of concerns about side effects, and pursue iADT. However, even intermittent treatment with GNRH agonist therapy may not lead to rapid recovery of testosterone during the off-treatment period. In the pivotal HERO trial of relugolix (GNRH antagonist) the testosterone recovery time was in weeks [PMID 32469183]. The objective of the study was to measure the time to testosterone suppression to castrate level and time to recovery of serum testosterone to non-castrate level in real-world patients with advanced prostate cancer undergoing intermittent relugolix therapy. Methods: In this IRB-approved retrospective study, the eligibility was: patients with advanced prostate cancer undergoing iADT with relugolix. iADT with relugolix was defined as initiating relugolix at PSA ≥ 10 ng/ml and holding relugolix when PSA ≤ 4 ng/ml. The primary endpoints were: 1) time to serum castrate level of testosterone after relugolix initiation and 2) time to recovery to non-castrate level after discontinuation of relugolix. Castrate level of serum testosterone was defined as serum testosterone level ≤ 50 ng/dL. Results: Overall 25 consecutive patients with advanced prostate cancer treated with iADT with relugolix were eligible and included. The median age was 75 [range 68-88]. Patients with a Gleason score of ≥ 8 comprised 44% of the cohort. The median PSA at the start of therapy was 18.2 ng/ml [5.1 – 99.1 ng/ml]. Median time to testosterone ≤ 50 ng/dl after relugolix initiation was 1.13 months [0.67 – 2.5 months], and median time to testosterone recovery after relugolix discontinuation was 1.4 months [0.83 – 6.57 months]. The median PSA nadir achieved with relugolix was 2.02 ng/ml [0.1 – 4.8], and median time to PSA nadir was 1.35 months from initiation of therapy (0.67 – 4.8 months). Median time to PSA relapse ≥ 10 ng/dl after holding relugolix was 3.4 months (0.9 – 8.23 months). Conclusions: This is the first real-world study to show that iADT with relugolix is associated with a rapid time to testosterone suppression and recovery. These results may guide patients’ counseling, monitoring of serum testosterone and PSA levels in patients wishing to pursue iADT for advanced prostate cancer. These hypothesis-generating data need external validation.
Impact of exposure to clinical trials and standard-of-care therapy in metastatic or recurrent prostate cancer: An update.
Authors: Grace G Kim, Heba Mohamed, Ishmam Bhuiyan, Corin Macphail, Taylor Sidhu, Amir Emami, Longlong Huang, Shaun Zheng Sun, Scott Tyldesley, Jenny J. Ko
Journal: Journal of Clinical Oncology (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 1 st 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.
Effect of combined treatment with sipuleucel-T and IL-15 on tumor control, tumor-infiltrating immune effectors, and key mediators of immunoresistance in a preclinical prostate cancer model.
Authors: Russell Kent Pachynski, Muhammad Azeem Saeed, Bo Peng, Brian Andrew Van Tine, Nadeem Anwar Sheikh, Todd A. Fehniger
Journal: Journal of Clinical Oncology (2024)

177 Background: Sipuleucel-T (sip-T) is an autologous therapeutic vaccine produced using a tumor antigen-cytokine fusion protein, and the only FDA approved cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC) patients. Sip-T significantly improves overall survival (OS), but has limited impact on PSA and radiographic responses. Here, we present the first high dimensional analysis of the sip-T product; we used a preclinical model of human prostate cancer to show the effects of IL-15 on anti-tumor efficacy, tumor infiltration of effector cells, and reversal of immunosuppressive mediators. Methods: We performed a comprehensive assessment of the sip-T product collected from prostate cancer patients using mass cytometry (CyTOF). Control and IL-15 stimulated sip-T were evaluated, and changes in leukocyte subsets as well as markers of activation and exhaustion were identified. Using a preclinical mouse model of human prostate cancer, we examined the effects of IL-15 treatment on sip-T. CyTOF, flow cytometry, RNAseq, and qPCR were used to evaluate the effects of IL-15 on sip-T phenotype, function, and in vitro and in vivo efficacy. Results: CyTOF analysis revealed that CD3+ T cells constituted the highest proportion of sip-T, followed by B-cells, natural killer (NK) cells, NKT, and monocytes, with only a small percentage of dendritic cells. Following sip-T stimulation with IL-15, a significant expansion and activation of CD8+ T-cell and NK cell populations was seen. Co-culture of sip-T with IL-15 and control or prostate-relevant antigens showed significant activation and expansion of CD8 T and NKT cells in an antigen-specific manner, with significantly increased tumor cytotoxicity and evidence of antigen spread. IL-15 treatment combined with sip-T in a preclinical mouse model showed significant suppression of tumor growth compared to sip-T alone, with increased tumor-infiltrating lymphocytes (TIL). A significant increase in interferon (IFN)-γ producing CD8+ T and NKT cells within the tumor microenvironment was seen in the IL-15 group. Tumor transcriptomic analyses revealed IL-15 treatment was able to reverse immunoresistance, with significant decreases in PD-L1, CTLA, TIGIT, B7-H3, and others compared to sip-T alone. Conclusions: This is the first study to evaluate the sip-T product using CyTOF, and the first pre-clinical in vivo prostate tumor modeling of sip-T. IL-15 treatment significantly enhances anti-tumor efficacy, effector immune cell activation and tumor infiltration, and reverses key mediators of immune suppression. Studies with modified IL-15 cytokines are ongoing and will be presented.
Prospective evaluation of the Kaiser Permanente prostate cancer risk calculator in biopsy-naïve men with mild PSA elevations.
Authors: Joseph Presti, Brandon Horton, Stacey Alexeeff, Stephanie Prausnitz, Andrew Avins
Journal: Journal of Clinical Oncology (2024)

290 Background: To assess the impact on biopsy outcomes in biopsy-naïve men with mild PSA elevations (&lt;10 ng/ml) when provided risk estimates using a novel prostate cancer risk calculator. Methods: This prospective study was conducted in urology departments in Kaiser Permanente Northern California in men with PSA elevations that were &lt;10 ng/ml between March 2021 and March 2023. Patient variables (age, race, family history of prostate cancer, body mass index, and PSA level) were entered into our validated calculator. Risk estimates for high-grade cancer (Gleason score ≥7) and overall cancer were shared with the patient who accepted or declined the biopsy. We compared age, race, family history for prostate cancer, BMI, PSA level, predicted high-grade and overall cancer risks between those that accepted and those that declined biopsy. The outcomes of those who underwent biopsy were compared to historical data of biopsy-naïve men with PSA elevations &lt;10 ng/ml who underwent biopsy in the three years prior to the Covid pandemic between January 2016 and December 2019 (n=5141). Results: After 24 months, the calculator was used to estimate risk for 1962 biopsy-naïve men with mild PSA elevations. 1455 (74%) accepted the biopsy. Those with a family history for prostate cancer were slightly more likely to accept biopsy. Age (continuous and categorical), and BMI (continuous and categorical) were not associated with decision for biopsy. Similarly, race/ethnicity when analyzed as four categories (White, Black, Asian, Hispanic) or as two categories (Black vs. all others) was not associated with decision for biopsy. The men who accepted the biopsy had higher predicted median high-grade cancer risks (24% [IQR 17-31%] vs. 20% [IQR 14-29%]; p&lt;0.0001) and higher predicted median overall cancer risks (48% [IQR 40-56%] vs 45% [IQR 37-53%], respectively; p&lt;0.0001) than those who declined the biopsy. Compared to the historical group, use of the risk calculator resulted in a biopsy population enriched with high-grade cancer: 29% vs 25%; similar rates of low-grade cancer: 24% vs 24%; and fewer negative biopsies: 47% vs. 51%, respectively; overall p=0.013. Conclusions: In biopsy-naïve men with mild PSA elevations, use of our risk calculator resulted in a biopsy population that had more high-grade cancer and fewer negative biopsies compared to a historical group. Only family history and higher predicted cancer risks by the calculator were associated with biopsy acceptance.
Does use of apalutamide enhance outcomes in combination with radiotherapy in metastatic hormone-sensitive prostate cancer? A real-world experience from the UK.
Authors: Prantik Das, Anand Sharma, Salil Vengalil, Yakhub Khan, JunHao Lim, Abdelfattah Elmasry, Rania Mohammed, Aruni Ghose, Seheli Bandyopadhyay, Hasanthi Nillegoda, Bahaaeldin Baraka, Syeda Tasmia, Navin Mathiyalagan
Journal: Journal of Clinical Oncology (2024)

73 Background: Management of metastatic prostate cancer has undergone a significant change over the past decade, with the introduction of several novel agents and repurposing of others. Latest update from STAMPEDE trials shown prostate radiotherapy (RT) improves OS, without detriment in QoL in metastatic home sensitive prostate cancer mHSPC along with Docetaxel in those with low volume metastatic disease. There is no published data on impact of radiotherapy to prostate on Apalutamide treated mHSPC patients. Here we report our real-world experience of Apalutamide in mHSPC with radiotherapy. Methods: Patients with mHSPC (N = 266) from 5 UK centres, were treated with Apalutamide (240 mg) and ADT along with radiotherapy to prostate as per treating clinician’s discretion. The primary endpoint was objective rate (ORR) as determined by patients achieving a PSA decline of ≥90% (PSA90) and ≥50% (PSA50) and secondary endpoints included biochemical progression free survival (bPFS) and safety. Results: The median age for the whole cohort was 73.4 years (interquartile range 52 - 91), A total of 11.6% had received prior radical treatment (prostatectomy or radiotherapy for localised disease) and 88.4% had de novo metastatic disease. Median baseline PSA was 47 ng/ml (range 0.4-17100). The proportion of patients PSA90 and PSA50 at 3, 6 and 12 months is shown in the Table. Median PSA nadir was 0.1 ng/ml(rage 0.01- 48.2) and median time to reach nadir was 6 months (range 3-24 months). 13.5% (35) patients were treated with radiotherapy (RT) after at least 3 months (range 3 -6 months) of starting apalutamide. Patients received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) of radiotherapy (68 % vs 32%). Higher number of patients in RT group had achieved PSA90 compared to no radiotherapy cohort (97.14 % vs 87.3%, p =0.15). Patients treated with RT had median post treatment of PSA 0.01 ng/ml compared to 0.1 ng/ml in non RT group (p=0.0062). After median follow up of 8.4 months, proportion of patients shown biochemical progression in RT vs non RT group were 5.7 % vs 15 % respectively (p= 0.04). Patients with de novo metastatic disease have shown poor PSA response and higher chance of progression compared to patients who had initial radical treatment. Radiotherapy was well tolerated, with 17 % adverse events (Radiation Therapy Oncology Group grade 3–4) reported in radiotherapy group. Conclusions: Early experience of using apalutamide and radiotherapy in mHSPC showed improved PSA response and delayed progression. Treatment was well tolerated. Further follow up and clinical trials are needed to understand the impact on overall survival. [Table: see text]
Implementation outcomes of a multidisciplinary approach for Lu177-PSMA-617 therapy.
Authors: Marybeth Nedrud, John Wang, Valeria Maldonado Grijalva, Colm Kelleher, Terence Z. Wong, Hannah Dzimitrowicz McManus, Matthew Labriola
Journal: Journal of Clinical Oncology (2024)

80 Background: Lu177-PSMA-617 (LuPSMA) is a recently approved treatment for patients with metastatic castration resistant prostate cancer (mCRPC). Successful treatment in real-world practice requires coordination between nuclear medicine, radiation safety, and medical oncology. We report outcomes from implementation of a multidisciplinary approach for LuPSMA administration at our institution. Methods: Our practice prior to treatment included collaborative radiologist review of PSMA PET/CT and oncologist review of prior therapies, performance status, and baseline laboratory values to establish candidacy. For each administration, procedures included confirming IV patency, use of a shielded infusion pump, IV hydration, and standardized radiation safety recommendations. On treatment, practices included scheduled laboratory monitoring, standardized treatment holds and dose reductions, coordination of care with a dedicated advanced practitioner, and mid-treatment conventional imaging. Retrospective chart review was completed for 100 mCRPC patients who received ≥1 dose of LuPSMA from June 2022 to August 2023 under this protocol. Outcomes including number of treatments, dose reductions/holds, PSA, and clinical imaging responses were reviewed. Results: Ninety-eight patients were included in the analysis (2 patients were excluded due to prior LuPSMA on clinical trial). In patients completing LuPSMA at time of data collection, median number of treatments was 4.0 (IQR=4.0, n=95), with 41% receiving all 6 planned treatments (n=39/95). During treatment, 16% experienced a treatment hold (n=16/98) with 25% ultimately completing 6 treatments (n=4/16; median=3.0, IQR=3.25). Holds were due to worsening symptoms (44%, n=7/16) or cytotoxicity (44%, n=7/16). Dose reductions occurred in 8% (n=8/98), with 38% completing 6 treatments (n=3/8; median treatments= 4.5, IQR= 3.0). Early discontinuation primarily occurred due to clinician-assessed progression (57%, n=32/56) or cytotoxicity (25%, n=14/56). Of those with early discontinuation due to progression, 70% had a rising PSA at time of discontinuation (n=21/30) and all had worsening disease on available mid-treatment imaging (n=15/15). For the remainder with early discontinuation due to progression, 20% had stable PSA (n=6/30) and 10% had decreasing PSA at time of discontinuation (10%, n=3/60). In those with stable or rising PSA, 75% terminated treatment due to worsening disease on available mid-treatment imaging (n=6/8). Conclusions: Our protocol for LuPSMA administration allows for early identification of clinical progression and completion of therapy when appropriate. Treatment holds and dose reductions facilitate therapy completion in select patients. Mid-treatment imaging may identify worsening disease in the setting of stable or decreasing PSA, underlying the potential importance of this practice for clinical decision making.
Association of multiparametric magnetic resonance imaging findings with oncologic outcomes in non-palpable localized prostate cancer.
Authors: Abhishek Kumar, Dominic LaBella, Scarlett Acklin-Wehnert, Rajan T. Gupta, Joseph Kamel Salama, Matthew J Boyer
Journal: Journal of Clinical Oncology (2024)

281 Background: Multiparametric magnetic resonance imaging (mpMRI) is becoming increasingly integrated into the evaluation and medical decision making for localized prostate cancer. However, mpMRI findings have not been correlated with prostate cancer outcomes and therefore are not currently included in staging. The purpose of this study was to test the association between mpMRI detected extraprostatic extension with oncologic outcomes in patients with non-palpable prostate cancer. Methods: We used the Veterans Affairs Prostate Data Core to identify patients diagnosed with cT1N0M0 prostate cancer between 2000-2021 with an mpMRI prior to definitive treatment. We reviewed MRI reports to identify presence of extracapsular extension (MRI-T3a), seminal vesicle invasion (MRI-T3b), and adjacent organ invasion (MRI-T4). We assessed the impact of mpMRI findings on metastasis free survival with multivariable Fine-Gray competing-risks regression. Results: Overall, 3,142 veterans with cT1N0M0 prostate cancer were included. There were 1,411 (45%) Black patients. By clinical staging, 904 (29%) had low risk, 1,626 (52%) had intermediate risk, and 612 (19%) had high risk disease. The majority of patients were treated with radiation (N=2,267; 72%). There were 217 (7%) patients with MRI-T3a disease, 87 (3%) patients with MRI-T3b disease, and 26 (1%) patients with MRI-T4 disease. The median follow-up time was 5.4 years (90% CI, 1-13 years). The 5-year cumulative incidence of metastases for patients with low, intermediate, and high risk prostate cancer were 3% (95% CI, 2-4%), 7% (95% CI, 6-8%), and 15% (95% CI, 12-18%). The 5-year cumulative incidence of metastases for patients with MRI-T3a, MRI-T3b, and MRI-T4 disease were 15% (95% CI, 10-20%), 29% (95% CI, 29-39%), and 40% (95% CI, 13-66%). After controlling for age, race, risk stratification (which includes prostate specific antigen (PSA) and grade group), local therapy, and co-morbidities, the presence of MRI-T3a (HR 1.58, 95% CI 1.09-2.29, p=0.02), MRI-T3b (HR 3.38, 95% CI 2.31-4.95, p&lt;0.0001), and MRI-T4 disease (HR 4.47, 95% CI 2.32-8.62, p&lt;0.0001) were independently associated with worse metastasis free survival. Similar results were obtained with PSA and grade group as individual variables. Conclusions: Extraprostatic extension observed on mpMRI is independently prognostic of metastasis free survival in patients with non-palpable prostate cancer. mpMRI is a critical imaging modality that should be widely available for patients with prostate cancer, and studies are ongoing to define its role as a standard staging modality.
Real-world treatment (Tx) sequences and time to discontinuation (rwTTD) in the first-line (1L) metastatic castration-resistant prostate cancer (mCRPC) setting.
Authors: Emily Nash Smyth, Samuel Whipple, Mark Guinter, Nadine Haddad, Wenxian Piao, Zhanglin Lin Cui, Arjun Vasant Balar
Journal: Journal of Clinical Oncology (2024)

55 Background: There is limited real-world data on tx sequencing in metastatic prostate cancer. Additionally, while guidelines support adding novel hormonal agents (NHA) to androgen deprivation tx (ADT) for metastatic hormone-sensitive prostate cancer, use is limited because of clinical and/or pt-driven factors. We evaluated tx patterns, rwTTD, and time-to-chemotherapy (rwTTC) for 1L mCRPC pts, including Black/African Americans (BAA) treated predominantly in a community oncology setting. Additionally, we analyzed systemic treatments prior to 1L mCRPC as well as progression to 2L mCRPC. Methods: This retrospective study included pts with mCRPC from the nationwide Flatiron Health EHR-derived, deidentified database who initiated 1L tx between 1/2013 and 1/2023. Study end was 4/2023. Tx patterns were described by time period (TP) of 1L initiation: TP1 - 01/2013–12/2017 and TP2 - 01/2018–01/2023; Kaplan-Meier analyses were conducted for rwTTD/TTC and a Cox proportional hazards regression model was used to determine the association between pt characteristics and rwTTD/TTC for 1L mCRPC. Subgroup analyses were performed for BAAs. Results: Of the 8915 1L-tx pts (median age 74 yrs), 871 (10%) were BAA (median age 70 yrs) and 5870 (66%) were NHA-naïve at 1L mCRPC. Overall, the percent of pts who were NHA-naïve decreased from 2018 (72%) to 2023 (39%) and a similar trend was observed for BAA (74% [2018] to 25% [2023]). 1L NHA use in mCRPC increased from TP1 to TP2 (overall: 70% to 80%; BAA: 73% to 83%), primarily driven by enzalutamide (Enz) (overall: 30% to 39%; BAA: 33% to 38%) and decrease in chemotherapy (overall: 16% to 12%; BAA: 17% to 13%). The top 3 1L mCRPC regimens for the overall population and BAA were abiraterone (Abi) (35%; 38%), Enz (32%; 33%), and docetaxel (10%; 11%). Among pts who progressed to 2L mCRPC, the most common sequences for patients tx with Abi or Enz for 1L mCRPC were ADT monotherapy in the prior line of tx and a switch to Abi (19%) or Enz (24%) upon progression from 1L to 2L. 1L rwTTD for the overall cohort is in the Table. Age ≥80 years, ECOG PS ≥1, socioeconomic status = 5 (highest), and median time ≤39.8 months from initial dx to mCRPC were associated with a higher hazard of discontinuation (all p ≤0.05). Conclusions: Overall, most pts received their first NHA in 1L mCRPC; NHA use increased and chemotherapy use decreased from TP1 to TP2. There was heterogeneity in tx sequences in patients treated with an NHA in 1L mCRPC; some pts were rechallenged with a different NHA in 2L despite lack of robust prospective data to support use. Overall, 1L rwTTD was short with a small numerical increase in TP2. Factors contributing to discontinuation, such as treatment resistance, need to be better understood to further improve real-world outcomes. [Table: see text]