bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utility of ctDNA burden as a prognostic biomarker for efficacy in TALAPRO-2: A phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Azad Arun , Fizazi Karim , Laird Douglas , Matsubara Nobuaki , De Giorgi Ugo , ButtIgliero Consuelo , Karsh Lawrence Ivan , Joung Jae Young , Yip Steven , Zschaebitz Stefanie , Albacker Lee A. , Healy Cynthia G. , Lin Xun , Chelliserry Jijumon , Agarwal Neeraj 
Published: June 2024

5020 Background: TALAPRO-2 (NCT03395197) demonstrated that 1L TALA + ENZA significantly improved radiographic progression-free survival (rPFS) vs PBO + ENZA for pts with mCRPC. ctDNA burden is a candidate prognostic biomarker with potentially broad utility across treatments and tumor types. We assessed the potential prognostic utility of baseline (BL) ctDNA burden and changes in ctDNA burden at Week 9 (WK 9) in TALAPRO-2 pts. Methods: Retrospectively analyzed serial ctDNA samples from BL and WK 9 were assessed using FoundationOneLiquid CDx. Plasma tumor fraction was calculated based on aneuploidy (Husain et al. JCO Precis Oncol. 2022. PMID: 36265119). We categorized ctDNA burden as high (ctDNA burden quantifiable) vs low (unknown ctDNA burden). Data cutoff date was August 16, 2022. Results: In the all-comers intent-to-treat population, 678 pts were evaluable for ctDNA burden at BL: 26% (89/337) of TALA + ENZA pts were ctDNA-high and 74% (248/337) were ctDNA-low; 29% (98/341) of PBO + ENZA pts were ctDNA-high and 71% (243/341) were ctDNA-low. High ctDNA burden at BL was prognostic of inferior rPFS in the TALA + ENZA and PBO + ENZA arms (Table). A relatively favorable median rPFS was observed for pts with low ctDNA at BL and WK 9 for TALA + ENZA (n=206) and PBO + ENZA (n=207), as reported in the Table. At WK 9, 72 pts in the TALA + ENZA and 77 pts in the PBO + ENZA arms were evaluable for ctDNA conversion from high to low. In both treatment arms, conversion from high to low ctDNA was prognostic of improved rPFS vs pts who remained ctDNA-high (Table). Pts who remained ctDNA-low had a more favorable rPFS vs conversion from high to low ctDNA: TALA + ENZA, hazard ratio (HR) 95% confidence interval (CI), 0.45 (0.29–0.71), P=0.0003; PBO + ENZA, 0.34 (0.23–0.52), P<0.0001). Conclusions: High ctDNA burden at BL was negatively prognostic, and ctDNA conversion from high to low at WK 9 was prognostic of improved rPFS in TALAPRO-2. Limitations included not all clinical trial sites were able to perform ctDNA collection and most samples were below the limit of quantification. These results support the broad prognostic utility of ctDNA burden in mCRPC. Clinical trial information: NCT03395197 . [Table: see text]
Clinical and genomic landscape of neuroendocrine prostate cancer (NEC) vs. prostate adenocarcinoma (AdenoK).
Authors: Gebrael Georges , Ostrowski Micah , Williams Jessica , Hage Chehade Chadi , Narang Arshit , Ozay Zeynep Irem , Chawla Neal Shiv , Mathew Thomas Vinay , Chehrazi-Raffle Alex , Swami Umang , Agarwal Neeraj , Maughan Benjamin L. 
Published: June 2024

5026 Background: NEC represents an aggressive form of prostate cancer, characterized by a high incidence of visceral metastases and a poor prognosis [PMID: 23169519]. A previous study has shown that, in a cohort of 30 patients (pts) with NEC, there was a significant enrichment for the loss of RB1 and the mutation or deletion of TP53 in these pts compared to those with AdenoK [PMID: 26855148]. Herein, we sought to compare the genomic landscape of pts with NEC to those with AdenoK using a large real-world genomic dataset. Methods: In this IRB-approved retrospective study, the de-identified Tempus Lens dataset was used to identify patients diagnosed with NEC and AdenoK across all stages and having comprehensive genomic profiling (CGP). Baseline demographic information was collected. Pathological variables were summarized using descriptive statistics to compare the NEC and AdenoK groups, using the Chi-square test with a significance threshold of P < 0.05. Genomic alterations with an incidence of ≥ 5% were included in the analysis. Homologous recombination repair (HRR) alterations in 14 pre-specified genes per the olaparib FDA label were also compared between both groups. Results: A total of 13,683 pts (AdenoK: 13472; NEC: 211) were included in the analysis. The median age of the NEC cohort was 65 [24 – 90+], with 55.9% of pts identified as White. Of pts with NEC, 37.9% were never smokers, while 32.7% were ex-smokers. In the AdenoK cohort, the median age was 66 [21- 90+], with 45.4% of patients identified as White. 36.62% of pts never smoked and 29.33% were ex-smokers. In the NEC cohort, the three most common alterations were TP53(63.98%), RB1(53.08%), and PTEN(28.91%). Compared to AdenoK, the NEC cohort had a significantly higher prevalence of TP53 (63.98 vs 34.97%; P<0.001), RB1 (53.08 vs 6.09%; P<0.001), PTEN (28.91 vs 18.1%; P<0.001), BRCA2(15.17 vs. 10.05%; P=0.01), TMPRSS2-ERG(25.12 vs. 19.29%; P=0.03), MYC(7.11 vs. 2.78%; P < 0.001), CDKN1B(6.16 vs. 2.11%; P < 0.001), and a lower frequency of SPOP (2.84 vs 9.22%; P=0.01), and ATM (6.64 vs 12.33%; P=0.01). HRR alterations frequency was similar between the NEC and AdenoK, respectively (38.83 vs. 38.66%, P=0.73). Conclusions: This is the largest real-world study characterizing the genomic features of prostate NEC compared to AdenoK. Our findings are consistent with prior studies suggesting a distinct genomic profile of NEC. These data can help in an improved understanding of the genetic drivers of this aggressive form of prostate cancer.
High dose chemotherapy in male patients with germ cell cancer: A population-based study by the SWENOTECA group.
Authors: Jansson Anna , Cohn-Cedermark Gabriella Elisabeth , Negaard Helene F. S. , Tandstad Torgrim , Stahl Olof , Hedlund Annika , Karlsdottir Asa , Hellström Martin , Langberg Carl Wilhelm , Sköld Camilla , Haugnes Hege Sagstuen , Glimelius Ingrid 
Published: June 2024

5040 Background: Selected patients with advanced germ cell tumors have a poor prognosis. These include patients with brain, bone or liver metastases, very elevated tumor markers or primary mediastinal tumor. High-dose chemotherapy (HDCT) with autologous stem cell support is recommended in the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) guidelines in selected poor risk patients with poor response to/relapse after intense primary treatment. From the year 2011, the HDCT-regimen consisted of two cycles of carboplatin and etoposide. Our aim of this study was to evaluate survival and toxicity in patients treated with HDCT within the population-based SWENOTECA cancer care program in 2011-2021. Methods: All patients treated with HDCT according to guidelines in Sweden and Norway between 2011-2021 were included, in total 80 patients (76 non-seminoma and 4 seminoma). This reflected approximately 3% of all non-seminoma patients. HDCT was administered in three different clinical situations: delayed tumor marker decline during primary or intensified primary treatment (n=26), progressive disease during primary treatment (n=29) (defined as progressive disease within <3 months from last cycle of chemotherapy), or relapse with poor prognosis (n=25). The overall survival (OS) and failure-free survival (FFS) were calculated, and the toxicity was described. Results: The 5-year overall survival (OS) and failure free survival (FFS) after HDCT was 55% and 43% respectively. HDCT due to delayed tumor marker decline had a more favorable outcome, 5-year OS of 75% and 5-year FFS of 53%. HDCT due to relapse resulted in a 5-year OS of 61% and 5-year FFS of 58%. Patients treated with HDCT due to progressive disease during primary treatment had a markedly less favorable 5-year OS of 29% and 5-year FFS of 18%. Four patients (5%) died due to treatment. The most common treatment-related grade 3-4 toxicities were infections (n=69, 86%). Conclusions: In this population-based study, we have shown that HDCT for patients with advanced germ cell cancer according to the SWENOTECA cancer care program is achievable and leads to favorable OS and FFS rates. Furthermore, even though patients that receive HDCT due to progressive disease have a relatively poor outcome, 20-30% of patients do achieve long-term survival. [Table: see text]
Circulating tumour DNA fraction as a predictor of treatment efficacy in a randomized phase 2 trial of [177Lu]Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel (TheraP ANZUP 1603).
Authors: Kwan Edmond Michael , Hofman Michael S , Ng Sarah WS , Emmett Louise , Sandhu Shahneen , Buteau James Patrick , Iravani Amir , Joshua Anthony M. , Francis Roslyn J. , Subhash Vinod , Lee Sze Ting , Scott Andrew Mark , Martin Andrew James , Stockler Martin R. , Donnellan Gráinne , Annala Matti , Tolmeijer Sofie H. , Azad Arun , Davis Ian D. , Wyatt Alexander William ,   TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2024

5055 Background: The TheraP trial showed that for patients with PSMA-positive, non-FDG-discordant mCRPC progressing after docetaxel, LuPSMA significantly improved biochemical and objective response rates, progression-free survival (PFS), and quality of life compared to cabazitaxel. While subsequent studies nominated high PSMA SUVmean to inform patient prioritization for LuPSMA, limited genomic data exists to guide optimal selection of these two life-prolonging therapies. We present an exploratory analysis of ctDNA fraction (ctDNA%) in baseline samples from the TheraP trial. Methods: We analyzed 180 baseline blood samples from participants who received ≥1 cycle of protocol-assigned treatment. Plasma cell-free DNA and matched white blood cell DNA underwent targeted sequencing to estimate ctDNA%. Prespecified ctDNA% categories (<2%, 2-30%, and >30%) were associated with previously validated imaging thresholds (PSMA SUVmean ≥10 and FDG metabolic tumor volume [MTV] ≥200mL), rate of PSA reduction ≥50% (PSA50-RR), and PFS, using chi-square test, logistic regression and Cox regression, respectively. Results: ctDNA% was evaluable in 178 (99%) participants, with ctDNA ≥2% in 85%. Median ctDNA% was 28% in ctDNA≥2% samples, and balanced across treatment arms. The odds of a PSA50 response to LuPSMA vs cabazitaxel were significantly higher for men with ctDNA <2% (OR infinite, p=0.0067; PSA50-RR 100% vs 58%), with no difference at ctDNA >30% (OR 1.1, p=1.0; PSA50-RR 46% vs 44%). Higher ctDNA% was associated with shorter PFS in LuPSMA- but not cabazitaxel-treated patients (LuPSMA: HR 5.0, p<0.001 for ctDNA <2% vs >30%; cabazitaxel: HR 1.4, p=0.35 for ctDNA <2% vs >30%; interaction p=0.035). The predictive potential of ctDNA% was additive to PSMA SUVmean in LuPSMA-treated patients. Higher ctDNA% categories were enriched for patients with high FDG MTV and low PSMA SUVmean disease (Table). Conclusions: ctDNA% is a candidate predictive and prognostic biomarker for differential response to LuPSMA versus taxane chemotherapy in patients with molecular imaging-selected mCRPC progressing after docetaxel. Clinical trial information: NCT03392428 . [Table: see text]
BRCA1/2 reversion mutations (BRCArev) in advanced prostate cancer in the absence of prior PARP inhibitor (PARPi) therapy.
Authors: Lin Douglas I. , L Elizabeth , Danziger Natalie , Ye Huihui , Decker Brennan J. , Graf Ryon P , Ross Jeffrey S. , Elvin Julia A. , McKay Rana R. 
Published: June 2024

5056 Background: In prostate cancer (PCA), BRCA1/2 alterations confer sensitivity to PARPi; however, in cases other than PCA with homozygous BRCA deletions, somatic BRCArev may restore BRCAfunction and mediate treatment resistance. In this study, we analyzed liquid biopsies of men with advanced PCA to (1) identify BRCArev, (2) to determine the clinical context in which BRCArev developed, and (3) to ascertain potential effect of prior chemotherapy on duration of PARPi response. Methods: BRCA1/2mutations were examined via liquid biopsies (FoundationOne Liquid CDx) during the course of clinical care for PCA patients during a 12-month period (from 01/2023 to 12/2023). Clinicopathological features and treatment history were extracted from medical records and/or treating oncologists’ notes. Results: Among 416 PCA patients with detected BRCA1/2 alterations, 25 (6.0%) patients harbored BRCArev that were predicted to restore BRCA function. Ten of 25 (40%) patients had detailed clinical and treatment history available. In three of 10 (30%) patients, somatic BRCArev were detected in the absence of prior PARPi therapy. All three PARP-naïve patients had been previously treated with chemotherapy (platinum or docetaxel) and radiation. Two patients had castration-resistant prostatic adenocarcinoma, while the third patient had de novo high-stage prostatic small cell neuroendocrine carcinoma without prior androgen deprivation. In all three PARP-naïve patients, multiple reversion mutations were detected per patient post-chemotherapy/radiation. Two of the three patients were predicted to have an original germline BRCA2alteration. The remaining 7 BRCArev-positive patients (70%) had prior PARPi treatment (all Olaparib). In PARPi-treated patients, duration of PARPi treatment prior to identification of BRCArev ranged from 5 to 24 months. 4 out of 7 PARPi-treated patients had received prior docetaxel, and duration of PARPi response was longer in chemo-naïve patients compared with those who had received prior docetaxel before PARPi (Mean: 18.6 vs 8.3 months, respectively). Conclusions: In men with BRCA-mutated PCA, chemotherapy and/or radiation may induce BRCArev in the absence of PARPi therapy. Testing of post-chemotherapy or radiation patients for BRCArev may be warranted prior to the start of PARPi therapy in patients with PCA. Our results support early PARPi therapy prior to radiation or chemotherapy as post-chemotherapy/radiation BRCArev may potentially dampen the future success of subsequent PARPi strategies.[Table: see text]
Association of genomic alterations with clinical outcomes following lutetium-177-PSMA vipivotide tetraxetan in men with metastatic castrate-resistant prostate cancer.
Authors: Gauntner Timothy , Gheeya Jinesh S. , Khorasanchi Adam , Xu Menglin , Hasanov Elshad , Collier Katharine A. , Meng Lingbin , Zimmerman Danielle Elise , Wang Peng , Folefac Edmund , Monk Paul , Mortazavi Amir , Clinton Steven K. , Yang Yuanquan (Aaron) 
Published: June 2024

5057 Background: Lutetium-177-PSMA vipivotide tetraxetan (Lu177) is approved for men with PSMA-positive metastatic castrate-resistant prostate cancer (mCRPC) previously treated with androgen receptor signaling inhibitors and taxane chemotherapy. The tumor genomic alterations conferring sensitivity or resistance to Lu177 are unknown. We investigated the association of genomic variants with clinical outcomes in men with mCRPC treated with Lu177. Methods: Somatic & germline DNA sequencing data were examined from men treated with ≥1 cycle Lu177 at The James Cancer Hospital of The Ohio State University from 3/2022 – 10/2023. Pathogenic variants from tissue or blood testing were identified. Sets of genes with similar biological function were annotated, including homologous recombination repair (HRR) genes ( BRCA1, BRCA2, ATM, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD51D, RAD54L), established tumor suppressor genes ( TP53, RB1, PTEN) and cell cycle genes ( CCND1, CCND3, CDK4, CDK6, CDK12, CDKN1B, CDKN2B) associated with prostate cancer. The impact of genomic variants on PSA50 response (Chi-Square & Fisher’s exact test), median overall survival (OS) and median progression-free survival (PFS) (Kaplan-Meier method) and OS or PFS (Cox proportional hazards model) was assessed. Results: Of 153 patients treated with Lu177, 120 underwent genomic sequencing: 109 had somatic testing (76 tissue-based, 33 blood-based), 50 had germline and 39 had both somatic & germline testing. Patients with amplification of cell cycle genes (n=8) had poorer OS of 5.1 months (mos.) vs 13.4 mos. for those without amplification (p=0.001, HR 4.26, 95% CI 1.79-10.11), and shorter PFS of 4.3 vs 7.4 mos. (p=0.027, HR 2.40, 95% CI 1.10-5.22). Patients with loss or mutation of HRR genes (n=32) had OS of 13.7 vs 12.2 mos. for those with no HRR alterations, but this was not significant (p=0.101, HR 0.57, 95% CI 0.29-1.12). No other genomic alterations were significantly associated with OS or PFS and none were associated with PSA50 response. The table lists the most frequently altered genes in PSA50 responders vs non-responders (differences not significant by Fisher’s exact test). Conclusions: Genomic alterations warrant investigation in larger cohorts as prognostic and predictive biomarkers for Lu177 therapeutic response. Our data suggest that amplification of genes impacting cell cycle regulatory pathways may be of particular interest. Our findings support continued efforts to determine the impact of cyclin dependent kinase (CDK) 4/6 inhibitors for high-risk and metastatic prostate cancer, either alone or in combination with agents such as Lu177.[Table: see text]
Rezvilutamide (REZ) plus docetaxel (DOC) in patients (pts) with chemo-naïve metastatic castration-resistant prostate cancer (mCRPC) after progression on abiraterone (ABI).
Authors: Liu Zhenhua , Wei Qiang , Feng Ping , Jiang Shusuan , Luo Hong , Liao Hong , Yu Dexin , Chen Zhiwen , Zhang Dahong , Dai Tao , Li Zeng , Zhang Zhiqiang , Bai Hong , Liu Feng , Wang Wenliang , Lin Jiaqin , Wang Yike 
Published: June 2024

5059 Background: Despite DOC is recommended for chemo-naïve mCRPC pts previously treated with novel hormone therapy, prognosis remains unfavorable. Herein we report the safety, PK, and preliminary efficacy of addition of REZ (a novel androgen receptor inhibitor) to DOC in chemo-naïve mCRPC pts who had progressed after ABI. Methods: This was a multicenter, 2-part, phase 2 study. Part 1 included a 3 + 3 dose escalation phase and a dose expansion phase. Eligible pts were enrolled to receive REZ (160/240 mg, PO, QD) plus DOC (75 mg/m2, IV, D1, Q3W, up to 10 cycles [C]), followed by REZ monotherapy (240 mg, PO, QD). REZ was given continuously staring from C1D2. DOC was concurrent with prednisone (5 mg, PO, BID). Both dose levels of REZ were selected to be expanded. Primary endpoint of part 1 was safety. Results: As of Aug 31, 2023, 36 pts were enrolled (18 with REZ 160 mg plus DOC and 18 with REZ 240 mg plus DOC). In the REZ 160 mg plus DOC and REZ 240 mg plus DOC groups, rate of pts with ECOG PS of 1 was 83.3% and 61.1%, rate of pts with Gleason score ≥ 8 was 88.9% and 72.2%, rate of pts with >10 bone metastases was 66.7% and 44.4%, and median baseline prostate-specific antigen (PSA) level was 81.7 ng/mL (range: 2.7-5993.0) and 144.0 ng/mL (2.9-3720.0). No DLTs were reported. Treatment-related adverse events of grade ≥ 3 occurred in 32 (88.9%) pts (14 [77.8%] pts with REZ 160 mg plus DOC, and 18 [100.0%] pts with REZ 240 mg plus DOC), with the most common being decreased neutrophil count, decreased white blood cell count, and anemia. C2/C1 ratio of AUC0-24h and Cmax of DOC was 0.73 and 0.78 when combined with REZ 160 mg, while that was 0.58 and 0.68 when combined with REZ 240 mg, which indicated influence of CYP3A strong inducer REZ on CYP3A4 substrate DOC with stronger impact at REZ 240 mg. Rate of PSA response at week 12 was 75.0%, time to PSA progression was 10.5 mo (95% CI, 5.6-11.3), and radiological PFS was 13.8 mo (95% CI, 5.7-19.6) with REZ 160 mg plus DOC, while that with REZ 240 mg plus DOC was 60.0%, 14.1 mo (95% CI, 4.1-21.4), and 8.5 mo (95% CI, 5.6-not reached) (Table). Conclusions: REZ plus DOC was well tolerated with promising efficacy in chemo-naïve mCRPC pts who had progressed after ABI. Clinical trial information: NCT04603833 . [Table: see text]
Biomarkers associated with outcomes from KEYLYNK-010: Pembrolizumab (pembro) plus olaparib (ola) versus next-generation hormonal agent (NHA) in previously treated metastatic castration-resistant prostate cancer (mCRPC).
Authors: Yu Evan Y. , Park Se Hoon , Goh Jeffrey C. , Shin Sang Joon , Mehra Niven , McDermott Raymond S. , Fong Peter C.C. , Greil Richard , Sade Juan Pablo , Huang Yi-Hsiu , Kramer Gero , Suzuki Hiroyoshi , Poehlein Christian Heinrich , Qiu Ping , Dettman E.J. , Wang April , Chen Cai , Cristescu Razvan , Marton Matthew J. , Antonarakis Emmanuel S. 
Published: June 2024

5064 Background: Pembro + ola did not significantly improve rPFS or OS vs NHA in unselected patients (pts) with previously treated mCRPC in the phase 3 KEYLYNK-010 study (NCT03834519). Here, we present the results of prespecified biomarker analyses with respect to rPFS or OS. Methods: Pts were randomly assigned 2:1 to pembro + ola or NHA. PD-L1 combined positive score (CPS) was measured by IHC (22C3 pharmDx); HRRm, BRCAm, TP53, PTEN, SPOP, ATM, CDK12, TMB, and MSI were analyzed in tissue samples using FoundationOne CDx or ctDNA using FoundationOne Liquid CDx; AR-V7 was analyzed using Epic Sciences’ CTC assay. Associations (continuous scale) with outcomes were evaluated using adjusted Cox proportional hazards regression, and 1- (pembro + ola) and 2-sided (NHA) P values were calculated; significance was prespecified at α < .05. For biomarkers with sufficient sample size for subgroup analysis, rPFS and OS HRs were evaluated for pembro + ola vs NHA. Results: Of 782 treated pts, PD-L1 was evaluable in 730 (pembro + ola, 490; NHA, 240); HRRm, BRCAm, TP53, PTEN, SPOP, ATM, and CDK12 in 718 (pembro + ola, 489; NHA, 229); TMB in 414 (pembro + ola, 275; NHA, 139); MSI in 316 (pembro + ola, 210; NHA, 106); and AR-V7 status in 544 (pembro + ola, 367; NHA, 177). In the biomarker-evaluable population, 28% had HRRm, 10% had BRCAm, 45% had TP53m, 34% had PTENm, 8% had SPOPm, 7% had ATMm, 7% had CDK12m, 4% were TMB-H (≥10 mut/Mb), 2% were MSI-H, and 13% were AR-V7 positive. For pembro + ola, positive associations were only observed between PD-L1 CPS and rPFS ( P = 0.034) and between HRRm and BRCAm and rPFS (adjusted P = 0.003 and < 0.001, respectively). No associations were observed for NHA (all P > 0.05). rPFS and OS HRs for pembro + ola vs NHA by biomarker status are shown (Table), with notable results observed for AR-V7 status. Conclusions: For pembro + ola, PD-L1 CPS had a weak positive association with rPFS, while HRRm and BRCAm had strong positive associations with rPFS; these biomarkers did not correlate with NHA outcomes. We observed a potential benefit with pembro + ola over NHA (for rPFS and OS) in AR-V7–positive mCRPC pts, which requires validation. Clinical trial information: NCT03834519 . [Table: see text]