Prognostic implications of PSA levels at 7 months in metastatic hormone-sensitive prostate cancer treated with enzalutamide: Landmark analysis of ENZAMET (ANZUP 1304).

作者: Pook, David William ; Mc Laughlin, Ronan Andrew ; McDermott, Raymond S. ; Thomson, Alastair ; North, Scott A. ; Sweeney, Christopher ; Reaume, M. Neil ; Sandhu, Shahneen ; Thomas, Hayley ; Horvath, Lisa ; Tan, Thean Hsiang ; Chowdhury, Simon ; Stockler, Martin R. ; Parnis, Francis ; Chi, Kim N. ; Frydenberg, Mark ; McCaffrey, John ; Zielinski, Robert Richard ; Marx, Gavin M. ; Davis, Ian D.

5079 Background: ENZAMET (NCT02446405) showed that enzalutamide added to testosterone suppression (TS) with or without docetaxel improves overall survival (OS) compared with TS plus standard non-steroidal anti-androgen (NSAA) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We assessed PSA levels in ENZAMET participants at 7 months after randomization to determine correlations with OS. In CHAARTED, participants with mHSPC high volume disease (HV), 20% achieved PSA ≤ 0.2 with ADT (androgen deprivation therapy) alone versus 44% with low volume disease (LV) and for HV with ADT + Docetaxel, 36% achieved PSA ≤ 0.2 vs 64% with LV. Methods: Participants were included if they were followed for at least 7 months after randomization, and had availability of PSA and outcome data. Landmark analysis at 7 months used prognostic classifiers as previously identified in SWOG 9346 and CHAARTED of PSA ≤ 0.2 and > 0.2 at 7 months after initiation of therapy. Results: The total number of ENZAMET participants (pts) with PSA at 7 months of ≤0.2ng/mL was 646 of 1125 (57%): 271/562 (48%) in the NSAA arm versus 375/563 (67%) in the ENZA arm. Five-year OS for TS + NSAA (±Doc) arm PSA ≤ 0.2 = 71% vs PSA > 0.2 = 36% and for TS + ENZA (±Doc) arm PSA ≤ 0.2 = 74% vs PSA > 0.2 = 43%. The % of pts with PSA levels at 7 months ≤0.2ng/mL and corresponding 5-year OS outcomes by key prognostic groups (HV vs LV) ± docetaxel is shown (Table). In comparison with CHAARTED in those with HV, 37% achieved PSA ≤ 0.2 with ADT alone versus 61% with LV which increased to 55% for HV and 79% for LV respectively with addition of enzalutamide. In those with HV treated with ADT + D 39% achieved PSA ≤ 0.2 vs 58% with LV increasing to 60% for HV and 74% for LV respectively with addition of enzalutamide. Conclusions: A PSA nadir of ≤0.2 at 7 months is associated with a longer OS regardless of treatment and prognostic group (HV vs LV). Enzalutamide increased the rate of achievement of PSA <0.2 for all groups. Clinical trial information: NCT02446405 . [Table: see text]

2024-06-01·Journal of Clinical Oncology

A first-in-human phase 1a dose-escalation study of BGB-15025 (HPK1 inhibitor) as monotherapy and in combination with tislelizumab (TIS; anti-PD-1 antibody) in patients (pts) with advanced solid tumors.

作者: Wang, Yongsheng ; Ba, Yi ; Tran, Ben ; Luo, Suxia ; Chang, Victoria ; Zhang, Teresa ; Galsky, Matt D. ; Ma, Jiafang ; Bishnoi, Sarwan K. ; Zhang, Heather ; Lau, Peter Kar Han ; Deva, Sanjeev ; Naicker, Kirsha May ; Zhang, Yanqiao ; Yap, Timothy A. ; Yu, Cunjing ; Zhou, Caicun

2585 Background: Hematopoietic progenitor kinase 1 (HPK1), a critical negative feedback regulator of T-lymphocyte and dendritic cell activation, is a potential target for IO treatment (tx). BGB-15025, a potent, selective, small-molecule HPK1 inhibitor, showed preliminary antitumor effects in preclinical studies as monotherapy (mono tx) and enhanced antitumor effects in combination with TIS. We present dose-escalation results from an open-label, multicenter, phase 1 study (NCT04649385) of BGB-15025 mono tx and in combination with TIS in pts with advanced solid tumors. Methods: Eligible pts (≥18 yrs) with previously treated (pts with prior exposure to CPIs were eligible) locally advanced/metastatic solid tumors and ECOG PS ≤1 were enrolled. Oral BGB-15025 mono tx was escalated through 7 doses (20 mg QD–240 mg BID); 5 doses (60 mg QD–240 mg QD) were given in combination with TIS 200 mg IV Q3W (combo tx). Primary objectives were assessment of safety and tolerability, determination of the maximum tolerated/administered dose (MTD/MAD) and recommended dose(s) for expansion (RDFE) for mono tx or combo tx. Select secondary and exploratory objectives included preliminary antitumor activity, PK, and PD. Results: As of Nov 21, 2023, 60 and 49 pts received mono tx and combo tx, respectively (median age: 59.0 yrs and 62.0 yrs; median follow-up: 2.3 months and 2.8 months). Most pts were male (56.7% [mono tx]; 67.3% [combo tx]) and received a median of 2 lines of systemic therapy in the metastatic setting (range: 0–7 [mono tx]; 0–5 [combo tx]). The most common tumors were RCC, NSCLC, cervical cancer, CRC, GC/GEJC, and HNSCC. The most common TRAEs (Table) for mono tx were diarrhea (18.3%), vomiting (15.0%), and blood creatinine increased (15.0%); and for combo tx were nausea (30.6%), diarrhea (28.6%), and fatigue (20.4%). No DLTs were observed with mono tx. 5 DLTs were observed with combo tx (2 ALT/AST increased, 1 colitis, 1 immune-related hepatitis, 1 GGT increased). The MAD was 200 mg BID for mono tx and MTD was 150 mg QD for combo tx. For mono tx, there were no responders and disease control rate (DCR) was 35.0%; 3 pts remained on tx for >6 months (2 pts are still on tx for >60 and 84 weeks). For combo tx, the unconfirmed ORR was 18.4% for all doses combined and 31.3% for RDFE, DCR was 57.1% for all doses combined and 56.3% for RDFE. Conclusions: These preliminary results show BGB-15025 mono tx or combo tx with TIS was generally tolerable. The antitumor activity of BGB-15025 was improved when given in combination with TIS. Further investigation of BGB-15025 + TIS +/- chemotherapy is ongoing in the expansion phase. Clinical trial information: NCT04649385 . [Table: see text]

2024-02-01·Journal of Clinical Oncology

Radiographic progression without PSA progression in metastatic hormone-sensitive prostate cancer (mHSPC): A retrospective analysis from the ENZAMET trial (ANZUP 1304).

作者: Davis, Ian D. ; Tan, Thean Hsiang ; Zielinski, Robert Richard ; Frydenberg, Mark ; Thomson, Alastair ; Chi, Kim N. ; Parnis, Francis ; McCaffrey, John ; Marx, Gavin M. ; McDermott, Raymond S. ; Sandhu, Shahneen ; Stockler, Martin R. ; Chowdhury, Simon ; Horvath, Lisa ; Sweeney, Christopher ; North, Scott A. ; Pook, David William ; Martin, Andrew James ; Inderjeeth, Andrisha Jade ; Reaume, M. Neil

151 Background: ENZAMET randomized 1125 participants with mHSPC to compare enzalutamide (ENZA) versus a standard non-steroidal anti-androgen (NSAA) and demonstrated superior progression-free survival and overall survival (PFS and OS) with ENZA. Radiographic progression in the absence of prior/concurrent PSA progression (rProg1st) is an emerging biomarker of poor clinical outcomes. We sought to determine the frequency of rProg1st, and correlate the impact of enzalutamide on transitions between disease states for the ENZAMET cohort. Methods: The ENZAMET dataset was analyzed using a multi-state Cox proportional hazards regression model that partitioned the clinical experience of participants (pts) into 4 states: (1) Evt-Free (event-free), (2) rProg1st (radiologic progression recorded without prior/concurrent evidence of confirmed PSA progression), (3) OtherProg (All Other type of clinical progression events (PSA and treatment switch, excluding death), (4) Death. Results: Radiographic progression was recorded in 388/1125 (34%) pts. Radiographic progression without confirmed prior/concurrent PSA progression per protocol was recorded in 114/1125 (10%) with similar proportions in those assigned ENZA 55/114 (48%) vs NSAA 59/114 (52%). Baseline characteristics of the 114 pts with rProg1st were similar to the other pts in ENZAMET, and were similar in the ENZA and NSAA groups (Table 1). Compared with NSAA, ENZA delayed both rProg1st (HR 0.66, 95%CI: 0.46 to 0.96, p=0.03) and OtherProg (HR 0.37, 95%CI: 0.31 to 0.44, p<0.001). 5-year OS rates were 24% (95%CI: 18-34) in the rProg1st group versus 42% (95%CI: 38-47) in the OtherProg group. Of those who had not progressed (495/1125) with a median follow-up of 68 months, 8% had died of causes other than prostate cancer. As previously reported ENZA prolonged overall survival in the whole trial cohort (N=1125, HR 0·70, 95%CI 0·58 to 0·84, p<0·0001). Conclusions: Participants who had radiographic progression without prior/concurrent PSA progression had worse overall survival whether assigned NSAA or enzalutamide. Enzalutamide reduced the hazards for, and delayed the times to, rProg1st and OtherProg. There were no baseline characteristics that helped identify these pts upfront; we plan molecular biological analyses to help identify this unique group earlier. Clinical trial information: NCT02446405 . [Table: see text]

100 项与 Ashford Cancer Centre Research Pty Ltd. 相关的药物交易

登录后查看更多信息

100 项与 Ashford Cancer Centre Research Pty Ltd. 相关的转化医学

登录后查看更多信息