bluuebunny/crossref_metadata_2025 huggingface dataset:
Radium-223 (Rad) and niraparib (Nira) treatment (tx) in castrate-resistant prostate cancer (CRPC) patients (pts) with and without prior chemotherapy (chemo).
Authors: Kelly William Kevin , Leiby Benjamin , Einstein David Johnson , Szmulewitz Russell Zelig , Sartor A. Oliver , Yang Eddy Shih-Hsin , Sonpavde Guru
Published: May 2020

5540

Background: Despite multimodality txs such as surgery, radiotherapy, hormonal tx and chemo, metastatic CRPC (mCRPC) prognosis remains poor. Research suggests PARP-1 is a key regulator of androgen receptor (AR) signaling and transition to lethal CRPC. Nira is a safe, potent and selective PARP-1/2 inhibitor that has shown single agent clinical activity in CRPC, and Rad is an alpha particle emitter. Addition of PARP inhibition may further enhance the clinical benefit of Rad. Nira has a favorable safety profile however, data on safety, tolerability and efficacy of Nira plus radiotherapy is limited. We hypothesize that targeting the PARP-1/AR axis in combination with radiation is safe and will improve mCRPC management. Methods: This is a phase (ph) Ib dose finding study (NCT03076203) of pts with progressive mCRPC using Time-to-Event Continual Reassessment Method (TITE-CRM). The primary objective is to determine the optimum ph II dose of Nira plus Rad (55 kBq/kg of body weight) in pts with and without prior chemo. Secondary endpoints include PSA reduction at 12 weeks (wks) and radiographic progression-free survival at 6 months. Pts enrolled to one of three dose levels of Nira (100, 200, and 300 mg PO daily). After completing 6 cycles of Rad, pts continued on Nira alone until objective progression, tx intolerance or pt decision. TITE-CRM identifies the maximum tolerated dose (MTD) based on toxicities observed over 12 wks of tx. Results: Between Oct 2017 and Jan 2020, 30 pts were enrolled (15 per stratum). Median age was 70 years; ECOG performance status was 0. The MTD of Nira was 100 mg in the chemo-exposed arm and 200 mg in the chemo-naïve arm. 19 Grade ≥ 3 adverse events were possibly related to tx: lymphocyte count decrease (n = 4, 13%), neutrophil count decrease (n = 3, 10%), anemia (n = 3, 10%), hypertension (n = 3, 10%), platelet count decrease (n = 2, 7%), creatinine increase (n = 1, 3%), hydronephrosis (n = 1, 3%), nausea (n = 1, 3%), white blood cell count decrease (n = 1, 3%). Tx duration and PSA response are shown in the table. Conclusions: Nira plus Rad was determined to be safe and tolerable. The MTD of Nira was identified and is pending ph II investigation. Managed by: Prostate Cancer Clinical Trials Consortium; Funded by: Janssen Scientific Affairs and Bayer Healthcare Pharmaceuticals, Inc Clinical trial information: NCT03076203 . [Table: see text]
Prognostic markers for overall survival and outcome to LuPSMA radionuclide treatment in patients with metastatic castration-resistant prostate cancer.
Authors: Gafita Andrei , Calais Jeremie , Wang Hui , Weber Manuel , Rathke Hendrik , Kratochwil Clemens , Esfandiari Rouzbeh , Armstrong Wesley R , Sandhu Shahneen Kaur , Tauber Robert , Delpassand Ebrahim , Haberkorn Uwe , Weber Wolfgang A , Herrmann Ken , Czernin Johannes , Hofman Michael S , Fendler Wolfgang Peter , Eiber Matthias
Published: May 2020

5548

Background: The aim of this international multicenter retrospective analysis was to identify prognostic markers for the clinical outcome in late-stage mCRPC patients treated with 177Lutetium-prostate-specific membrane antigen (LuPSMA) radionuclide treatment. Methods: Patients with progressive mCRPC treated with LuPSMA at six centers in Germany, USA, and Australia were considered for inclusion. Eligible patients had 24 predefined, pretherapeutic covariates (demographics, prior mCRPC treatments, and PSMA PET/CT derived parameters) and survival data available. Endpoints included overall survival (OS) and PSA progression-free survival (PSA-PFS). Covariates were tested using univariate and mulitvariate proportional hazards regression Cox models. Results: 267/414 (64%) patients met inclusion criteria and were analyzed. 113 patients participated in clinical trials (ACTRN12615000912583, NCT03042312), while 154 were enrolled in compassionate-access programs. After a median follow-up of 22.5 months, median OS was 13.0 months (95%CI 11.6-14.4); 83% of the patients died. Median PSA-PFS was 4.0 months (95%CI 3.2-4.7). In the multivariate analysis, factors associated with shorter OS were: shorter time since diagnosis of prostate cancer (HR=2.04; p=0.002), lower number of prior systemic therapies (≤3; HR=1.56; p=0.006), prior exposure to chemotherapy (HR=1.42; p=0.05), lower hemoglobin levels (HR=1.13; p=0.002), higher number of lesions (≥20: HR=1.53; p=0.009), multiple sites of metastases (bone/LN only vs. bone + LN; HR=1.39; p=0.03) and visceral involvement (M1c) (HR=1.45; p=0.01). Factors associated with longer PSA-PFS were: longer time since diagnosis of prostate cancer (HR=0.44; p<0.001), higher hemoglobin levels (HR=0.32; p=0.03), presence of pelvic lymph nodes (LN) metastasis (N1) (HR=0.68; p=0.01), no distant lymph node metastases (M1a) (HR=0.66; p=0.01), no skeleton involvement (HR=0.44; p=0.01), no visceral metastases (M1c) (HR=0.51; p<0.001), higher PSMA-positive tumor volume (HR=0.87; p=0.04), and higher SUVmean (HR=0.94; p=0.002). Conclusions: This retrospective analysis identified prognostic factors for survival and treatment response to LuPSMA. Along with the conventional risk factors in mCRPC, PSMA PET/CT can be a useful tool for stratifying patients and guide patient’s selection for LuPSMA radionuclide treatment.
Modulation by treatment of tumor infiltrating lymphocytes (TILs) and PDL1 expression in triple-negative breast cancer in the ETNA trial.
Authors: Bianchini Giampaolo , Smart Chanel , Mansutti Mauro , Lück Hans-Joachim , Zambelli Stefania , Olier Clara , Anton Antonio , Bisagni Giancarlo , Merlini Laura , Murillo Serafin Morales , Calvo Martínez Lourdes , Chacon Jose Ignacio , Semiglazov Vladimir , Thill Marc , Chan Arlene , Tusquets Ignasi , Licata Luca , Valagussa Pinuccia , Viale Giuseppe , Gianni Luca
Published: May 2020

555

Background: We assessed TILs and PDL1 expression before, during and after neoadjuvant treatment in TNBC patients enrolled in the ETNA study, and investigated associations with clinical outcome. Methods: In ETNA patients randomly received paclitaxel or nab-paclitaxel followed by 4 cycles of an anthracycline regimen, including 219 centrally confirmed TNBC. We successfully measured stromal and intratumoral TILs (sTILs, iTILs) and PDL1 status (Ventana SP142, IC≥1%) on biopsies before [n = 186/213 (84.9%)], on d1 cycle 2 (d1c2) of therapy [n = 41/186 (22.0%)], and at surgery [SX, n = 65/129 (34.9%)]. We investigated the expression and modulation over time of TILs and PDL1 and their association with pCR and event-free survival (EFS). Results: Prevalence of PDL1+ was 35.5% (baseline), 20.6% (d1c2) and 30.1% (SX). At each time-point sTILs and iTILs were higher in PDL1+ cases (p≤0.01). An effect of age of the tumor blocks (5-7.5 years) or pre-analytical issues could not be ruled out for the relatively low rate of PDL1 positivity. Paired PDL1 at baseline and d1c2 showed conversion in 25.7% (pos to neg [11.4%] or neg to pos [14.3%]). Comparing PDL1 at baseline and SX, the conversion rate was 30% (pos to neg [8.3%] or neg to pos [21.6%]). sTILs and iTILs significantly increased at cycle 2, more significantly in pCR (p≤0.001) than in RD (p≤0.05) cases, and a not significant trend of decrease was observed at surgery PDL1+ tumors had a higher pCR rate (54.7% vs 32.5%, p = 0.004). PDL1 retained significance (OR 2.00 [1.04-3.88], p = 0.039) after adjustment for sTILs (OR 1.21 [1.03-1.42], p = 0.021). High iTILs and sTILs at d1c2, but not PDL1 status, were predictive of pCR. Notably, adjusting for sTILs, PDL1+ tumors at d1c2 showed a trend for association with lower pCR rate (OR 0.06 [0.01-1.15], p = 0.062). sTILs at cycle 2 was the most informative variable (OR 1.61 [1.28-1.61], p = 0.004) and provided independent information to baseline biomarkers. Baseline PDL1 and biomarkers at cycle 2 were not associated with EFS. In surgical samples with RD, higher sTILs, but not iTILs and PDL1 status, were associated with a trend for a lower risk of recurrence (HR 0.19 [0.02-1.39], p = 0.068). Conclusions: sTILs assessment on core biopsies after one cycle of taxane is a promising early biomarker of pCR. PDL1, as well as sTILs and iTILs, provided independent prediction of pCR and were strongly modulated by treatment. The modulation of PDL1 expression should be considered whenever PDL1 is assessed in view of identifying candidates to atezolizumab in 1st line advanced setting.
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]
HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer.
Authors: Shore Neal D. , George Daniel J. , Saad Fred , Cookson Michael , Saltzstein Daniel R. , Tutrone Ronald F. , Akaza Hideyuki , Bossi Alberto , van Veenhuyzen David , Selby Bryan , Fan Xiaolin , Kang Vicky , Walling Jacqueline M. , Tombal Bertrand F. ,   Test Abstract Group
Published: May 2020

5602

Background: LHRH agonists are the mainstay for medical castration in advanced prostate cancer; however, they cause an initial testosterone (T) surge with a delayed onset of castration and require depot injection. Relugolix is the first oral GnRH receptor antagonist, which was previously shown to rapidly suppress T levels. The HERO trial compared the safety and efficacy of relugolix with leuprolide acetate in advanced prostate cancer patients. Methods: HERO is a 48-week, global, pivotal phase III trial that randomized 934 patients with androgen-sensitive advanced prostate cancer in a 2:1 ratio to receive relugolix 120 mg orally QD after a single l or leuprolide acetate 3-month depot injection. The primary endpoint was to achieve and maintain serum T suppression to castrate levels (< 50 ng/dL) through 48 weeks. Key secondary endpoints included castration rates at Day 4, profound castration (< 20 ng/dL) rates at Days 4 and 15, PSA response rate at Day 15 and FSH levels at Week 25. Testosterone recovery was evaluated in a subset of 184 patients. Results: A total of 96.7% (95% CI: 94.9%, 97.9%) of men on relugolix achieved and maintained castration through 48 weeks compared to 88.8% on leuprolide. The difference of 7.9% (95% CI: 4.1%, 11.8%) demonstrated non-inferiority (margin -10%) and superiority (P < 0.0001) of relugolix to leuprolide. All key secondary efficacy endpoints tested demonstrated superiority over leuprolide (P < 0.0001) (Table). In the testosterone recovery subset, median T levels were 270.76 ng/dL in the relugolix compared to 12.26 ng/dL in the leuprolide group 90 days after discontinuation of therapy. In a prespecified analysis, the incidence of major adverse cardiovascular events (MACE) was lower in the relugolix group than in the leuprolide group (2.9% vs. 6.2%, respectively); otherwise the safety and tolerability profiles were generally similar. Conclusion: Relugolix achieved castration as early as Day 4 and demonstrated superiority over leuprolide in sustained T suppression through 48 weeks, faster T recovery after discontinuation and a 50% reduction in MACE. Relugolix has the potential to become a new standard for T suppression for patients with advanced prostate cancer. Clinical trial information: NCT03085095 . [Table: see text]
Radioparp: A phase I of olaparib with radiation therapy (RT) in patients with inflammatory, locoregionally advanced or metastatic triple-negative breast cancer (TNBC) or patient with operated TNBC with residual disease—Preliminary results.
Authors: Kirova Youlia M. , Loirat Delphine , Berger Frederique , Rodrigues Manuel , Bazire Louis , Pierga Jean-Yves , Ricci Francesco , Cao Kim , Vincent -Salomon Anne , Laki Fatima , Ezzili Cyrine , Raizonville Laurence , Mosseri Veronique , Neffati Souhir , Ezzalfani Mounia , Fourquet Alain
Published: May 2020

571

Background: Preclinical studies have shown that cell lines and murine models of TNBC phenotype are more sensitive to PARP1 inhibitors. This evidence provides strong rationale for developing a new therapeutic approach to TNBC based on targeting the DNA-repair defects via PARP inhibition. Methods: The purpose of this study was to report the Maximal Tolerated Dose (MTD) of Olaparib (O) administered concurrently with locoregional RT and evaluate the Dose-Limiting Toxicity (DLT). Results: Twenty-four pts with performance status 0-1 were enrolled between 09/2017 and 11/2019. Of them, 21 underwent adjuvant RT-O because poor response to NAC, and 3 received preoperative RT+O because of progression after NAC. The patients’ profile is given in table. All patients received full course RT-O, as following: 4 pts at dose 50mg bid; 8 at 100x2; 7 at 150x2, and 5 at 200x2. No DLT was observed. Two pts (8.7%) experienced acute grade 3 dermatitis no grade 4 toxicities related to the RT were observed. The O-related toxicity was acceptable with mostly grade 1-2 symptoms. The only grade 3-4 hematological toxicity was lymphopenia in 11 cases. Conclusions: Dose of O was escalated to the target dose of 200 mgx2, without DLT. Further follow up is needed to evaluate the late toxicities. Clinical trial information: NCT03109080 . [Table: see text]
Neoadjuvant chemotherapy (NACT) and HER2 double inhibition including biosimilar trastuzumab (ONTRUZANT) for HER2-positive early breast cancer (EBC): Population-based real world data from the Danish Breast Cancer Group (DBCG).
Authors: Andersson Michael , Jensen Maj-Britt
Published: May 2020

577

Background: Increasingly, HER2-positive early breast cancer (EBC) is treated by NACT combined with trastuzumab and pertuzumab followed by surgery. Ontruzant is registered as a biosimilar trastuzumab based on the totality of evidence including a randomized phase III study of NACT+Herceptin versus NACT+Ontruzant demonstrating similar pCR-rates (Pivot et al. J Clin Oncol 2018;36:968). However, no data exist for the efficacy of the combination of NACT with pertuzumab+Ontruzant (p+O). This investigator-initiated study was conducted to assess real world efficacy in HER2-positive EBC patients treated with NACT+p+O based on data from DBCG. DBCG has since 1977 provided guidelines for treatment of breast cancer and collected data from Danish hospital departments of surgery, pathology, and oncology prospectively on NACT, date and type of surgery and patho-anatomic findings. Methods: From the DBCG database, information was extracted for consecutive patients with unilateral early HER2-positive breast cancer registered to have received NACT+p+O from September 1, 2018 to August 31, 2019. pCR was defined as absence of residual invasive tumor in the breast and axillary lymph nodes (ypT0/Tis ypN0(i-)). Results: 215 patients received NACT+p+O. Median age was 54.8 years (range 24-81). NACT used, in combination with concurrent p+O, was cyclophosphamide+epirubicin followed by paclitaxel (62% on 6 cycles and 35% on 8 cycles) or other chemotherapy followed by paclitaxel (3%). Overall, 56% of patients achieved a pCR (Table). 68% of node-positive patients before receiving NACT+p+O had tumor-free axillary nodes after completing NACT+p+O. Conclusions: Real-world data from a nationwide population based study demonstrated a pCR-rate with NACT+p+O comparable to that seen in clinical studies with NACT+p+Herceptin (Chen et al. BMC Cancer 2019;19:973). pCR-rate was highly dependent on estrogen receptor (ER)-status and malignancy grade but not on clinical nodal status and tumor size. 68% of patients with cN+ converted to ypN0(i-). [Table: see text]
Influence of denosumab on disseminated tumor cells (DTC) in the bone marrow of breast cancer (BC) patients with neoadjuvant treatment: A GeparX translational substudy.
Authors: Wimberger Pauline , Blohmer Jens U. , Krabisch Petra , Link Theresa , Just Marianne , Sinn Bruno Valentin , Simon Eike , Solbach Christine , Fehm Tanja N. , Denkert Carsten , Kühn Cristin , Rhiem Kerstin , Tesch Hans , Kümmel Sherko , Petzold Andrea , Stoetzer Oliver J. , Meisel Cornelia , Kuhlmann Jan Dominik , Nekljudova Valentina , Loibl Sibylle
Published: May 2020

580

Background: DTCs in the bone marrow are observed in up to 30% at primary diagnosis of BC and their presence is an independent prognostic factor for reduced survival. It was shown that antiresorptive therapy eradicates DTCs and improves prognosis in DTC-positive BC patients (pts). In the GeparX phase III prospective randomized trial, denosumab (a monoclonal IgG2-anti-RANKL-antibody) was investigated as add-on treatment to neoadjuvant chemotherapy (NACT) with two different nab-paclitaxel schedules in early high-risk primary BC. In a translational substudy, we analyzed for the first time the influence of short-term denosumab treatment (24 weeks) on the presence of DTCs. Methods: A total of 167 pts from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive pts were re-analyzed for DTCs after NACT±Denosumab. Results: Overall, 60/167 pts (35.9%) treated with NACT±Denosumab had a pathological complete response (pCR; 55.4% in TNBC, 43.3% in HER2+, 15.3% in HR+/HER2-). At baseline, 43/167 pts (25.7%) were DTC-positive and 41 of those were available for re-analysis of DTCs after NACT±Denosumab. DTC eradication was observed in 77.8% after NACT+Denosumab and in 69.6% after NACT alone (p = 0.726). Due to the limited number of pts eligible for DTC-re-analysis after NACT, a subtype specific analysis for the effect of denosumab was not possible. There was no significant association between pCR and i) the presence of DTCs at baseline (37.1% DTC-negative vs 32.6% positive, p = 0.71) or ii) the eradication of DTCs after NACT±Denosumab (36.7% vs 27.3%, p = 0.72). Notably, in TNBC, we observed a tendency that DTC-positivity at baseline or DTC-persistence after NACT could be associated with reduced pCR rate (40.0% in DTC-positive vs. 66.7% in DTC-negative pts, p = 0.16; 25% in DTC-persistent pts vs. 50% in DTC-eradicated pts, p = 0.59). Conclusions: Denosumab in addition to NACT does not improve pCR, but the suspected effect of denosumab on DTC eradication should be further analyzed in TNBC. Key words: GeparX trial, denosumab, disseminated tumor cells, bone marrow, neoadjuvant chemotherapy. Funding: GeparX and DTC substudy were financially supported by Amgen and Celgene. Clinical trial information: NCT02682693 .
One-year follow-up of health-related quality of life in the Swedish PREDIX HER 2 trial, evaluating docetaxel, trastuzumab sc, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2 positive breast cancer.
Authors: Brandberg Yvonne , Foukakis Theodoros , Andersson Anne , Bjohle Judith , Bosch Ana , Carlsson Lena , Einbeigi Zakaria , Fredholm Hanna , Isaksson-Friman Erika , Hellstrom Mats , Johansson Hemming , Lekberg Tobias , Lindman Henrik , Bergh Jonas C. S. , Hatschek Thomas
Published: May 2020

590

Background: Neoadjuvant therapy combining docetaxel, trastuzumab and pertuzumab (DTP) was compared to trastuzumab emtansine (T-DM1) in the randomised phase II PREDIX HER2 trial. Patients, ≥18 years with HER2 positive breast cancer, ≥20mm or with verified lymph node metastases, were randomised to six courses of DTP (Standard group) or T-DM1 (Experimental group) before surgery. After operation patients in the Standard arm received two, and those in the Experimental arm four courses of EC. Since there were no differences in proportions of complete response at surgery and in the event-free survival between the groups, health-related quality of life (HRQoL) is of special interest. Methods: HRQoL was measured, using European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 + EORTC QLQ-BR23, before randomisation, after six courses before surgery, at three months and one year after surgery. Results: Response rate for the questionnaires varied between 87% and 99% for the 198 included patients. There were no between-group differences at baseline. Results after six courses revealed statistically significant differences (p≤0.01), favouring the Experimental group on 12 out of 21 of the EORTC QLQ-C30 and BR23 variables (Physical-, Role-, and Social- functioning, Global quality of Life, Fatigue, Dyspnea, and Diarrhea, Body image, Sexual functioning, Sexual enjoyment, Systemic therapy side effects and Upset by hair loss). Three months after surgery, however, statistically significant differences in favour of the Standard group were found for six variables (Physical functioning, Nausea/vomiting, Dyspnea, Constipation, Systemic therapy side effects, Upset by hair loss). No other between group differences were found with one exception: lower levels of Breast symptoms in the Experimental group. One possible explanation is that patients in the Experimental group were still on chemotherapy at that assessment point, whereas the majority in the Standard group had terminated their treatment. No differences were found between the groups at the one-year after surgery follow-up, where the levels on most variables had returned to baseline values. Conclusions: HRQoL was better in the Experimental group during neoadjuvant treatment. Three months after surgery, however, HRQoL was in favour or the Standard arm. HRQoL returned to baseline levels for most variables at the one-year follow-up and no between-group differences were found. Clinical trial information: NCT02568839 .
A randomized phase II trial of secondary cytoreductive surgery (SCS) +/- carboplatin hyperthermic intraperitoneal chemotherapy (HIPEC) in patients (pts) with recurrent platinum-sensitive ovarian cancer (EOC).
Authors: Zivanovic Oliver , Chi Dennis , Zhou Qin , Iasonos Alexia , Makker Vicky , Grisham Rachel N. , Konner Jason A. , Diaz John Paul , Brown Amy K. , Langstraat Carrie L , Paroder Viktoriya , Soldan Krysten , Su Katy , Gardner Ginger J. , Jewell Elizabeth Lin , Long Kara , Tew William P. , Lichtman Stuart M. , Sonoda Yukio , O'Cearbhaill Roisin Eilish
Published: May 2020

6016

Background: The role of HIPEC for recurrent EOC is not well defined. The aim of this phase II study was to determine the proportion of pts without evidence of disease progression at 24 months post SCS +/- intraoperative carboplatin HIPEC. Methods: After SCS to ≤ 0.5 cm residual visible disease pts were intraoperatively randomized to carboplatin HIPEC (800mg/m2 for 90 minutes) or no HIPEC. The HIPEC arm received 5 additional and the standard arm received 6 postoperative cycles of IV platinum-based chemotherapy without maintenance treatment. Based on an exact binomial single stage “pick the winner” design, each arm is considered “winner” if ≥ 17/49 pts are without evidence of disease progression at 24 months post SCS. Secondary objectives include postoperative grade ≥ 3 toxicity and complications within 4 weeks post SCS, and pharmacokinetics of carboplatin HIPEC. Results: Of 98 pts, 49 (50%) were randomized to the HIPEC arm. The arms were well balanced for age, stage, histology, BRCA mutation status, prior chemotherapy, and disease-free interval. Complete gross SCS was achieved in 94% of the standard and 82% of the HIPEC arm (p = 0.12). Bowel resection was performed more frequently in the standard (65%) compared to the HIPEC arm (37%; p = 0.008). Median operative time was shorter in the standard (296 minutes) compared to the HIPEC arm (475 minutes; p < 0.001). There was no perioperative mortality and no difference in use of ostomies, length of stay or postoperative toxicity. At a median follow-up of 27.7 months (range: 8.8-81.8 months) 70 of 98 pts progressed and 26 died with a median progression free survival (PFS) of 14.3 months (12.1-16 months) and a median overall survival (OS) of 55.2 months (47.7-not reached). At 24 months post SCS 32 pts progressed within 24 months in the standard versus 35 in the HIPEC arm. There was no statistically significant difference in median PFS (15.4 vs 12.3 months, p = 0.173) or median OS (69.2 vs 53.1 months, p = 0.317) between arms. These are preliminary efficacy estimates as 83/98 pts have a minimum of 24 months follow-up. Conclusions: The HIPEC arm did not reach the predefined “winner” endpoint; the standard arm is still undetermined as 6 pts did not reach 24 months follow-up. No perioperative mortality, and no increased perioperative morbidity or toxicity was seen with HIPEC. SCS with carboplatin HIPEC followed by 5 cycles of platinum-based chemotherapy was not superior to SCS without HIPEC followed by 6 cycles of platinum-based chemotherapy. Clinical trial information: NCT01767675.