Measurable Soft Tissue Disease Research Articles

1368P TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with DNA damage response alterations (DDRm) – Exploration of tumor genetics associated with prolonged benefit

TALAPRO-1 enrolled men with progressive mCRPC, measurable soft-tissue disease, and tumor DDRm involved directly or indirectly in homologous recombination repair (11-gene panel). Enrolled men had received 1–2 taxane-based chemotherapy regimens and progressed on ≥1 novel hormonal therapy. Confirmed objective response rate (primary endpoint; per RECIST 1.1; blinded independent central review [BICR]) was 29.8%. The molecular bases of prolonged clinical benefit with poly(ADP-ribose) polymerase inhibitors are incompletely understood, although limited evidence suggests that patients exhibiting large deletions in BRCA genes may experience extended benefit. Exploratory post hoc biomarker analyses assessed tumor genetics associated with prolonged antitumor benefit in TALAPRO-1. Tumor alterations were assessed using FoundationOne®CDx. Zygosity of tumor alterations was predicted using somatic-germline-zygosity. Prolonged benefit was assessed as radiographic progression-free survival ([rPFS]; RECIST 1.1/PCWG3; BICR) time to event or censoring. Data cutoff was Sept 4, 2020 (primary completion date). Of 104 men in the efficacy population, 16 had rPFS of ≥12 months. Of their 16 tumors, 15 (94%) had BRCA2 alterations, including 10 large structural variants (9 copy number loss, 1 rearrangement) and 5 short variants (SV; 4 homozygous). In contrast, only 6/27 (22%) men with rPFS <2.0 months exhibited BRCA2 alterations (1 rearrangement, 1 non-defined, and 4 SV with 2 homozygous). Of 61 men with rPFS <12 months but ≥2 months, 36 (59%) had BRCA2 alterations (9 copy number loss, 1 rearrangement, 21 SV [11 homozygous], 2 multiple alterations [1 homozygous], and 3 not defined). Conversely, TP53 alterations were less common for men with rPFS ≥12 months vs <2 months (2/16 vs 14/27; P=0.02 Fisher’s exact test, 2-tails), potentially reflecting negative prognosis or a subgroup less sensitive to PARP inhibition. Based on these retrospective, exploratory analyses of TALAPRO-1, men exhibiting prolonged benefit typically exhibited BRCA2 copy number loss or homozygous alterations, and lacked TP53 alterations.

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021)

Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer. COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960. Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6-21·7). Objective response rate was 23% (95% CI 17-32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3-4 treatment-related adverse events, with the most common being pulmonary embolism (11 [8%] patients), diarrhoea (nine [7%]), fatigue (nine [7%]), and hypertension (nine [7%]). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug. Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination. Exelixis.

Abstract CT031: TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)– Exploration of genomic loss of heterozygosity (gLOH) and potential associations with antitumor activity

Abstract Background: TALAPRO-1 enrolled men with progressive mCRPC, measurable soft-tissue disease, and tumor DDRm involved directly or indirectly in homologous recombination repair (HRR) (11 gene panel). Men had received 1-2 taxane-based chemotherapy regimens and progressed on ≥1 novel hormonal therapy. The primary endpoint was objective response rate ([ORR] per RECIST 1.1; blinded independent central review [BICR]). Exploratory ad hoc biomarker analyses assessed gLOH and associations with antitumor activity. Methods: gLOH was calculated as previously described (Sokol et al., JCO Precis Oncol 2020; PMID: 32903788). Of 104 men in the HRR-deficient measurable disease population (hereafter referred to as the efficacy population), 55 were evaluable for gLOH, 45 were non-evaluable for gLOH, and four lacked central lab gLOH results. Potential association of gLOH high/low status with response was explored using two high/low thresholds: 8.8% based on literature showing that this threshold optimally distinguished prostate cancers bearing BRCA biallelic alterations from BRCA-wildtype (Sokol et al., JCO Precis Oncol 2020; PMID: 32903788), and an agnostic threshold based on the median gLOH score in TALAPRO-1 (9.2%) in the gLOH-evaluable efficacy population. Data cutoff was Sept 4, 2020 (primary completion date). Results: gLOH ranged from 1.39% to 30.2% in the gLOH-evaluable efficacy population. Based on the 8.8% gLOH threshold, ORR was significantly higher for gLOH-high (53.3% [16/30], 95% confidence interval [CI] 34.3-71.7%) vs gLOH-low (12.0% [3/25], 95% CI 2.5-31.2%; odds ratio [OR] 8.381, 2-sided P=0.0017; Fisher’s exact test). Similar results were yielded based on the 9.2% gLOH threshold. Next, potential associations of gLOH score with response within HRR gene alteration groups of the efficacy population were explored using the 8.8% threshold. Within the BRCA2 group, ORR was robust regardless of gLOH status, but was significantly higher for gLOH-high (70.6%, 12/17) than for gLOH-low (23.1%, 3/13) (P=0.0253). Within the ATM group, ORR was numerically higher for gLOH-high (50.0%, 2/4) than gLOH-low (0%, 0/6), but not significantly (P=0.1333). Radiographic progression-free survival (RECIST 1.1; BICR) in the gLOH-evaluable efficacy population was numerically superior for gLOH-high versus gLOH-low using either threshold (hazard ratio 0.68), but not significantly. Conclusions: Based on these retrospective, exploratory analyses of TALAPRO-1, gLOH-high status was associated with response within the gLOH-evaluable efficacy population. Further exploration of gLOH as a candidate predictive biomarker for talazoparib in prostate cancer is warranted. Citation Format: Johann S. de Bono, Niven Mehra, A. Douglas Laird, Elena Castro, Philippe Barthelemy, Remy Delva, Giorgio V. Scagliotti, Marco Maruzzo, Adam Stirling, Jean-Pascal Machiels, Herlinde Dumez, Vincent Renard, Julia F. Hopkins, Lee A. Albacker, Hsiang-Chun Chen, Cynthia G. Healy, Jijumon Chelliserry, Tanya Dorff, Karim Fizazi. TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)– Exploration of genomic loss of heterozygosity (gLOH) and potential associations with antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT031.

TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)—Exploration of germline DDR alteration landscape and potential associations with antitumor activity.

157 Background: TALAPRO-1 enrolled men with progressive mCRPC with measurable soft-tissue disease and tumor DDRm involved directly or indirectly in homologous recombination repair (HRR) (11 gene panel). These men had received 1–2 taxane chemotherapy and progressed on ≥1 novel hormonal therapy. The primary endpoint was objective response rate ([ORR] per RECIST 1.1; central review). Exploratory ad hoc biomarker analyses assessed germline DDR/HRR (gHRR) alteration landscape and associations with antitumor activity. Methods: Alterations were defined as known/likely pathogenic variants. gHRR alteration (gHRRm) frequency was assessed in the study population evaluable for saliva sequencing (n = 91) using Ambry CustomNext-Cancer (9/11 genes from the tumor panel assessed). Potential associations between gHRRm status and antitumor activity were explored in the HRR-deficient measurable disease population evaluable for gHRRm (n = 70). The potential association of germline vs somatic tumor HRRm and antitumor activity was also assessed in the HRR-deficient measurable disease population (n = 104) using saliva data and somatic-germline-zygosity (SGZ) prediction (when saliva results were unavailable) to annotate tumor alteration origin. This analysis was limited to short variants. Data cutoff was Sept 4, 2020 (primary completion date). Results: Using Ambry saliva results, 19 gHRRm were identified in 18/91 (20%) evaluable patients (pts) ( BRCA2 = 10; ATM = 4; CHEK2 = 4; RAD51C = 1; 1 pt had both ATM and RAD51C). As expected for germline sequencing, all 19 alterations were short variants (12 SNV, 7 InDels). For 17/19 gHRRm, central lab tumor F1CDx records were available: in all 17 cases, identical tumor alterations were found. Of these 17 tumor HRRm, 16 were evaluable for tumor SGZ prediction of origin or zygosity: 15/16 germline, with 1/16 somatic; 9/16 homozygous (incl 7/9 BRCA2), with 7/16 heterozygous (incl 2/9 BRCA2). ORR was 31% (5/16) in men with gHRRm and 26% (14/54) in men without gHRRm ( P = 0.7519, 2-sided Fisher exact test). Based on tumor sequencing results, annotated using saliva results and SGZ predictions, ORR was 25% (10/40) in men with gHRRm and 19% (4/21) in men with only somatic HRRm ( P = 0.7528). Conclusions: Here we report a 20% incidence of gHRRm for this population of men with mCRPC preselected based on tumor HRRm status, which may be impacted by low Ns and assay specific differences in variant calling. In this population, no association with differential antitumor activity was observed with gHRRm status as assessed using germline results alone, or assessed holistically using a combination of tumor and saliva results and SGZ prediction.

Talazoparib (TALA), an oral poly (ADP-ribose) polymerase (PARP) inhibitor for men with metastatic castration-resistant prostate cancer (mCRPC) and DNA damage response (DDR) alterations: Detailed safety analyses from TALAPRO-1 trial.

5047 Background: PARP inhibitors have recently been approved for the treatment of mCRPC. In this Phase 2 study, we explore the safety profile of TALA in men with mCRPC with the aim of understanding how patients (pts) with adverse events (AEs) were managed during the trial. Methods: TALAPRO-1 (NCT03148795) is a single-arm, open-label, phase 2 study of TALA in pts with progressive mCRPC, measurable soft tissue disease, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received ≥1 taxane-based chemotherapy and progressed on ≥1 novel hormonal therapy (enzalutamide/abiraterone). The primary objective was confirmed objective response by central independent review; the assessment of safety included AEs, incidence of dose modifications and of permanent treatment discontinuation due to AEs, and clinical laboratory tests. Results: In the TALA-treated population (1 mg/daily; n=127), 95.3% (121/127) experienced all-causality AEs. The most common (≥15%) hematologic AEs were anemia (any grade, 48.8%; G3, 30.7% [no G4 events]), thrombocytopenia (all grade, 18.9%; G3/4, 8.7%), and neutropenia (all grade, 16.5%, G3, 7.9% [no G4]). Median time from first dose of TALA to onset of first episode of G≥3 anemia, neutropenia, and thrombocytopenia was 56, 48, and 17 days, respectively. G3 anemia lasted a median of 7 days, G3 neutropenia lasted a median of 12 days, G3 and G4 thrombocytopenia lasted a median of 8 and 11 days, respectively. Hematologic AEs typically occurred during the first 4–5 months of TALA treatment and were managed by dose modifications and supportive care. 34.6% of pts received a blood transfusion product, and most transfusions occurred when hemoglobin was between 7.0–10.0 g/dL. Overlapping G3/4 hematologic AEs were infrequent on TALA (anemia + neutropenia 4.7%; anemia + thrombocytopenia 5.5%; neutropenia + thrombocytopenia 1.6%). In pts who had anemia, 12.6% also had fatigue; in those with thrombocytopenia, 4.7% had a subsequent bleeding event; in those with neutropenia, 1.6% had an overlapping infection. The most common non-hematologic AEs (≥15%) were nausea (any grade, 33.1%; G3/4, 2.4%), decreased appetite (any grade, 28.3%; G3/4, 3.1%), and asthenia/fatigue (any grade, 23.6%/19.7%; G3/4, 3.9%/1.6%). In the treated population, dose reduction of TALA due to all-causality AE occurred in 33 pts (26.0%). Treatment discontinuation due to all-causality AEs was low and occurred in 15 pts (11.8%); the most frequent (≥2 pts) AEs leading to discontinuation of TALA were back pain and platelet count decrease (each, 1.6% [2/127 pts]). There were no treatment-related deaths. Conclusions: A manageable safety profile and durable antitumor effects were observed with TALA in men with heavily pretreated mCRPC in this phase 2 study. Clinical trial information: NCT03148795.

TALAPRO-1: Phase II study of talazoparib (TALA) in patients (pts) with DNA damage repair alterations (DDRm) and metastatic castration-resistant prostate cancer (mCRPC).

93 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) show antitumor activity in mCRPC/DDRm pts treated with novel hormonal therapy (NHT). TALAPRO-1 is an open-label study evaluating TALA (a potent PARP inhibitor/trapper) in men with mCRPC/DDRm. We report a planned interim analysis (IA; Dec 2019). Updated results at a Sep 4 2020 cut-off, available in November 2020, will be presented at the meeting. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) for metastatic disease and progressed on ≥1 NHT (enzalutamide/abiraterone acetate) given for mCRPC. DDRm are defined as known/likely pathogenic variants or homozygous deletions. Pts receive oral TALA 1 mg/day (moderate renal impairment 0.75 mg/day) until radiographic progression, unacceptable toxicity, consent withdrawal, or death. Primary endpoint is objective response rate (ORR). Secondary endpoints: time to objective response; response duration; prostate-specific antigen (PSA) decrease ≥50%; circulating tumor cell (CTC) count conversion (to CTC = 0 and &lt;5 per 7.5 mL blood); time to PSA progression; radiographic progression-free survival (rPFS); overall survival; safety. A planned efficacy/safety IA was done when 60 pts with DDRm and measurable disease completed ≥6 months of TALA/no longer followed. Radiographic responses are based on investigator assessments. Results: 113 pts received TALA (cut-off Dec 12 2019); 75 pts were evaluable for IA, with DDRm, had measurable disease, received ≥16 weeks’ treatment, and were assessed for ORR (54.7% BRCA1/2, 4.0% PALB2, 22.7% ATM; 18.7% other DDRm).All pts evaluable for IA had prior docetaxel; 45.3% cabazitaxel. Confirmed ORR, rPFS, and composite response (investigator-assessed) in pts who received TALA for ≥16 weeks are in the table. Most common treatment-emergent adverse events: anemia (42.5%); nausea (32.7%). Conclusions: TALA monotherapy has encouraging antitumor activity in docetaxel-pretreated mCRPC pts with BRCA1/2 alterations and was generally well tolerated. Funding: Pfizer Inc. Clinical trial information: NCT03148795. [Table: see text]

Abstract B02: 5-Hydroxymethylcytosine profiles in circulating cell-free DNA are biomarkers of disease burden in children with neuroblastoma

Abstract Background: 5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker of open chromatin and active gene expression. The level of 5-hmC expression serves as a biomarker in adults with cancer, and we recently demonstrated the prognostic significance of tumor whole-genome 5-hmC profiling in children with neuroblastoma. Here, we used Nano-hmC-Seal technology to profile 5-hmC in circulating cell-free DNA (cfDNA) in blood samples from patients with neuroblastoma and age-matched healthy children. Methods: Plasma was collected from 32 children with neuroblastoma at various time points during therapy and 34 well children. 5-hmC sequencing was performed using 100ng of cfDNA extracted from plasma. Metastatic disease burden was classified as high, moderate, low, or none based on Curie MIBG scores, the percentage of tumor cells in bone marrow samples, and/or measurable disseminated soft tissue disease. Results: One hundred cfDNA 5-hmC profiles were generated from 27 high-risk, 3 intermediate-risk, and 2 low-risk patients and 34 well controls. Hierarchical clustering based on 5-hmC levels of 347 genes separated the samples into three main clusters corresponding to high, moderate, and low/no disease burden in the bone, bone marrow, and/or soft tissue. Using functional gene pathways, two subsets of patients within the low/no cluster were revealed that correlated with low tumor burden or no clinically detectable metastatic disease (sensitivity 70%, specificity 76.9%). 5-hmC profiles tracked closely with changes in disease status in 15 patients with serial samples. Samples from patients with a detectable tumor burden had genes with elevated 5-hmC in pathways of neuronal stem cell maintenance and the epigenetic regulatory complexes PRC2 and CTCF/cohesion. Conclusions: cfDNA 5-hmC profiles correlate with disease burden in children with neuroblastoma and may serve as sensitive biomarkers of treatment response. Analysis of transcriptional networks regulated by these epigenomic modifications may lead to a deeper understanding of the pathways that drive resistance to treatment. Citation Format: Mark A. Applebaum, Erin K. Barr, Jason Karpus, Meritxell Oliva, Alexandre Chlenski, Helen R. Salwen, Emma Wilkinson, Marija Dobratic, Elizabeth A. Sokol, Barbara E. Stranger, Chuan He, Susan L. Cohn. 5-Hydroxymethylcytosine profiles in circulating cell-free DNA are biomarkers of disease burden in children with neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B02.

TALAPRO-1: Phase II study of talazoparib (TALA) in patients (pts) with DNA damage repair alterations (DDRm) and metastatic castration-resistant prostate cancer (mCRPC) – updated interim analysis (IA).

5566 Background: PARP inhibitors (PARPi) show antitumor activity in mCRPC/DDRm pts treated with novel hormonal therapy (NHT). TALAPRO-1 is an open-label study evaluating TALA (potent PARP inhibitor/trapper) in men with mCRPC/DDRm. We report a planned IA (Dec 2019). Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) for metastatic disease and progressed on ≥1 NHT (enzalutamide/abiraterone acetate) given for mCRPC. DDRm are defined as known/likely pathogenic variants or homozygous deletions. Pts receive oral TALA 1 mg/day (moderate renal impairment 0.75 mg/day) until radiographic progression, unacceptable toxicity, consent withdrawal or death. Primary endpoint is objective response rate (ORR). Secondary endpoints: time to OR; response duration; PSA decrease ≥50%; circulating tumor cell (CTC) count conversion (to CTC = 0 and &lt;5 per 7.5 mL blood); time to PSA progression; radiographic PFS (rPFS); overall survival; safety. A planned efficacy/safety IA was done when 60 pts with DDRm and measurable disease completed ≥6 months of TALA/no longer followed (DDR population [DDRp]). Radiographic responses are based on investigator assessments. Results: 113 pts received TALA (cutoff Dec 12, 2019); 75 pts were DDRp, had measurable disease, received ≥16 wk treatment, and were evaluable for ORR (54.7% BRCA1/2, 4.0% PALB2, 22.7% ATM; 18.7% other DDRm).All DDRp pts had prior docetaxel; 45.3% cabazitaxel. Confirmed ORR, rPFS, and composite response (investigator-assessed) in pts who received TALA for ≥16 weeks are in the table. Most common treatment-emergent adverse events: anemia (42.5%); nausea (32.7%). Conclusions: TALA monotherapy has encouraging antitumor activity in docetaxel-pretreated mCRPC pts with BRCA1/2 alterations and was generally well tolerated. Clinical trial information: NCT03148795 . [Table: see text]

TALAPRO-1: A phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—First interim analysis (IA).

119 Background: Phase 2 and 3 studies with poly(ADP-ribose) polymerase inhibitors (PARPi) have demonstrated antitumor activity in patients (pts) with mCRPC with DDRmut who were previously treated with novel hormonal therapy (NHT). We report the first IA of a Phase 2 study of TALA, a potent inhibitor and trapper of PARP. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRmut likely to sensitize to PARPi (including ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) and progressed on ≥1 NHT (enzalutamide/abiraterone acetate). Pts receive oral TALA 1 mg/d (moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or consent withdrawal. Primary endpoint is objective response rate (ORR; blinded independent review). Secondary endpoints are time to OR, duration of response, prostate-specific antigen (PSA) decrease ≥50%, circulating tumor cell (CTC) count conversion (to CTC = 0 and &lt;5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival (rPFS), overall survival, safety, pt-reported outcomes, and pharmacokinetics. A planned IA of safety and efficacy was performed after 20 pts with BRCA1/2 mutations were on treatment for ≥8 wks. Results: 81 pts received TALA as of June 5, 2019; 43 pts enrolled by Feb 12, 2019 were evaluable for the primary endpoint (20 BRCA1/2, 2 PALB2, 14 ATM, 7 other). All had received docetaxel and 49% prior cabazitaxel. Overall ORR (95% CI) was 25.6% (13.5–41.2), ORRBRCA1/2 50.0% (27.2–72.8), ORRATM 7.1% (0.2–33.9). Overall median (95% CI) rPFS was 5.6 months (mo) (3.5–8.2), rPFSBRCA1/2 8.2 mo (5.6–NE), rPFSATM 3.5 mo (1.7–8.1). Most common treatment-emergent adverse events (≥20%) were anemia, nausea, asthenia, decreased appetite, constipation, and platelet count decreased. Conclusions: TALA monotherapy demonstrates encouraging antitumor activity in docetaxel-pretreated mCRPC pts, especially those with BRCA1/2mut, and was generally well tolerated. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03148795.

The new international neuroblastoma response criteria.

Over recent years significant advances in histopathology and functional imaging techniques for the diagnosis and restaging of children with neuroblastoma have led to better quantification of disease and assessment of disease response, allowing for better treatment stratification. In this review we summarise recent changes to the International Neuroblastoma Response Criteria including the use of RECIST (Response Evaluation Criteria in Solid Tumours) guidance for measurable soft-tissue disease, replacement of technetium-99m-methylene diphosphonate (MDP) bone scans with metaiodobenzylguanidine (MIBG) scan or [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT scanning, and a new category of minimal residual bone marrow disease.

TALAPRO-1: An open-label, response rate phase II study of talazoparib (TALA) in men with DNA damage repair (DDR) defects and metastatic castration-resistant prostate cancer (mCRPC) who previously received taxane-based chemotherapy (CT) and progressed on greater than or equal to one novel hormonal therapy (NHT).

TPS342 Background: There are no approved therapies for mCRPC that has progressed on taxane and NHT. Preclinical studies showed that DDR-positive prostate tumors may be sensitized to PARP inhibition. TALA inhibits PARP, causing cell death in BRCA1/2-mutated cells. Methods: This study (NCT03148795) is enrolling patients (pts) (N ≈ 100) with measurable soft tissue disease per RECIST v1.1, progressive mCRPC, DDR likely to sensitize to PARP inhibition, ECOG performance status ≤ 2, and no brain metastases, who received 1-2 CT regimens (including ≥ 1 taxane-based CT) and progressed on ≥ 1 NHT (enzalutamide/abiraterone acetate). Prior use of PARP inhibitors, cyclophosphamide, mitoxantrone, or platinum-based CT ≤ 6 mos before study or progression on a platinum-based CT at any time are excluded. Pts will receive TALA 1 mg/d orally (pts with moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or withdrawal of consent. TALA should not be discontinued based on increased prostate specific antigen (PSA) or circulating tumor cell (CTC) count alone. Primary endpoint is best objective response (OR) rate (complete/partial soft tissue response; exact 2-sided 95% confidence interval). Responses must be confirmed ≥ 4 wks later by computed tomography/magnetic resonance imaging with no evidence of bone progression ≥ 6 wks later per PCWG3 criteria. Secondary endpoints include time to OR, duration of response, PSA decrease ≥ 50%, CTC count conversion (to CTC = 0 and &lt; 5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival, overall survival, safety, pt-reported outcomes, and pharmacokinetics of TALA. Efficacy will be assessed every 8 wks for the first 24 wks, then every 12 wks thereafter. An initial safety and efficacy analysis will be performed on 20 pts after ≥ 8 wks of treatment. An interim efficacy analysis is planned when 60 pts have completed ≥ 6 mos of treatment. This study was sponsored by Pfizer Inc. Previously presented at ESMO 2018, FPN 859TiP, De Bono JS et al. Reused with permission. Clinical trial information: NCT03148795.

A phase I study of TRC105 (Anti-CD105 [endoglin] antibody) in metastatic castration resistant prostate cancer (mCRPC).

3043 Background: Pre−clinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane protein expressed on the surface of proliferating vascular endothelial cells. The expression of CD105 is required for the formation of new blood vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal antibody that binds to human CD105 (endoglin). It inhibits angiogenesis and tumor growth through inhibition of endothelial cell proliferation, antibody-dependent cellular cytotoxicity, and induction of apoptosis. The primary objective is to evaluate safety and identify the maximum tolerable dose (MTD) of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate, evaluation of progression free survival (PFS), overall response rate (ORR) and overall survival (OS). Methods: Patients with an ECOG performance status (PS) ≤ 2, progressive mCRPC and either chemotherapy-naïve or post-docetaxel treatment were eligible. Six cohorts of patients, on escalating dose levels, receive TRC105 intravenously at doses of 1, 3, 10, 15, or 20 mg/kg IV every 2 weeks (cohorts 1, 2, 3, 5, and 6) or 10 mg/kg IV weekly (cohort 4) on a 4 week cycle. Response is assessed with imaging studies every 2 months for the first four months and then every 3 months thereafter. Results: Sixteen patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), median ECOG PS is 1 (range 0−2), median Gleason score is 8 (range 6−10), median on−study PSA is 147.5 (range 0.1-3373), and median number of prior (non-hormonal) therapies is 3 (range 0−6). Median time on study is 16 weeks (range 8-28 weeks). One patient experienced a dose limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 patients with measurable soft tissue disease achieved stable disease for at least two cycles. Conclusions: TRC105 is tolerated up to 15 mg/kg every two weeks with early evidence of clinical activity in mCRPC. An additional cohort (6), with dosage of 20 mg/kg, is currently under investigation. Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of this study.

A phase I study of TRC105 (anti-CD105 [endoglin] antibody) in metastatic castration-resistant prostate cancer (mCRPC).

117 Background: Preclinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane protein expressed on the surface of proliferating vascular endothelial cells. The expression of CD105 is required for the formation of new blood vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal antibody that binds to human CD105 (endoglin). It inhibits angiogenesis and tumor growth through inhibition of endothelial cell proliferation, antibody-dependent cellular cytotoxicity, and induction of apoptosis. The primary objective is to evaluate safety and identify the maximum tolerable dose (MTD) of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate, evaluation of progression free survival (PFS), overall response rate (ORR) and overall survival (OS). Methods: Patients with an ECOG performance status (PS) ≤ 2, progressive mCRPC and either chemotherapy-naïve or post-docetaxel treatment were eligible. Five cohorts of patients, on escalating dose levels, receive TRC105 intravenously at doses of 1, 3, 10 or 15 mg/kg IV every 2 weeks (cohorts 1, 2, 3, and 5) or 10 mg/kg IV weekly (cohort 4) on a 4 week cycle. Response is assessed with imaging studies every 2 months for the first four months and then every 3 months thereafter. Results: Seventeen patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), median ECOG PS is 1 (range 0−2), median Gleason score is 8 (range 6−10), median on−study PSA is 147.5 (range 0.1-3373), and median number of prior (non-hormonal) therapies is 3 (range 0−6). Median time on study is 16 weeks (range 8-28 weeks). One patient experienced a dose limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 patients with measurable soft tissue disease achieved stable disease for at least two cycles. Two patients remain on study (in cohort 5). Conclusions: TRC105 is tolerated up to 15 mg/kg every two weeks with early evidence of clinical activity in mCRPC. Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of this study.

A phase I study of TRC105 (anti-CD105 monoclonal antibody) in metastatic castration-resistant prostate cancer (mCRPC).

e15070 Background: TRC105 is a human/murine chimeric IgG1 monoclonal antibody to CD105 (endoglin) that inhibits angiogenesis and tumor growth through inhibition of endothelial cell (EC) proliferation, antibody−dependent cellular cytotoxicity and induction of apoptosis. CD105 is highly expressed on proliferating vascular ECs. Preclinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. Methods: The primary objective is to evaluate safety and identify the maximum tolerable dose of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate and overall response rate (ORR). Eligibility requires ECOG performance status (PS) ≤ 2 and progressive mCRPC. Three cohorts of 3-6 patients receive TRC105 at doses of 1, 3 or 10 mg/kg IV over 1−4 hours every 2 weeks of a 4 -week cycle. Premedications are dexamethasone, acetaminophen, famotidine, and diphenhydramine. PSA is evaluated prior to each treatment and response is assessed every 2 cycles with imaging studies. Results: Nine patients are enrolled in cohorts 1−3. Median age is 66 (range 47−84), ECOG PS 1 (1−2), Gleason score 8 (6−10), on−study PSA 231 (0.14 – 2923), and number of prior therapies after gonadotropin-releasing hormone agonist or anti−androgen therapy 3 (0−6). Median time on study is 16 weeks (8 – 28). Dose-limiting toxicity was not observed. Grade 1 to 2 infusion reactions occurred in 5 patients. PSA declines were seen in two of three patients in cohort 3 (17 and 59% from baseline); each had progressed on docetaxel and at least one second−line agent. Six of 8 evaluable patients with measurable soft tissue disease achieved stable disease (1 in cohort 1, 2 in cohort 2 and 3 in cohort 3); one patient in cohort 3 remains on study (8 weeks). Conclusions: TRC105 is tolerated at doses up to 10 mg/kg every 2 weeks with early evidence of clinical activity in patients with mCRPC. Accrual is ongoing to evaluate higher doses and more frequent dosing.

Phase II study of XL184 in a cohort of patients (pts) with castration-resistant prostate cancer (CRPC) and measurable soft tissue disease.

127 Background: XL184 is an oral, potent inhibitor of MET and VEGFR2. MET pathway activation promotes tumor growth, invasion and metastasis. Overexpression of MET and/or its ligand HGF are associated with prostate cancer metastasis. In preclinical studies, androgen ablation upregulates MET signaling. Preliminary data from the open label Lead-in Stage of an ongoing adaptive design phase II randomized discontinuation trial are presented. Methods: Eligible pts had CRPC, measurable disease with or without bone metastasis, and disease progression on ≤1 prior non-hormonal systemic treatment. XL184 was administered orally for 12 weeks (wks). Tumor (RECIST) and bone scan response (complete or partial resolution) were assessed every 6 wks. Primary endpoint is objective response rate at wk 12. Pts with SD at wk 12 will enter a placebo-controlled randomized phase. Results: As of 10/4/10, 72 pts have been enrolled. Median time on study was 50 days (range, 6+-350+ days). Median age was 69 yrs; 45% of pts were docetaxel-pretreated. All pts had measurable disease, including 69% with visceral metastases. To date, there are 24 response evaluable pts, defined as enrolled ≥12 wks prior to data cutoff. 5/24 (21%) pts had a partial response (≥30% reduction) in measurable disease with 3 responses confirmed at 12 wks and 2 unconfirmed responses ongoing. 6/24 (25%) had PSA declines of ≥50%. 13 of 15 (87%) pts with known bone metastases had either complete or partial resolution of lesions on bone scan. Bone scan responses were associated with investigator-reported improvement in bone pain in 11/15 (73%) with pain at baseline. Effects on osteoclast and osteoblast activity were observed: plasma C-telopeptide declined ≥50% in 8/12 (66%) pts and serum total alkaline phosphatase (tALP) declined ≥50% in 5/8 (63%) pts with bone metastases and baseline elevated tALP. The most common AEs ≥Grade 3 severity (related) were fatigue (10%), diarrhea (3%) and elevated AST (3%). Conclusions: XL184 results in tumor responses, partial or complete resolution of lesions on bone scan, and symptom relief in pts with metastatic CRPC, including those pretreated with docetaxel. XL184 also decreased biomarkers of both osteoblast and osteoclast activity. [Table: see text]

A phase I study of TRC105 (anti-CD105 monoclonal antibody) in metastatic castration-resistant prostate cancer (mCRPC).

171 Background: TRC105 is a human/murine chimeric IgG1 monoclonal antibody to CD105 (endoglin) that inhibits angiogenesis and tumor growth through inhibition of endothelial cell (EC) proliferation, antibody-dependent cellular cytotoxicity and induction of apoptosis. CD105 is highly expressed on proliferating vascular ECs. Preclinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. Methods: The primary objective is to evaluate safety and identify the maximum tolerable dose of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate and overall response rate (ORR). Eligibility requires ECOG performance status (PS) ≤ 2 and progressive mCRPC. Three cohorts of 3-6 patients receive TRC105 at doses of 1, 3 or 10 mg/kg IV over 1–4 hours every 2 weeks of a 4 week cycle. Premedications are dexamethasone, acetaminophen, famotidine, and diphenhydramine. PSA is evaluated prior to each treatment and response is assessed every 2 cycles with imaging studies. Results: Eight patients are enrolled in cohorts 1–3. Median age is 65 (range 47–84), ECOG PS 1 (1–2), Gleason score 8 (6–10), on–study PSA 201 (0.10 – 3,373), and number of prior therapies after gonadotropin-releasing hormone agonist or anti-androgen therapy 2.5 (0–6). Median time on study is 14 weeks (7–16). Dose-limiting toxicity was not observed. Grade 1 to 2 infusion reactions occurred in 4 patients. PSA declines were seen in both patients in cohort 3 (26% and 51% from baseline); each had progressed on docetaxel and at least one second-line agent. Five of 6 evaluable patients with measurable soft tissue disease achieved stable disease (2 in cohort 1, 2 in cohort 2 and 1 in cohort 3); the latter 3 patients in cohorts 2 and 3 remain on study. Conclusions: TRC105 is tolerated at doses up to 10 mg/kg every 2 weeks with early evidence of clinical activity in patients with mCRPC. Accrual is ongoing to evaluate higher doses and more frequent dosing. No significant financial relationships to disclose.

407 Phase 2 study of XL184 in a cohort of ovarian cancer patients (pts) with measurable soft tissue disease

407 Phase 2 study of XL184 in a cohort of ovarian cancer patients (pts) with measurable soft tissue disease

406 Phase 2 study of XL184 in a cohort of patients (pts) with castration resistant prostate cancer (CRPC) and measurable soft tissue disease

406 Phase 2 study of XL184 in a cohort of patients (pts) with castration resistant prostate cancer (CRPC) and measurable soft tissue disease

Oral vinorelbine as a fixed-weekly schedule in taxanes-refractory advanced HRPC: A single institution experience

e16084 Background: Vinorelbine (VRL) has been shown to be active in hormone-refractory prostate cancer (HRPC). Oral formulation of VRL represents a significant advance in the treatment of advanced cancer. The recommended doses are 60–80 mg/m2(d1–8 q3wks).We evaluated efficacy and toxicity of different VRL schedule administered as a fixed-weekly dose of 60 mg/m2. The purpose of this study was to evaluate the toxicity profile and efficacy of this schedule in terms of PSA response, objective response and clinical benefit (CB) response. Methods: Pts characteristics were: PS 0–2, adequate bone marrow, liver and renal functions. Oral VRL was adminestered at weekly dose of 60 mg/m2 until disease progression/intolerable toxicity. PSA response was defined as a &gt;50% fall in PSA from baseline, confirmed by a second PSA value 4 or &gt; weeks later. Pts with measurable soft tissue disease met traditional guidelines for tumour responses. Progression was defined by objective disease progression or PSA increase of &gt;50% above nadir or &gt;25% above baseline. Pts were monitored clinically and with serial PSA measurements every 1 week. Results: Thirty seven pts with progressive HR metastatic prostate cancer were evaluated. Mean (range) age was 67 years (50–88), median PSA level was 90 ng/ml (1- 4314), and median Gleason score was 7 (6–9). 23 (62%) pts had previous taxane chemotherapy and 14 pts (38%) were chemo-naive. Pts received a mean of 5.5 cycles (1cycle=3wks) (range:1–24). Median follow-up was 12 months. Thirty three of 37 Pts (97%) achieved a decline in serum PSA. CB response was achieved in 15 out of 37 pts(40%). The PSA response was observed in 13 pts (35%). Objective response was not observed and only 6 pts showed SD (16%). The relative dose-intensity was 94%. There were no reported grade 3–4 toxicities. Only 1 treatment discontinuation was observed (esopahgitis g2). Toxicities consisted primarily of g2 anemia (25%) and mild nausea (32%). Conclusions: Oral Vinorelbine administered as a fixed-weekly schedule of 60 mg/m2 is a safe regimen in pts with advanced HRPC. This regimen of oral vinorelbine is an effective and well-tolerated treatment in this setting, despite a major dose-intensity administered. Further studies will be evaluated in chemo-naive and/or elderly population. No significant financial relationships to disclose.

Efficacy of low-dose ketoconazole in hormone refractory prostate cancer patients (HRPC): A single institution experience

16117 Background: The management of HRPC remains controversial. Among the options, second-line hormonal therapy is commonly used. Ketoconazole, an antimycotic which affects the synthesis of androgens and other steroids, has shown direct cytotoxic effects in prostate cancer. This study describes our experience with low-dose ketoconazole treatment for HRPC. Methods: All eligible pts had histologically proven adenocarcinoma of the prostate, and all pts had progressive castration resistant prostate cancer by consensus criteria and had received no prior hormonotherapy. Pts received 400 mg ketoconazole orally 3 times daily, and orally replacement hydrocortisone. PSA response was defined as a >50% fall in PSA from baseline, confirmed by a second PSA value 4 or > weeks later. Pts with measurable soft tissue disease met traditional guidelines for tumour responses. Progression was defined by objective disease progression or PSA increase of >50% above nadir or >25% above baseline. Pts were monitored clinically and with serial PSA measurements every 1 month. Results: Data for 73 pts were analysed. Median age was 73 years(57–89), median PSA was 67.8 ng/ml (range: 7.5–347.0), with a median performance status of 90%(range: 70–90%). Of the 70 pts (PSA data missing in 3 pts), 33 (47.0%) showed a decrease in PSA >50% (95% CI 37.5%-61.4%) with a median duration of 7.8 months (range 4–41 months). We observed objective responses in 12 of 34 pts(35%) with measurable soft tissue disease and bone metastasis. Age, PSA at diagnosis, Performance status, Gleason score and bone scan result were not significantly associated with response to ketoconazole treatment in univariate or multivariate analyses. A longer duration of primary androgen deprivation therapy (ADT) and total duration of previous hormonal therapy was associated with a longer time to progression.Toxicity was mild with 5 of 73 patients(7.0%) discontinued therapy because of gastrointestinal side-effects or moderate elevated transaminases. No acute hepatitis or adrenal insufficiency was observed. Conclusions: Low-dose Ketoconazol is an effective and well-tolerated treatment in pts with HRPC and should be considerate in a subset of pts with low-volume disease and a rising PSA level despite ADT. No significant financial relationships to disclose.