bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostate cancer biomarker enrichment and treatment selection (PC-BETS) study: A Canadian cancer trials group phase II umbrella trial for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Chi Kim N. , Mukherjee Som , Saad Fred , Winquist Eric , Ong Michael , Kolinsky Michael Paul , Sacher Adrian G. , Ferrario Cristiano , Salim Muhammad , Macfarlane Robyn Jane , Iqbal Nayyer , Hotte Sebastien J. , Annala Matti , Petrovic Jelena , Tu Dongsheng , Rushton Moira Katherine , Vera Badillo Francisco Emilio , Smoragiewicz Martin , Wyatt Alexander William 
Published: May 2020

5551 Background: Genomic characterization of mCRPC has identified commonly occurring alterations but also recurrently mutated genes at much lower frequencies. To efficiently evaluate anti-tumor activity of novel targeted therapies in mCRPC patients (pts) we initiated an umbrella trial using circulating tumour DNA (ctDNA) to enrich accrual for cancers with alterations that may predict response. Methods: mCRPC pts that have progressed after treatment with a next generation AR-pathway inhibitor (ARPI) were enrolled to this multi-center, multi-arm, 2-stage phase II trial. Plasma cell-free DNA was subjected to targeted sequencing and pts allocated to a treatment arm by a Tumor Board (TB) based on a priori criteria (biomarker positive, BM+) or by randomization if biomarker negative (BM-). Primary objective was to determine the clinical benefit rate (CBR: PSA decline ≥50% (PSA50), CR/PR, or stable disease ≥12 weeks). We report on 1st-stage activity of arms evaluating inhibitors of CDK4/6 (palbociclib), WEE1 kinase (adavosertib), cMET (savolitinib) and the AR inhibitor darolutamide. Additional planned arms include inhibitors of AKT (ipatasertib), Polo-like Kinase 4 (CFI-400945), immune checkpoints (durvalumab, tremelimumab) and carboplatin. Results: 250 pts were screened from two sequential trials over 29 months at 11 centers. Median time from blood draw to TB decision was 35 days. 169 pts (68%) had detectable ctDNA (≥1%) with a mean ctDNA fraction of 24% (range 1-95%). Commonly detected genomic alterations involved AR (49% gain, 24% mutation), TP53 (49%), PTEN/PI3K pathway (35%), DNA repair (23%: mismatch repair (5%), BRCA2 (8%), ATM (3%), CDK12 (5%), other (2%)) and CTNNB1/APC (14%). To date, 46 BM+ pts and 37 BM- patients were enrolled: median age 70 years (53-88), 100% had prior ARPI, 45% had prior docetaxel, 17% with visceral metastases. Accrual and CBR are presented in table. Adverse events were as expected. Conclusions: Prospective centralized screening of ctDNA to stratify mCRPC pts into a precision oncology trial is feasible. Activity was seen in 4 of 7 evaluable cohorts with darolutamide and adavosertib, meeting the threshold for expansion of these arms. Clinical trial information: NCT03385655, NCT02905318 . [Table: see text]
Primary analysis of a phase II study of metastasis-directed ablative therapy to PSMA (18F-DCFPyL) PET-MR/CT defined oligorecurrent prostate cancer.
Authors: Glicksman Rachel , Metser Ur , Vines Doug , Chan Rosanna , Valliant John , Chung Peter W. M. , Gospodarowicz Mary K. , Bayley Andrew , Catton Charles N. , Warde Padraig Richard , Helou Joelle , Raman Srinivas , Green David , Perlis Nathan , Fleshner Neil , Hamilton Robert James , Zlotta Alexandre , Finelli Antonio , Jaffray David , Berlin Alejandro 
Published: May 2020

5553 Background: Despite maximal local therapies (MLT) (radical prostatectomy followed by radiotherapy [RT]), 20-30% of men will progress to incurable prostate cancer (PCa). Most recurrences in this scenario are characterized by rise in PSA with negative bone scan (BS) and computed tomography (CT). We conducted a phase II trial for men with rising PSA after MLT using 18F-DCFPyL (PSMA) PET-MR/CT followed by metastasis-directed therapy (MDT) to PET positive foci. We report the results of our primary analysis. Methods: Patients with rising PSA (0.4-3.0 ng/mL) after MLT, negative BS/CT and no prior salvage ADT were eligible. All patients underwent PSMA PET-MR and PET-CT. Those with limited disease burden amenable to MDT underwent either stereotactic ablative RT (SABR) or surgery (lymph node dissection). No ADT was used. The primary endpoint was biochemical response rate (complete [undetectable PSA] or partial [PSA decline ≥50% from baseline]) following MDT. A Simon’s two-stage study design was employed. Estimated time of delay in salvage ADT was calculated using the Kaplan-Meier method. Toxicity was prospectively recorded (CTCAE v4.0). Results: After a median of 63 months (range 3-180) post MLT, 72 patients underwent PSMA PET-MR/CT with median PSA 0.98 ng/mL (range 0.4-3.1). Sixteen patients had negative and 56 had positive PET-MR/CT scans, of which 37 (51%) were amenable to MDT. The median number of treated lesions was 2 (range 1-5). Of the treated patients, 30 (81%) had miT0N1M0 disease, 2 (5.5%) had miT0N1M1a, 2 (5.5%) had miT0N0M1a and 3 (8%) had miT0N0M1b. Twenty-seven patients underwent SABR (median 30 Gy in 3 fractions) and 10 had surgery. At a median of 11 months (range 1-29) post MDT, 8 patients (22%) had complete (CR) and 14 (38%) had partial (PR) responses. Among the 8 CRs, 5 had surgery and 3 had SABR; of the 14 PRs, 2 had surgery and 12 had SABR. The estimated median delay in salvage ADT for the entire cohort, PR and CR subgroups was 13 months (IQR 8-20), 16 months (IQR 13-20) and 30 months (IQR not reached), respectively. Two grade 2+ toxicities were observed, both in surgical patients: deep venous thrombosis and ureteric injury requiring stent placement. Conclusions: 18F-DCFPyL PET-MR/CT has high detection rates (78%) in men with rising PSA after MLT. We observed a favorable therapeutic index with MDT (60% response rate) for patients with metachronous PSMA-unveiled oligometastatic PCa following MLT. Phase III studies using validated intermediate clinical endpoints are needed before integration into routine practice. Clinical trial information: NCT03160794 .
Pain progression at initiation of cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) is associated with a poor prognosis: a post-hoc analysis of PROSELICA.
Authors: Delanoy Nicolas , De Bono Johann S. , Mercier Florence , Geffriaud-Ricouard Christine , Eisenberger Mario A. , Oudard Stephane 
Published: May 2020

5558 Background: PROSELICA phase III trial (NCT01308580) showed that cabazitaxel 20 mg/m2 (C20) is non-inferior to C25 in mCRPC patients (pts) post-docetaxel (DOC) (Eisenberger JCO 2017). Pts enrolled were symptomatic or not. This post-hoc analysis evaluates the influence of progression type at randomization on outcomes. Methods: Progression type at randomization was defined as follows: PSA progression only (PSA-p; no radiological progression (Radio-p), no pain), Radio-p (± PSA-p, no pain) or pain progression (pain-p, ±PSA-p, ±Radio-p). The relationship between progression type and overall survival (OS), radiological progression-free survival (rPFS) and PSA response (confirmed PSA decrease ≥ 50%) was analyzed. Results: All patients randomized (n = 1200) had received prior DOC and 25.7% had received prior abiraterone or enzalutamide. Progression type was evaluable in 1065 pts (PSA-p = 24.5%, radio-p = 20.9%, pain-p = 54.6%). Pain progression was associated with clinical and biological features of aggressive disease and worse outcomes (decreased PSA response, rPFS and OS) vs PSA-p or radio-p (Table). The survival (rPFS and OS) on C25 was numerically higher than on C20 in pts with radio-p and pain-p. Conversely, C20 and C25 equally benefited pts with PSA-p only. In multivariate analysis (all arms combined), pain progression was an independent predictor of poor OS. Conclusions: This post-hoc analysis of PROSELICA shows that pain progression at initiation of cabazitaxel in mCRPC pts previously treated with DOC is prognostic. The activity of C25 was numerically higher than C20 in patients with radiological or pain progression. Clinical trial information: NCT01308580 . [Table: see text]
Efficacy and safety in older patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel (CBZ) versus abiraterone (ABI) or enzalutamide (ENZ) in the CARD study.
Authors: Sternberg Cora N. , Castellano Daniel , De Bono Johann S. , Fizazi Karim , Tombal Bertrand F. , Wülfing Christian , Kramer Gero , Eymard Jean-Christophe , Bamias Aristotelis , Carles Joan , Iacovelli Roberto , Melichar Bohuslav , Sverrisdottir Asgerdur , Theodore Christine , Feyerabend Susan , Helissey Carole , Poole Elizabeth , Ozatilgan Ayse , Geffriaud-Ricouard Christine , De Wit Ronald 
Published: May 2020

5559 Background: In the CARD (NCT02485691) study, radiographic PFS (rPFS), PFS and OS were significantly improved with CBZ vs. androgen-signaling-targeted agents (ARTA; ABI or ENZ) in pts with mCRPC who had received docetaxel (DOC) and progressed within 12 months (mo) on an alternative ARTA. This analysis evaluated the impact of age (< 70 vs. ≥ 70 years) on the efficacy and safety of CBZ and ARTAs in CARD. Methods: 255 pts with mCRPC were randomized 1:1 to CBZ (25 mg/m2 IV Q3W + prednisone [P] + G-CSF) vs. ABI (1000 mg PO + P) or ENZ (160 mg PO) until disease progression, unacceptable toxicity or pt request. Pts were eligible if they had received ≥ 3 cycles of DOC and progressed ≤ 12 mo on the previous alternative ARTA. Primary endpoint was rPFS. Subgroup analysis of older (≥ 70 years; n = 135) and younger (< 70 years; n = 120) pts was pre-specified for rPFS; others were post hoc. Results: rPFS was significantly improved vs. ARTA in both older (median 8.2 vs. 4.5 mo; HR 0.58; 95% CI 0.38–0.89) and younger pts (median 7.4 vs. 3.2 mo; HR 0.47; 95% CI 0.30–0.74). Median OS for CBZ vs. ARTA was 13.9 vs. 9.4 mo (HR 0.66; 95% CI 0.41–1.06) in older pts and 13.6 vs. 11.8 mo (HR 0.66; 95% CI 0.41–1.08) in younger pts. PFS, tumor, PSA and pain responses also favored CBZ, regardless of age. Grade ≥ 3 adverse events (AEs) occurred in 57.8% vs. 49.3% of older pts receiving CBZ vs. ARTA and 48.4% vs. 42.1% in younger pts. AEs leading to death were more frequent with ARTA, mainly due to disease progression. Conclusions: CBZ had improved efficacy outcomes vs. ARTA in pts with mCRPC previously treated with DOC and the alternative ARTA, regardless of age. Grade ≥ 3 cardiac AEs were more frequent in older pts treated with ARTA. A higher rate of AEs was reported in older vs. younger pts, for ARTA and CBZ. CBZ and ARTA had different safety profiles in older compared with younger pts. Clinical trial information: NCT02485691 . Funding: Sanofi. [Table: see text]
Basal subtype and clinical estrogen receptor status of genomically basal breast tumors in Caucasian, African American, and Latin American patients.
Authors: Kaklamani Virginia G. , Graham Cathy , Tedesco Karen L. , Sivapiragasam Abirami , Crozier Jennifer A. , Shah Apurva N. , Menicucci Andrea , Wang Shiyu , Bolner Michelle L , Yoder Erin , Audeh William ,   FLEX Investigators' Group
Published: May 2020

556 Background: Genomically basal-type breast cancer is a heterogenous subtype that occurs at higher frequencies in non-Caucasian patients. Triple negative breast cancer (TNBC) has been refined into distinct transcriptomic groups including the basal-like immunoactive (BLIA), basal-like immunosuppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES) subtypes. Here we report the distribution of triple negative subtypes in genomically basal cancers from Caucasian (CA), African American (AA), and Latin American (LA) patients and the association of clinical estrogen receptor (ER) status. Methods: The FLEX Registry (NCT03053193) is an ongoing, prospective study evaluating primary tumors from patients with stage I-III breast cancer who receive the 70-gene signature and 80-gene signature (80-GS) molecular testing and consent to clinically annotated full transcriptome data collection. This sub-analysis evaluated 143 80-GS Basal type tumors from patients with self-reported ethnicity (60 CA, 59 AA, 24 LA). TNBC subtypes BLIA, BLIS, LAR, and MES were derived using an adjusted version of the 80-gene centroid signature published by Burstein and colleagues (2015). Differences in clinical ER expression between ethnicities were assessed by Fisher’s exact test. Results: Basal indices from 80-GS were not influenced by patient ethnicity (one-way ANOVA, p = 0.182). The frequency of BLIA, BLIS, LAR, and MES subtypes did not vary significantly by ethnicity (Fisher’s exact test, p = 0.671). The majority of tumors in all ethnic groups were BLIS (67% CA, 75% AA, 63% LA), followed by BLIA (22% CA, 22% AA, 25% LA), with low frequency of LAR (5% CA, 1.7% AA, 8.3% LA) and MES (5% CA, 1.7% AA, 4.2% LA) subtypes. Nearly one third (31%) of Basal type tumors were defined by IHC as ER positive and were present in all TNBC subtypes (39% BLIA, 29% BLIS, 33% LAR, and 20% MES); ER receptor expression ranged from 1-90% and was not associated with specific basal subtype (p = 0.8) nor ethnicity (P = 0.76). Progesterone receptor expression ranged from 1-50%. Conclusions: This analysis demonstrated that genomic Basal type tumor classification by 80-GS encompasses all TNBC subtypes evaluated regardless of ethnicity. Additionally, we show that IHC ER positive tumors occur in all TNBC subtypes assessed. These findings confirm the heterogeneous nature of basal breast tumors in CA, AA, and LA patients and highlight the clinical need to delineate basal biology in the ER+ cohort to advance treatment for basal-like tumors. Clinical trial information: NCT03053193 .
Olaparib (O) in patients (pts) with prostate cancer with BRCA1/2 inactivating mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Pisick Evan P. , Garrett-Mayer Elizabeth , Halabi Susan , Mangat Pam K. , Yang Eddy Shih-Hsin , Dib Elie G. , Burgess Earle Frederick , Zakem Michael Howard , Rohatgi Nitin , Bilen Mehmet Asim , Warren Sasha L. , Anderson Sarah T. , Rygiel Andrew Lawrence , Schilsky Richard L. 
Published: May 2020

5567 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Advanced prostate cancer (PC) pts with germline or somatic BRCA1/2 inactivating mutations treated with O are reported. Methods: Eligible pts had advanced PC, no remaining standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Tumor genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received O tablets or capsules dosed at 300 mg (n=24) or 400 mg (n=5), respectively, orally twice daily until disease progression. Simon 2-stage design tested the null disease control (DC) (objective response (OR) or stable disease at 16+ weeks (wks) (SD16+) according to RECIST) rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Pts had radiographic evaluations at 8 and 16 wks and then every 12 wks. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 29 pts with BRCA1/2 inactivating mutations were enrolled from Aug 2016 to Jul 2019; 4 were identified as ineligible after enrollment due to bone only disease and removed from analyses. Demographics and investigator-reported outcomes are summarized in the Table. Nine pts with OR and 8 with SD16+ were observed for DC and OR rates of 68% (90% CI: 53% - 77%) and 36% (95% CI: 18% - 57%), respectively. Six pts had at least one grade 3 AE or SAE at least possibly related to O including anemia, aspiration, dehydration, diabetic ketoacidosis, fatigue, and neutropenia. Conclusions: Monotherapy with O showed anti-tumor activity in heavily pre-treated PC pts with germline (1/2 pts with OR or SD16+) or somatic (16/23 pts with OR or SD16+) BRCA1/2 inactivating mutations. These findings extend results from recent trials of O in advanced prostate cancer pts with germline only BRCA1/2 mutations. Clinical trial information: NCT02693535 . [Table: see text]
Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.
Authors: Ledet Elisa Marie , Jaeger Ellen , Hatton Whitley , Moses Marcus W. , Sokolova Alexandra , Nakazawa Mari , Zhu Jason , Dellinger Beth , Elrefai Sara , McKay Rana R. , Cheng Heather H. , Burgess Earle Frederick , Antonarakis Emmanuel S. , Sartor A. Oliver 
Published: May 2020

5568 Background: The relevance of germline mutations in metastatic prostate cancer is well established; however, comparison of germline genetics in African American (AA) versus Caucasian (CA) men with metastatic prostate cancer (PCa) is limited. Methods: Germline data from self-identified AA and CA metastatic PCa patients (pts) were collected from 5 academic cancer centers. Various commercial cancer-specific germline testing panels were used to evaluate 12-86 genes. Pathogenic (P) or likely pathogenic (LP) mutations, and variants of unknown significance (VUS), were reported according to ACMG guidelines. Self-reported family history (FH) was annotated for 99% of pts. Statistical analyses included Chi-squared and Fischer’s exact tests. Results: A total of 821 metastatic PCa pts were assessed: 152 AAs and 669 CAs. For P/LP alterations, AAs had a frequency of 11.2% (17/152) as compared to a frequency of 14.6% (98/669) in CAs (p = 0.302). AA pts were more likely to have a VUS than CA pts, 61% vs 43% respectively (OR = 2.09, 95%CI [1.45, 2.99], p < 0.001). BRCA mutations were similar between races, but AA were more likely to have a BRCA1 P/LP alteration (OR = 6.00, 95% CI [1.33, 27.09], p = 0.025). AA pts were less likely to have a P/LP alteration in a non-BRCA gene (OR = 0.34, 95% CI [0.15, 0.80], p = 0.013). Among DNA repair genes, there were no significant difference between AA and CA pts (p = 0.574); however, there was a trend toward AA pts having fewer P/LP alteration in a non-BRCA DNA repair genes (OR = 0.26, 95% CI [0.06, 1.08], p = 0.071). In pts with >1 first degree relative (FDR) with ovarian cancer, P/LP germline alterations were more likely in CAs (OR = 2.33, 95% CI [1.05, 5.17], p = 0.043); but there were no significant differences in AAs (p = 0.098). Those with >2 FDRs with PCa were more likely to have a P/LP change in CAs (OR = 2.32, 95% CI [1.04, 5.15], p = 0.043), but there were no difference in AAs (p = 0.700). In pts with ≥2 FDRs with breast cancer, P/LP germline alterations were more likely in both AAs (OR = 9.36, 95% CI [1.72, 50.84], p = 0.019) and CAs (OR = 3.92, 95% CI [1.79, 8.59], p = 0.001). Conclusions: We did not observe a difference in the overall frequency of germline P/LP alterations between AA and CA men with metastatic PCa but VUSs were more common in AA men. These AA men have an overall frequency of BRCA mutations similar to CA men; however, BRCA1 mutations were more prevalent in these AAs. Non-BRCA P/LP mutations are significantly less frequent in AA pts. A positive family history of >2 FDRs with breast cancer was associated with P/LP alterations in both AA and CA pts.
RESTORE: A single-arm, open-label phase II trial of bipolar androgen therapy (BAT) in men with metastatic castration resistant prostate cancer (mCRPC)—A comparison of post-abiraterone (Abi) versus post-enzalutamide (Enza) patients (Pts).
Authors: Markowski Mark Christopher , Wang Hao , Schweizer Michael Thomas , Carducci Michael Anthony , Paller Channing Judith , Teply Benjamin A. , Eisenberger Mario A. , Luo Jun , Antonarakis Emmanuel S. , Denmeade Samuel R. 
Published: May 2020

5576 Background: A paradoxical inhibition of cell growth has been observed in both androgen-sensitive and castration resistant prostate cancer cell lines following the addition of high-dose testosterone.We have conducted several clinical trials investigating a mode of supraphysiologic testosterone therapy termed, BAT, in which testosterone levels are rapidly driven to the supraphysiologic range followed by a return to near-castrate levels over 28-day treatment cycles with favorable results. We previously reported the efficacy of BAT in mCRPC pts that were progressing on enza. In this study, we compared the effect of BAT in mCRPC pts whose last therapy was abi vs. enza. In addition, we examined the benefit of abi or enza rechallenge after progression on BAT. Methods: 59 mCRPC pts (n = 29 post abi; n = 30 post enza) were enrolled and received at lease one dose of BAT monotherapy, 400mg intramuscularly every 28 days. After clinical or radiographic progression on BAT, pts were rechallenged with the AR targeted therapy to which they were most recently resistant. The co-primary endpoints were a 50% decline in PSA from baseline (PSA50) for BAT and for enza/abi rechallenge. Results: 5/29 (17.2%) of post-abi pts compared to 9/30 (30%) in the post enza group achieved a PSA50 response (P = 0.36). Post BAT rechallenge with abi (n = 19) or enza (n = 22) resulted in a PSA50 response rate of 15.8% (n = 3) and 68.2% (n = 15), respectively (P = 0.001). The total duration of benefit (i.e. PFS on BAT + PFS on rechallenge = “PFS2”) was significantly longer in the post enza vs. post-abi patients (Median PFS2: 12.75 vs. 8.125 months; P = 0.04. Lastly, AR-V7 negative (n = 42) pts has a significantly longer median PFS2 compared to AR-V7 positive (n = 10) pts. (10.3 vs. 7.1 months, P = 0.005). Conclusions: Our data suggest that BAT may be more effective at resensitizing mCRPC to direct AR antagonists (i.e. enza) compared to abi. Detection of AR-V7 portended a worse outcome on BAT/rechallenge. Further clinical study is warranted. Clinical trial information: NCT02090114 . [Table: see text]