bluuebunny/crossref_metadata_2025_split huggingface dataset:
Testosterone recovery for relugolix versus leuprolide in men with advanced prostate cancer: Results from the phase 3 HERO study.
Authors: Tutrone Ronald F. , Saad Fred , George Daniel J. , Tombal Bertrand F. , Bailen James L. , Cookson Michael , Saltzstein Daniel , Brown Bruce , Lu Sophia , Shore Neal D. 
Published: February 2022

104 Background: In the phase 3 HERO study, the oral GnRH receptor antagonist, relugolix, showed sustained testosterone suppression superior to that of leuprolide (96.7% vs 88.8%; difference: 7.9% [95% CI, 4.1 to 11.8; P < 0.001]). Herein, we provide an analysis of the testosterone recovery data in a subgroup of 184 men from the HERO study who were not indicated to continue androgen deprivation therapy. Methods: The phase 3 HERO study was designed to evaluate relugolix in men with advanced prostate cancer. Overall, 934 men were randomized 2:1 to receive relugolix 120 mg orally once daily after a single oral loading dose of relugolix 360 mg on Day 1 or leuprolide injections every 12 weeks for 48 weeks. Testosterone recovery was assessed in 184 patients who completed 48 weeks of treatment and who did not plan to start alternative androgen deprivation therapy within the following 12 weeks (or within 24 weeks following the last injection of leuprolide 3-month depot). During the 90-day recovery period, assessments included time to testosterone recovery (≥ 280 ng/dL, the lower limit of the normal range) using the Kaplan-Meier method, PSA concentrations in testosterone recovery phase, and adverse events during the recovery phase. All analyses were conducted in a modified intent to treat population. Results: Overall, 137 men in the relugolix group and 47 men in the leuprolide group were included in these analyses. Mean (standard deviation) testosterone levels for men entering the recovery assessment were 427±142 ng/dL and 404±127 ng/dL in the relugolix and leuprolide groups, respectively. The cumulative incidence rate of testosterone recovery to ≥280 ng/dL at 90 days after drug discontinuation was 53.9% in the relugolix group compared with 3.2% in the leuprolide group (nominal p = 0.0017). Overall, 74 of the 137 men in relugolix group recovered testosterone with a median time to recovery of 86.0 days (95% CI: 65.0, 92.0), versus 2 of the 47 men in leuprolide group with a median time to recovery of 112.0 days (95% CI: 112.0, not estimable). At the 90-day follow-up visit, the median PSA values were 0.39 ng/mL (range: 0 to 233.1) and 0.06 ng/mL (0 to 14.0) in the relugolix and leuprolide groups, respectively. Incidence of adverse events were generally similar in the treatment groups during the recovery phase, with 96% of men experiencing at least one adverse event and 15% of men experiencing a grade ≥3 adverse event in both treatment groups during the recovery phase. Conclusions: Relugolix, an oral nonpeptide GnRH receptor antagonist, had a faster and more complete recovery of testosterone to normal levels after treatment discontinuation versus leuprolide in a subgroup of men from the phase 3 HERO study. Clinical trial information: NCT03085095.
Pembrolizumab (pembro) plus abiraterone acetate (abi) and prednisone (p) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from KEYNOTE-365 cohort D.
Authors: Ferrario Cristiano , Piulats Josep M. , Linch Mark David , Stoeckle Michael , Laguerre Brigitte , Arranz José A. , Todenhöfer Tilman , Fong Peter C.C. , Berry William R. , Emmenegger Urban , Mourey Loic , Mar Nataliya , Appleman Leonard Joseph , Joshua Anthony M. , Conter Henry Jacob , Li Xin Tong , Schloss Charles , Poehlein Christian Heinrich , De Bono Johann S. , Yu Evan Y. 
Published: February 2022

118 Background: Abi + p is a standard of care for mCRPC. Cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573) was used to evaluate safety and efficacy of the PD-1 inhibitor pembro + abi and p in patients (pts) who had not received chemotherapy for mCRPC. Methods: Chemotherapy-naive pts who had not previously used next-generation hormonal agents (NHAs) for mCRPC or were intolerant to enzalutamide or for whom enzalutamide was ineffective for mCRPC, whose disease progressed ≤6 months before screening, and who had ECOG PS score 0/1 were eligible. Enrolled pts received pembro 200 mg IV Q3W + abi 1000 mg PO QD and p 5 mg PO BID. Primary end points were PSA response rate (PSA decrease ≥50% from baseline), confirmed ORR per RECIST v1.1 by blinded independent central review, and safety. Secondary end points included rPFS per PCWG3-modified RECIST v1.1, DCR (CR + PR + SD or non-CR/non-PD ≥6 mo), DOR, OS, time to symptomatic skeletal-related event, radiographic bone progression, and radiographic soft tissue progression. Results: Of 103 treated pts, 35.9% had RECIST-measurable disease and 26.2% had previously received enzalutamide. Median (range) time from enrollment to data cutoff was 17.6 (9.7-27.0) months. Confirmed PSA response rate in all 103 pts was 56.3%. Overall, 78.6% of pts had a reduction in PSA level from baseline (confirmed and unconfirmed). For 37 pts with RECIST-measurable disease, ORR was 16.2% (1 CR; 5 PRs) overall, 7.7% for those who previously received enzalutamide (n = 13) and 21.7% for those who had not previously received NHAs (n = 23). Two pts with RECIST-nonmeasurable disease had a CR. DOR was not reached (NR; range, 2.1+ to 19.4+ mo); 4 pts had a response ≥12 months. DCR was 44.7% overall, 11.1% in pts who previously received enzalutamide (n = 27), and 57.3% in pts who had not previously used NHAs (n = 75). Additional analyses are listed in the table. Treatment-related AEs (TRAEs) were experienced by 90.3% of pts; 36.9% experienced grade 3-5 TRAEs. Overall, 18.4% of pts had a grade 3/4 ALT laboratory elevation and 12.6% had a grade 3/4 AST elevation. Five pts died of AEs; 1 was treatment-related (myasthenic syndrome). Conclusions: Pembro + abi and p showed antitumor activity in chemotherapy-naive pts with mCRPC. Safety was generally consistent with individual profiles of each agent, although there was an increased incidence of grade 3/4 ALT/AST laboratory elevations than reported for the individual treatments. Clinical trial information: NCT02861573. [Table: see text]
Progression-free survival (PFS) and overall survival (OS) in patients (pts) with de-novo, high-volume metastatic castration-sensitive prostate cancer (dn-hv-mCSPC) undergoing intensified androgen deprivation therapy (ADT).
Authors: Swami Umang , Chigarira Beverly , Sayegh Nicolas , McFarland Taylor Ryan , Tripathi Nishita , Nussenzveig Roberto , Kessel Adam , Tandar Clara , Goel Divyam , Cheney Jackson , Nordblad Blake , Thomas Vinay Mathew , Sirohi Deepika , Maughan Benjamin L. , Agarwal Neeraj 
Published: February 2022

133 Background: In the PEACE-1 trial (Fizazi, ESMO 2021), in pts with dn-hv-mCSPC, the addition of abiraterone to ADT + docetaxel (triplet therapy arm) resulted in a median OS of 61 months (OS on ADT + docetaxel arm was 42 months). However, independent contribution of docetaxel to efficacy of ADT + abiraterone in the triplet therapy arm of PEACE-1 trial is not clear. Furthermore, the efficacy of an novel hormonal therapy (NHT) specifically in dn-hv-mCSPC population has not been reported (LATITUDE trial’s eligibility did not include volume status). Herein, our objective was to assess PFS and OS in a cohort of dn-hv-mCSPC pts undergoing intensified ADT with either NHT (i.e. novel androgen receptor or androgen synthesis inhibitors) or docetaxel. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: presence of dn-hv-mCSPC (hv per CHAARTED criteria) undergoing intensified ADT with either NHT or docetaxel started within 3 months of diagnosis. Study endpoints: PFS was calculated per PCWG-2 - defined PSA progression or radiographic progression or clinical progression whichever occurred first; OS was defined as start of therapy to date of death or censored at last follow-up. A multivariate analysis using the Cox proportional hazards (Cox-ph) model was used; the relationship between treatment intensification with both PFS and OS was assessed and adjusted for age at diagnosis, Gleason score, presence of visceral metastases, and PSA at baseline. Results: 85 pts with dn-hv-mCSPC were included: 45 received ADT + NHT; 40 received ADT + docetaxel. In the NHT vs docetaxel arms: median PFS were 23 vs 14 months; and median OS were 63 vs 36 months respectively. See the table for Cox-ph and adjusted co-variate results. Conclusions: We for the first-time report the real-world survival outcomes with ADT + NHT specifically in pts with dn-hv-mCSPC. In addition, in these hypothesis-generating data, the OS of pts with dn-hv-mCSPC undergoing ADT + NHT or ADT + docetaxel were similar to those in the triplet therapy arm or ADT + docetaxel arm of PEACE-1 trial respectively. A randomized trial in pts with dn-hv-mCSPC comparing ADT + NHT vs triplet therapy may better characterize the benefit of the docetaxel component in the triplet therapy.[Table: see text]
Implications of androgen receptor (AR) alterations identified by genomic testing of tissue and blood from advanced prostate cancer (aPC) patients (pts).
Authors: Zengin Zeynep Busra , Henderson Nicholas , Park Joseph J. , Ali Alicia , Hwang Clara , Barata Pedro C. , Bilen Mehmet Asim , Graham Laura , Kilari Deepak , Tripathi Abhishek , Labriola Matthew , Rothstein Shoshana , Garje Rohan , Koshkin Vadim S , Patel Vaibhav G. , Schweizer Michael Thomas , Armstrong Andrew J. , McKay Rana R. , Alva Ajjai Shivaram , Dorff Tanya B. 
Published: February 2022

138 Background: AR alterations such as ligand binding domain mutations and amplification evolve under the selective pressure of testosterone suppression and AR targeted agents (ARTA) such as abiraterone or enzalutamide, but their relevance to ARTA treatment outcomes remain unclear. Methods: PROMISE is a multi-institutional retrospective clinical-genomic database inclusive of aPC pts who had tissue and/or blood based genomic testing by commercially available CLIA-certified platforms. We analyzed men who received second generation ARTA and stratified patients according to genomic testing timing (pre-/post-ARTA), castration resistance, type of AR alteration, and PSA decline ≥50% on first ARTA. Time to progression (TTP) from first ARTA initiation was estimated using the Kaplan-Meier method and differences between subgroups defined by AR alteration status were assessed using the log-rank test. Results: 854 pts who received ARTA and had tissue-based (n = 600) or blood-based (n = 335) genomic testing were included. Median age was 62 (range, 33-93). Pre- and post-ARTA genomic testing was available in 387 and 467 pts, respectively. AR alterations were identified in 16% (61/387) of pre-ARTA and 48% (226/467) of post-ARTA pts with AR amplifications in 10% (38/387) and 35% (161/467) of the pts, respectively. 15/52 pts who had pre- and post-ARTA testing developed a new AR alteration. In pre-ARTA cohort; castration status, median TTP, and PSA response for 1st ARTA according to alteration status are summarized in the table. In the post-ARTA group, the most common AR mutations were L702H (53%), followed by T878A (33%); whereas, in the pre-ARTA group, the H875Y (26%) mutation was most common. AR mutations in post-ARTA group were seen at similar rates regardless of prior docetaxel exposure (14.3% vs 18.0%, p = 0.46) and following first abiraterone vs enzalutamide/apalutamide exposure (48.6% vs 48.3%, p = 1.0). Conclusions: AR mutations, unlike amplifications, were associated with shorter TTP on abiraterone. Genomic testing should be considered before second line ARTA.[Table: see text]
HSD3B1 polymorphism in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate and prednisone (AAP): Pharmacodynamics and therapeutic implications.
Authors: Bastos Diogo Assed , Camargo Anamaria Aranha , Zylberberg Ricardo , Fontes Jardim Denis Leonardo 
Published: February 2022

140 Background: AAP prolongs survival in pts with mCRPC. Although it is widely used for mCRPC, no predictive biomarker for response has been identified so far. Methods: This study evaluated HSD3B1 genetic polymorphism and pharmacodynamic parameters from serum samples of mCRPC pts with disease progression after diethylstilbestrol (DES) treated with AAP in the AAP-DES study (NCT02217566). Peripheral blood samples were collected before initiating AAP therapy, after 12 weeks, and at disease progression. Sample analysis included HSD3B1 genotyping, abiraterone acetate (AbA) and D4-abiraterone serum levels, testosterone and dehydroepiandrosterone sulfate (DHEA-S) ultrasensitive analysis. Clinical characteristics, overall survival (OS), progression-free survival (PFS) and the rate of PSA decline ≥ 50% were assessed considering homozygous wild-type (AA) versus heterozygous variant (AC) + homozygous variant (CC) HSD3B1 genotypes. Results: Serum samples of 42 pts were analyzed. AA and AC + CC HSD3B1 genotypes were 50.0% each (95% CI:34.2-65.8). Mean ages at baseline was significantly higher in the AA group (71.1 years) compared to the AC+CC group (66.3 years) (p=0.047). Gleason score ≥8 was observed for 38.1% and 47.6% of AA and AC+CC genotypes, respectively (p<0.001). No statistically significant difference was observed between AA and AC+CC groups related to testosterone and DHEA-S level at baseline, week 12, and PSA progression. Serum levels of AbA and D4-abiraterone were similar, throughout treatment despite HSD3D1 genotype. Median OS was 21.3 months (95% CI: 14.8 - ; 14 events) for the AA genotype, and it was not reached at the AC+CC genotype group (9 events) (p=0.154). Regarding PFS, median estimates were 7.3 months (95% CI: 4.6 – 9.4; 16 events) for AA genotype and 7.9 months (95% CI: 5.6 – 14.4; 16 events) for AC+CC genotype (p=0.519). PSA decline ≥ 50% was 71.4% for AA genotype and 42.9% for AC+CC genotypes and the chance of PSA response in patients with AA genotype is 3.33 (95% CI: 0.93; 12.11) times greater than that in patients with AC or CC genotypes, despite not statistically significant differences (p=0.0614). Conclusions: In our study, the presence of HSD3B1 (1245C) was not significantly associated with clinical response during AAP treatment, as well as testosterone, DHEA-S, AbA and D4-abiraterone levels. The role of HSD3B1 polymorphism to predict clinical outcome of AR blockade for mCRPC patients still needs to be further analyzed in larger translational studies. [Table: see text]
Effect of PSMA-positive membranes secreted from prostate cancer cells on vascular endothelial cells.
Authors: Watanabe Ryuta , Maekawa Masashi , Kiyoi Takeshi , Kurata Mie , Miura Noriyoshi , Kikugawa Tadahiko , Higashiyama Shigeki , Saika Takashi 
Published: February 2022

141 Background: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA positron emission tomography/computed tomography has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear. Methods: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected from patients with prostate cancer via robotic surgery in 2019 at Ehime University. In vitro, we prepared conditioned medium derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the conditioned medium. We assessed angiogenic activities by treating HUVECs with LNCaP-derived conditioned medium using a tube formation assay that mimics angiogenesis. Results: Immunohistochemical positivity of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in four of 33 prostate cancer patients (12.1%). We also found that the 10,000 ´ g pellet fraction of the LNCaP-derived conditioned medium containing PSMA-positive membranes, including microvesicles, transformed HUVECs from “PSMA-negative” to “PSMA-positive.” Mass spectrometry revealed that the fraction contained an important growth factor. Furthermore, treating HUVECs with the 10,000 ´ g pellet fraction of the LNCaP-derived conditioned medium significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner. Conclusions: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which were found to enhance tumor angiogenesis in prostate cancer tissues. The endocytic process related to these PSMA-positive microvesicles in normal endothelial cells might be an attractive target to develop novel anti-angiogenic drugs, which could inhibit the transformation of normal endothelial cells into tumor endothelial cells (Watanabe et al., The Prostate. 2021. in press).
Germline BRCA2, ATM and CHEK2 alterations shape somatic mutation landscapes in prostate cancer.
Authors: Nakazawa Mari , Fang Mike , Lotan Tamara L. , Luo Jun , Isaacs William B. , Paller Channing Judith , Antonarakis Emmanuel S. 
Published: February 2022

148 Background: Prostate cancer (PCa) is a highly heritable malignancy. Germline mutations in homologous recombination repair (HRR) genes, especially in in ATM, BRCA2 and CHEK2, are common in men with PCa, but how these influence somatic mutations is unknown. Characterizing the somatic landscape of tumors from germline HRR-altered PCa patients may provide insights into further therapeutic strategies and identify individuals most likely to benefit from existing therapies. Methods: We retrospectively identified 118 men with germline HRR-altered PCa from Johns Hopkins with available somatic mutation data (g ATM, n = 30; g BRCA2, n = 58; g CHEK2, n = 30). In these patients, somatic NGS analysis were done primarily using prostatic (rather than metastatic) tissues. The proportion of patients in each group with somatic biallelic inactivation was determined. We then compared the somatic mutation landscapes of the 3 groups, focusing on key PCa-relevant genes including AR, TMPRSS2-ERG, PTEN, TP53, BRCA2, ATM, CDK12, APC, FOXA1, AKT1, PIK3CA, and KDM6A among others. Somatic mutation data from primary prostate cancer specimens (n = 3965) found in pooled studies (n = 23) from cBioPortal were included as a reference standard for comparison. Results: Biallelic somatic inactivation was detected in 59% (34/58) of g BRCA2-altered, 47% (14/30) of g ATM-altered, and 0% (0/30) of g CHEK2-altered patients. In all 118 germline HRR-altered individuals, the most common somatic mutations were in BRCA2 (31%), FOXA1 (26%), TMPRSS2-ERG (20%), TP53 (16%), PTEN (15%), and ATM (15%). g BRCA2-altered patients had a higher prevalence of somatic mutations in AR (9% vs 3% in cBioPortal, P < 0.05) and FOXA1 (29% vs 13% in cBioPortal, P > 0.05), suggesting a greater dependency on AR signaling, but a lower prevalence of TMPRSS2-ERG fusions (17% vs 33% in cBioPortal, P < 0.05). g ATM-altered patients had a strikingly low prevalence of somatic TP53 mutations (3% vs 25% in cBioPortal, P < 0.01), indicating mutual exclusivity between these genes. g CHEK2-altered patients had a higher prevalence of somatic CDK12 mutations (10% vs 0% in gATM/gBRCA2 patients, P < 0.05), implying an interaction between CHEK2 and CDK12. No differences were seen between the three groups with respect to alterations in the PI3K/PTEN pathway, WNT pathway, or chromatin-related genes. Conclusions: Biallelic inactivation was frequently observed in PCa patients harboring g ATM and g BRCA2 mutations, but not in those with g CHEK2 mutations. g BRCA2-altered patients were enriched for somatic AR (and FOXA1) mutations and were depleted for TMPRSS2-ERG fusions. g ATM-altered patients were depleted for somatic TP53 mutations, while g CHEK2-altered patients were enriched for somatic CDK12 mutations. Thus, germline mutations appear to impose selective pressures that influence somatic mutation landscapes in PCa.
Age-based assessment of cell-free DNA genomic profiles in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Knox Andrea , Fettke Heidi , Hauser Christine , Bukczynska Patricia , Ng Nicole , Foroughi Siavash , Graham Lisa-Jane K. , Mahon Kate Lynette , Tan Winston , Zheng Tiantian , Dai Chao , Du Pan , Jia Shidong , Horvath Lisa , Kohli Manish , Azad Arun , Kwan Edmond Michael , Wang Amy 
Published: February 2022

150 Background: With the evolving use of targeted therapies exploiting genomic vulnerabilities in mCRPC, screening patients for sensitizing alterations is of increasing relevance. However, the influence of age on the detection of relevant genomic alterations is incompletely understood. In this study, we compared the cell-free DNA (cfDNA) profiles of younger (age <70) versus older (age ≥70) men with mCRPC and assessed the relative prognostic impact of common genomic alterations. Methods: A next-generation sequencing-based Predicine cfDNA assay was used to profile 276 mCRPC patients from two independent international cohorts. The frequency of genomic alterations across age categories was compared using the chi-squared test, while circulating tumour DNA fraction (ctDNA%) was compared using the Mann–Whitney U test. Cox proportional hazards analysis with interaction testing was used to assess the association between age, genomic alteration and overall survival. Results: The median age of the combined cohort was 72 years (IQR 66-78), with 170 (62%) patients ≥70 years old. Despite differences in baseline characteristics (poorer performance status in older patients, higher Gleason score and de novo metastatic disease in younger patients), there was no significant difference in ctDNA% (median 22% vs 30%, p=0.6). We observed similar frequencies of genomic alterations across the 10 most commonly aberrant genes, including AR (<70 vs ≥70: 46% vs 49%, p=0.6), TP53 (40% vs 36%, p=0.6), BRCA2 (29% vs 21%, p=0.13) and PTEN (39% vs 35%, p=0.5). This similarity persisted when analysing mutations and copy number alterations in isolation. While driver alterations in both age categories were strongly associated with unfavourable outcomes (Table), an exploratory analysis revealed that copy number gain in PIK3CA may have a worse prognostic impact in younger men ( p for interaction = 0.03), with a lesser effect observed in AR gain ( p = 0.1) and MYC gain ( p = 0.1). Conclusions: The genomic profiles of pertinent alterations between younger and older men are comparable. Certain genomic alterations may carry a worse prognosis in younger men. Patients should be considered for precision medicine assessment and directed therapies, regardless of age. [Table: see text]