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Use of integrated multi-omics analysis to analyze prognostic molecular subtype in collecting duct carcinoma.
585 Background: Collecting duct carcinoma (CDC) originates from the principal cells of the collecting ducts in the renal medulla and accounts for less than 2% of all renal cell carcinomas (RCCs). Due to its low incidence, the transcriptomic features and molecular subtypes of CDC have only been described in small-sample studies. This study employs a multi-omics approach to investigate CDC, aiming to deepen our understanding of CDC and provide some references for future treatment options. Methods: A total of 103 tumor samples and 15 paired adjacent non-tumor samples underwent whole transcriptome sequencing. Clinical pathological characteristics, treatments, and prognostic information were collected for all patients. Molecular typing of CDC was performed using Non-negative Matrix Factorization. The clinical and biological characteristics of each subtype were analyzed. Tissues from different NMF classifications were collected for single-cell sequencing to compare the biological characteristics. To enhance clinical accessibility, plasma was analyzed by LC-MS/MS and correlated with RNAseq data to identify representative plasma biomarkers for different NMF subtypes. Results: Compared to normal tissue, CDC exhibited significant differences in various biological functions including mechanisms and regulation of ion and substance transport across cellular membranes, as well as pathways such as proximal tubule bicarbonate reclamation, aldosterone-regulated sodium reabsorption and protein digestion. Tumor samples were classified into two transcriptional subtypes through machine learning: NMF1 and NMF2. NMF1 subtype had a significantly longer overall survival compared to those with the NMF2 subtype (median OS of 7.06 months vs 2.04 months, P =0.014). The infiltration proportions of T cells, CD8+ T cells, cytotoxic lymphocytes, endothelial cells, myeloid dendritic cells, NK cells, and neutrophils were all higher in NMF1 tumor tissues compared to NMF2, while the proportions of fibroblasts and monocytic lineage were lower in NMF1. These immune infiltration results were further validated by single-cell sequencing analysis. Using Lasso regression combined with survival data, we identified characteristic gene sets for each NMF subtype. Further association analysis with plasma LC-MS/MS revealed distinct protein expression profiles for each NMF subtype. These findings suggest that the NMF1 subtype has a relatively better prognosis and a 'hotter' tumor microenvironment, potentially benefiting from immunotherapy and/or anti-angiogenic therapy. Plasma biopsies could serve as a basis for molecular typing. Conclusions: This study is the largest to date to integrate clinical prognostic information in a multi-omics investigation of CDC. It provides critical insights for clinical research on targeted therapies for specific molecular subtypes of CDC.
The significance of androgen receptor signaling pathway in mCRPC patients receiving olaparib monotherapy or combined treatment with abiraterone.
197 Background: Our previous research confirmed that for metastatic castration-resistant prostate cancer (mCRPC) patients with DNA damage repair (DDR) deficiency who have developed resistance to prior abiraterone, the combination of olaparib and abiraterone improves survival compared to olaparib monotherapy. However, further research is needed to identify subgroups who may benefit from olaparib alone or in combination with abiraterone, and to pinpoint risk factors significantly associated with poor prognosis in these patients. This study aims to explore the value of androgen receptor (AR) variant and androgen receptor activity (AR-A) at the transcriptomic level in evaluating the prognosis of mCRPC patients treated with olaparib alone or in combination with abiraterone. Methods: This study included 142 mCRPC patients who underwent targeted next-generation sequencing. Among them, 73 patients received olaparib monotherapy, while 69 patients received combined therapy. Bulk transcriptome sequencing was performed for 62 patients. Kaplan-Meier analysis was employed to evaluate patients' progression-free survival (PFS) and overall survival (OS). The AR-A score was calculated through a weighted linear sum of nine typical AR transcriptional target genes. Results: The combination of olaparib and abiraterone significantly improved PSA response and survival (PFS and OS) compared to olaparib monotherapy. Among mCRPC patients receiving olaparib monotherapy, those without AR pathogenic variant (AR-PV) had superior PFS and OS compared to those with AR-PV (median PFS: 5 months vs 3 months; median OS: 23 months vs 17 months). At the transcriptome level, for mCRPC patients receiving combined therapy, the average AR-A group exhibited better PFS and OS compared to the lower AR-A group (median PFS: 7 months vs 3 months; median OS: 17 months vs 10 months). Conclusions: For mCRPC patients treated with olaparib monotherapy, the absence of AR-PV can obtain better survival benefits. For patients treated with combined therapy, the average AR-A indicates a better survival benefit. For mCRPC patients with AR-PV or lower AR-A score, large-scale prospective randomized controlled clinical trials are needed to further explore therapy strategies that can improve their prognosis.
Phase 2 randomized study of high-risk metachronous oligometastatic prostate cancer with high-risk mutations treated with metastasis-directed therapy and niraparib/abiraterone acetate plus prednisone (KNIGHTS) trial.
TPS283 Background: Some patients with oligometastases may have the potential for long-term disease-free survival with just aggressive local therapy as shown by randomized trials for total consolidation of macroscopic metastases using metastasis-directed therapy (MDT). Long-term outcomes of pooled STOMP and ORIOLE trials in oligorecurrent metastatic castration-sensitive prostate cancer (omCSPC) demonstrated MDT improved progression free survival. However, men with high-risk mutations, including pathogenic alterations in ATM , BRCA1/2 , Rb1 , and TP53 , did poorly. Additional data suggests men with metastatic castration-resistant prostate cancer and similar mutations are sensitive to PARP inhibition (PARPi) with niraparib. We are launching a first-in-man biomarker-driven trial in omCSPC patients with high-risk mutations to evaluate the efficacy of MDT + androgen deprivation therapy (ADT) versus MDT + ADT + niraparib/abiraterone acetate plus prednisone (nira/AAP). Methods: This study is a multi-site, non-blinded, randomized phase II trial in patients with omCSPC. Men with histologically confirmed (at any site) omCSPC (≤3 metastases on standard imaging or ≤5 on Axumin/Choline/PSMA-PET/CT) and germ-line/somatic high-risk mutations ( TP53, BRCA1/2, PALB2, ATM, BRIP1, CHEK2, FANCA, RAD51B, RAD54L, MUTYH ) will be randomized (1:1) to MDT + 6- months ADT versus MDT + 6-months ADT + 6-months nira/AAP. A range of MDT radiation fractionation regimens are permitted. Subjects who meet eligibility criteria and qualify for enrollment will be stratified according to: (i) institution; (ii) conventional/enhanced imaging, (iii) PSADT <6-months, (iv) initial surgery/radiation, and (v) BRCA1/2 status. This study has been IRB approved (NCT06212583). We assume an accrual time of 24 months, with 18 months of additional follow-up time, and will randomize a total of 88 patients (44 patients in each arm). The primary endpoint will be to assess frequency of PSA failure (> 0.2 ng/mL post primary surgery or nadir + 2 post definitive radiation) with testosterone >100 ng/dl at 18-months after randomization (powered for 20% improvement over control arm by Fisher’s exact test). Secondary endpoints will include toxicity, health-related quality of life (HRQoL), time to locoregional progression, time to distant progression, time to new metastasis, radiographic progression-free survival, and duration of response. Discovery correlatives associated with clinical outcome will be assessed by collection of including, but not limited to, cell free DNA, circulating-tumor cells, immunologic biomarkers, microbiota and radiomics. Clinical trial information: NCT06212583 .
Homologous recombination repair mutation testing patterns in metastatic castration-resistant prostate cancer: Analysis of real-world data in the United States.
102 Background: Homologous recombination repair mutations (HRRms) have predictive/prognostic value in metastatic castration-resistant prostate cancer (mCRPC). While therapies are approved for patients (pts) with HRRm mCRPC, HRRm testing data is limited in the United States (US). This analysis utilized real-world secondary data to assess US HRRm testing patterns in pts with mCRPC. Methods: Data were drawn from the Adelphi Real World Prostate Cancer Disease Specific Programme, a cross-sectional survey with retrospective data collection including medical oncologists (ONC) and urologists (URO) and their mCRPC pts in the US from Nov’22 – Jul'23. ONC/URO reported demographics, disease characteristics, and HRRm testing status for ≥1 of 10 genes of interest ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51C ) for eight consecutively seen adult pts. Analyses were descriptive. Logistic regression assessed variables associated with receiving a HRRm test. Results: Overall, 70 ONC/URO reported on 448 pts, of whom 53% received HRRm testing (ONC 57%, URO 39%). Mean (standard deviation) pt age (years) was 69.2 (8.2) for pts who were tested (vs 70.6 [8.3] not tested). HRRm testing occurred in: 73% with a known family history of HRRm-related (prostate/breast/ovarian/pancreatic) cancer (vs 50% without); 53% with visceral metastases (vs 52% without); 61% with an initial localized diagnosis (Dx; vs 48% regional/47% metastatic); 56% of pts with a Gleason score (GS) ≥8 at initial Dx (vs 43% with <8); and 63% with private insurance (vs 48% with public). Metastatic disease at initial Dx (odds ratio [OR] 0.41), no known family history of HRRm-related cancer (OR 0.40), and a GS <8 at initial Dx (OR 0.51) were significantly associated with lower odds of HRRm testing (all p<0.05; Table). Conclusions: In this analysis, nearly half of pts did not receive a HRRm test. As with prior analyses, disparities in testing were evident for pts with a lower GS at initial Dx, metastatic disease at initial Dx and/or those without a family history of cancer, highlighting a need to increase HRRm testing in the US. Association of covariates with odds ratio for HRRm test. Covariate Odds ratio (95% confidence interval) p value Physician specialty: Urologist vs Medical oncologist 0.49 (0.19–1.30) 0.152 Age (years): ≥65 vs <65 0.91 (0.28–2.90) 0.867 Family history of HRRm-related cancer: No history vs Known history 0.40 (0.18–0.89) 0.025* Ethnicity: Non white vs White 0.94 (0.51–1.73) 0.843 Metastatic sites: Visceral metastases vs No visceral metastases 0.67 (0.35–1.29) 0.237 Gleason score: <8 vs ≥8 0.51 (0.27–0.97) 0.042* Initial diagnosis: Regional vs LocalizedMetastatic vs Localized 0.68 (0.28–1.69)0.41 (0.17–1.00) 0.408 0.049* Insurance status: Private vs Public 1.09 (0.47–2.52) 0.844 *Statistical significance ( P <0.05). HRRm, homologous recombination repair mutation.
Improving prostate cancer risk stratification using spatial single-cell tumor profiling.
413 Background: Effective prostate cancer (PCa) risk stratification is paramount to guide treatment considerations across all stages of PCa. Serum PSA, Gleason score (GS), and bulk-profiling tests (e.g. Decipher) form the cornerstone of risk stratification in clinical practice. New techniques such as Imaging Mass Cytometry (IMC) now enable tumor profiling with unprecedented resolution. We developed a novel IMC assay with the goal of identifying single cell subtypes prognostic of clinical outcomes in localized PCa. Methods: Spatial single-cell expression profiling with IMC was performed on primary PCa tumor biopsies and paired benign prostate samples obtained from patients with localized PCa who subsequently underwent radical prostatectomy. Cell subtypes were defined using the Phenograph cell-clustering approach. Per-sample “cell fraction” (percent abundance) of each cell subtype was defined as cell count of that subtype divided by total number of cells in the sample. Association between cell fraction of each cell subtype and both GS and Canary risk score was assessed using one-way analysis of variance (ANOVA) with Tukey's multiple comparison test. Biochemical progression-free survival (bPFS) and cancer-specific survival (CSS) were prespecified clinical endpoints. Analyses stratified by cell fraction tertiles were performed using the Kaplan-Meier method with Cox proportional hazards testing for significance. All hypothesis tests were performed using a two-tailed significance level of 0.05. Results: Co-expression patterns of 40 selected proteins in 3,429,844 cells comprising 604 biopsy samples obtained from 393 patients were measured. 28 of 393 patients (7%) were assigned a GS of 4+3 or higher. Single-cell clustering analysis revealed 16 distinct prostate, stromal, and immune cell subtypes including androgen-driven (AR+ PSMA+ KLK2+ CD46+) luminal prostate cancer cells (Subtypes 1, 8, 10), basal epithelial cells (Subtype 9), CD8+ T-cells (Subtype 14), CD4+ T-cells (Subtype 15), and antigen-presenting cells (Subtype 12). Subtypes 2, 7, and 9 were enriched in benign and low-risk samples; Subtypes 1, 6 and 12 were enriched in samples with GS of 4+3 or higher (P<0.001) and Canary high-risk ( P <0.01) samples. Patients with tumors enriched for Subtypes 6 and 12 demonstrated shorter bPFS ( P =0.008 and P =0.001 respectively) and shorter CSS ( P =0.02 and P =0.002 respectively) than those with tumors not enriched for these cell subtypes. Multivariable analysis including GS and Canary risk score revealed that Subtype 6 and Subtype 12 cell fraction were both independently prognostic of bPFS and CSS ( P <0.05). Conclusions: In our cohort of men with localized PCa, we identified single-cell features associated with biochemical recurrence and CSS that complement existing risk stratification approaches. Future work includes validation in independent cohorts and further investigation of spatial co-localization patterns between these prognostic cell types and neighboring cells of the tumor microenvironment.
Global real-world patients characteristics, treatment patterns, and impact of BCG shortage in patients with high-risk non-muscle invasive bladder cancer.
717 Background: Global guidelines recommend that High Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC) patients (pts) receive 1-3 years of Bacillus Calmette-Guérin (BCG) treatment (Tx). This global real-world study aimed to understand pt characteristics, Tx patterns and impact of the BCG shortage in pts with HR NMIBC. Methods: Physicians across EU5 (n=244), the US (n=55), Japan (n=44) and Canada (n=21) were recruited to the Adelphi HR NMIBC Disease Specific Programme: a cross-sectional survey with retrospective data collection extracted from medical record data for their next eight pts with HR NMIBC consecutively consulting with their physician. Tx patterns and characteristics were analysed descriptively. Data was collected from June to December 2023. Results: 364 physicians (55% urologists; 45% medical oncologists) provided data for 1930 pts with an initial diagnosis (IDx) of HR NMIBC. At IDx 73% presented with high grade T1 tumors, 21% had carcinoma in-situ, and 37% had multifocal tumors. The median time between IDx and data collection was 613 days. Tx patterns are described in the table. Of the 1395 pts who received intravesical therapy after IDx, 462 (33%) received induction Tx only, and 875 (63%) received induction followed by maintenance Tx. BCG was most commonly used induction Tx (28%), whilst 5% received intravesical chemo, similarly 56% received BCG maintenance Tx and 7% received chemo. Of those who completed BCG maintenance Tx (n=269) the median (IQR) duration was 336 (180-382) days. Physician reported BCG shortage affected 8% of HR NMIBC pts: 41% received fewer instillations, 37% received lower dosages, and 33% used different strains. Among the 29% of HR NMIBC pts who had ≥1 recurrence the median (IQR) time from IDx to 1 st recurrence was 426 (224-580) days. After 1 st recurrence, 57 pts received partial or radical cystectomies. Physicians surveyed stated that a median 20% of their overall NMIBC caseload were BCG unresponsive and 50% were BCG naïve. 45% of physicians reported having been affected by BCG shortage, ranging from 23% (Japan) to 71% (Canada), 61% reserved BCG for HR pts and 46% used intravesical chemotherapy as an alternative. Conclusions: BCG remains the most frequently prescribed Tx for HR NMIBC pts even though there have been shortage issues and many pts do not receive BCG maintenance. New Tx options that could safely reduce the amount of BCG administered without compromising pts’ outcomes are needed. Tx patterns of pts with HR NMIBC. Tx received After IDx n=1930, n (%) After 1st recurrence n=551, n (%) After 2nd recurrence n=130, n (%) TURBT + intravesical Tx 1209 (63) 194 (35) 40 (31) Other surgery + intravesical Tx 14 (1) 11 (2) 0 (0) Intravesical Tx only 172 (9) 31 (6) 10 (8) TURBT only 327 (17) 162 (29) 43 (33) Other surgery only 13 (1) 9 (2) 3 (2) Radical cystectomy only 0 (0) 44 (8) 6 (4) Other drug Tx ± surgery 88 (4) 41 (7) 9 (7) No Tx 107 (5) 59 (11) 19 (15)
Stage II embryonal predominant NSGCT: Minimizing treatment burden.
634 Background: Embryonal carcinoma predominance (ECP) in the orchiectomy specimen is linked to a higher risk of retroperitoneal and systemic relapse. Both chemotherapy and primary retroperitoneal lymph node dissection (RPLND) are recommended options for stage II disease, but the approach that minimizes treatment burden remains unclear. Methods: We queried the Indiana University Testicular Cancer Database to identify patients with non-seminomatous germ cell tumors (NSGCT) and ECP >50% in the orchiectomy specimen, stage II with retroperitoneal adenopathy <5 cm, and normal serum tumor markers. Patients with malignant transformation (n=3) or bilateral cancer (n=3) or receiving 1-2 cycles of BEP after orchiectomy were excluded (n=14). Treatment courses and outcomes were compared. Results: Between 2005 and 2022, 142 patients met the criteria. Of 67 patients who underwent primary RPLND, 62 had active EC in final pathology. Adjuvant chemotherapy (2 cycles of EP or BEP) was given to 5 patients. After a median follow-up of 37.7 months, 10 recurred, with a recurrence-free survival (RFS) of 85.1%. Following induction chemotherapy for documented recurrence, 9 patients were disease-free, with 1 disease-related death. Disease-free survival (DFS) was 98.5%. There were no in-field recurrences in the primary RPLND group. Of the 75 patients who received chemotherapy, 25 required post-chemotherapy (PC) RPLND, which revealed either teratoma or necrosis, and no active cancer was found. One recurred and needed re-do RPLND. Five patients who achieved complete remission after chemotherapy recurred, requiring second-line and high-dose chemotherapy. The RFS was 92%, with a median follow-up of 34.1 months. DFS was 97.3%. Univariate analysis showed pre-orchiectomy AFP >100 ng/mL (OR 7.6, 95% CI 1.6–54.9) and teratoma >5% in the orchiectomy specimen (OR 4.1, 95% CI 1.3–13.2) were associated with the need for PC-RPLND, but no parameters were predictive in multivariate analysis. Conclusions: Primary RPLND achieved complete remission as a single treatment modality in 85% of patients, compared to 67% for chemotherapy. Primary RPLND may reduce treatment burden in early-stage II ECP NSGCT in well-selected patients.
Avelumab maintenance therapy in patients (pts) with advanced urothelial carcinoma (UC) in Japan: Subgroup analyses by prior chemotherapy regimen from post-marketing surveillance (PMS).
692 Background: Avelumab was approved as maintenance therapy for pts with advanced UC that has not progressed after prior first-line platinum-based chemotherapy based on results from the JAVELIN Bladder 100 phase 3 trial, which showed a significant overall survival (OS) benefit. PMS data showed the safety and effectiveness of avelumab maintenance therapy in clinical practice in Japan. We report post hoc analyses of PMS data in subgroups defined by prior chemotherapy regimen. Methods: This prospective, multicenter, observational PMS evaluated pts with advanced UC who received ≥1 dose of avelumab between Feb and Dec 2021. The observation period was ≤52 weeks from start of avelumab in all pts. Data were analyzed in subgroups defined by prior chemotherapy for advanced UC: gemcitabine + cisplatin (GC), gemcitabine + carboplatin (GCa), or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC). Pt characteristics were analyzed using descriptive statistics, and time-to-event analyses (from the start of avelumab maintenance therapy) used the Kaplan-Meier method. Results: The study cohort included 453 pts. Median age was 73 years (range, 21-91). Primary tumor site was bladder in 244 pts (53.9%) and upper tract in 209 (46.1%). Prior chemotherapy regimen was GC in 267 (58.9%), GCa in 163 (36.0%), and ddMVAC in 9 (2.0%). In chemotherapy subgroups, age was ≥75 years in 86 (32.2%), 89 (54.6%), and 1 (11.1%), and renal impairment was reported in 77 (28.8%), 82 (50.3%), and 2 (22%), respectively. At data cutoff (Mar 6, 2024), median duration of avelumab maintenance therapy was 5.1 mo (IQR, 2.3-12.0), 128 pts (28.3%) remained on avelumab, and 184 (40.6%) had received subsequent treatment. Prespecified adverse drug reactions (ADRs) of any grade were observed in 144 (31.8%) overall, and in 93 (34.8%) in the GC subgroup, 45 (27.6%) in the GCa subgroup, and 3 (33.3%) in the ddMVAC subgroup; ADRs were grade ≥3 in 36 (7.9%) overall, and in 22 (8.2%), 12 (7.4%), and 0 in subgroups, respectively. Median time to treatment failure was 4.6 mo (95% CI, 3.8-5.3) overall, and 4.6 mo (95% CI, 3.4-5.6), 4.6 mo (95% CI, 3.1-6.5), and 5.1 mo (95% CI, 1.4-11.8), in subgroups. Median OS was not reached in any subgroup; the 1-year OS rate was 77.9% (95% CI, 73.7-81.5) overall, and 79.6% (95% CI, 74.3-84.0), 73.8% (95% CI, 66.2-80.0), and 88.9% (95% CI, 43.3-98.4) in subgroups. Conclusions: This PMS represents the largest prospective observational study of avelumab maintenance therapy in pts with advanced UC in Asia. Post hoc analyses showed the acceptable safety and effectiveness of avelumab maintenance therapy in subgroups defined by prior chemotherapy regimen. Findings are consistent with analyses from JAVELIN Bladder 100 and support the favorable benefit-risk profile of avelumab in clinical practice in Japan, irrespective of prior chemotherapy regimen.
Trastuzumab Duocarmazine in Pretreated Human Epidermal Growth Factor Receptor 2–Positive Advanced or Metastatic Breast Cancer: An Open-Label, Randomized, Phase III Trial (TULIP)
PURPOSE Human epidermal growth factor receptor 2 (HER2)–targeted therapy is standard of care for HER2-positive (HER2+) breast cancer, but most patients develop progressive disease with persistent HER2 expression. No definitive treatment guidance currently exists beyond second line. Trastuzumab duocarmazine (T-Duo) is a third-generation, HER2-targeted antibody-drug conjugate that demonstrated efficacy and acceptable safety in phase I studies of heavily pretreated patients with HER2+/HER2-low breast cancer. METHODS In this open-label, randomized, phase III trial, T-Duo was compared with physician's choice (PC) in patients with unresectable locally advanced/metastatic HER2+ breast cancer with progression during/after ≥2 HER2-targeted therapies or after trastuzumab emtansine (T-DM1). The primary endpoint was progression-free survival (PFS) by blinded independent central review. RESULTS In total, 437 patients were randomly assigned 2:1 to T-Duo (n = 291) or PC (n = 146). The median age was 56.0 years (range, 24-86); most patients (93.6%) had metastatic disease. The median time from diagnosis of metastatic disease to trial entry was 3.5 years; the median number of prior HER2-targeted therapies in metastatic setting was three. The median PFS was 7.0 months (95% CI, 5.4 to 7.2) with T-Duo versus 4.9 months (95% CI, 4.0 to 5.5; hazard ratio [HR], 0.64 [95% CI, 0.49 to 0.84]; P = .002) with PC. PFS benefit was maintained across most predefined subgroups. The median overall survival (first analysis) was 20.4 (T-Duo) versus 16.3 months (PC; HR, 0.83 [95% CI, 0.62 to 1.09]; P = .153). Objective response rate was 27.8% (T-Duo) versus 29.5% (PC); other efficacy end points—clinical benefit rate, duration of response, and reduction in target lesion measurement—tended to favor T-Duo. Grade ≥3 treatment-emergent adverse events occurred in 52.8% (T-Duo) versus 48.2% (PC). CONCLUSION Treatment with T-Duo was manageable, but tolerability was affected by prevalent ocular toxicity, leading to a higher discontinuation rate in the T-Duo arm. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who have progressed during/after ≥2 HER2-targeted therapies or after T-DM1.
Management of relapsed stage I seminomatous germ cell tumor with retroperitoneal or pelvic only relapse.
630 Background: For patients (pts) with stage 1 seminomatous germ cell tumor (SGCT) on active surveillance (AS), front-line therapy depends on the location and extent of relapse. We describe the characteristics and management of pts on AS with stage I SGCT with relapse in the retroperitoneum (RP) or pelvis only. Methods: The prospectively maintained Indiana University testicular cancer database was queried for pts with stage 1 SGCT on AS w/ RP or pelvic only relapse between 1990-2024. Pts were categorized into a chemotherapy, surgery, or radiation (XRT) group based on treatment at relapse. Comparisons between groups were done using Chi-square tests for categorical variables or Kuskal-Wallis test for continuous variables. Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS) using the log rank test to compare groups. Results: We identified 71 pts with stage 1 SGCT on AS w/ relapse in the RP or pelvis only. The median age at diagnosis was 37.2 yrs (range, 19.5-74.5). IGCCCG risk was good in all pts. At time of relapse, 37 pts (52.1%) were treated with chemo, 20 with surgery (28.2%), and 14 (19.7%) with XRT. The median time to relapse on stage I AS for pts treated with chemo was 9.5 months (0.84-91.7) compared to 19.9 months (1.6-60.2) with surgery and 13.1 months (4.6-48.8) with XRT (p=0.13). Chemo regimens used were BEP X 3 (62.2%), EP X 4 (21.6%), BEP X 4 (2.7%) and other (13.5%). 68 pts (95.8%) relapsed in the RP; 3 (4.2%) relapsed in the pelvis only. All 9 pts with lymph node (LN) size >5 cm were treated with chemo. In the 32 pts with LN size <3 cm, 12 (37.5%) were treated with surgery, 12 (37.5%) with chemo, and 8 (25%) with XRT. 11 total pts (15.5%) relapsed after front-line therapy and thus required multimodality treatment. This included 8 (21.6%) in the chemo group who relapsed; 2 out of 8 required RPLND while 6 were treated with salvage or high dose chemotherapy. 1 patient (5%) in the surgery group relapsed and required chemotherapy. In the XRT group, 2 pts (14.3%) relapsed; 1 was treated with salvage chemo and 1 with surgery. With a median follow-up time of 3.03 yrs (0-14.8), the 2-yr PFS for pts treated with chemo was 73.8%, surgery was 95%, and XRT was 92.3% (p=0.14). 2-yr OS was 100% for all treatment groups (p=0.58). Conclusions: In pts on AS with stage I SGCT w/ RP or pelvic only relapse, there was no difference in survival outcomes based on front-line therapy received. In this cohort of pts carefully selected for RPLND, the majority were cured with single-modality therapy; most of these pts had RP lymph nodes <3cm with a longer median time to relapse while on AS.
Pathological complete response and potential for bladder preservation by theranostic instillation therapy targeting CXCR4 in combination with systemic chemotherapy: The Bladder BRIDGister experience.
691 Background: Patients with muscle invasive urothelial carcinoma (MIBC) achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NACT) have improved prognosis. Previously we did show that luminal tumors respond better to NACT (Ecke et al 2022), while chemoresistant tumors express radioligand targets CXCR4 and FAP. First-in-Human treatment of chemotherapy resistant T4 MIBC using two cycles of Lu 177 FAP combined with one cycle of pembrolizumab results in durable complete response (Baum et al, submitted). The objective of this study was to eradicate treatment naïve T2a MIBC with limited probability to respond to chemotherapy by adding intravesical Lu 177 CXCR4 instillation into the bladder before first NACT cycle to justify subsequent adopted clinical trials. Methods: A reference cohort (n=100) for subtype classification was constructed. RNA from FFPE tissues was extracted, relative gene expression of luminal and non-luminal target were analyzed by RT-qPCR. FFPE tissue from initial TURB of MIBC patients under evaluation for subsequent therapy were analyzed accordingly and individual target mRNA were added to the cluster analysis to determine subtype and target expression level. PET/CT Imaging by Ga 68 CXCR4 was performed in selected patients. In case of tumor specific, high uptake subsequent Lu 177 CXCR4 was instilled one week before initiation of ddMVAC. Response was evaluated by Ga 68 CXCR4 PET/CT and control resections by TURB. Results: A luminal pT2 G3 MIBC patient with elevated CXCR4 expression level by RT-qPCR and validated by immunohistochemistry, who was predicted to be unresponsive to NACT, was selected for CXCR4 instillation therapy. Subsequent Ga 68 CXCR4 whole body PET/CT proved tumor specific uptake and excluded nodal involvement as well as distant metastasis. Thereafter 4GB Lu 177 CXCR4 was applied via catheter as intravesical Radio-Ligand-Therapy (iRLT) followed by three cycles ddMVAC. Thereafter a control Ga 68 CXCR4 was performed before starting the planned second cycle of iRLT and ddMVAC. Intravesical Ga 68 CXCR4 PET/CT revealed complete response, with no tumor uptake being visible anymore. TURB including muscle tissue revealed complete absence of malignancy with only inflammatory immune reaction being left after RLT based NACT. Conclusions: Combination of molecular in vitro diagnostics identifies high risk MIBC with elevated CXCR4 target gene expression, that exhibit high radioligand uptake in vivo and are amenable for intensified treatment by adding iRLT to systemic ddMVAC treatment. First clinical results are promising and justify clinical approaches as part of phase 1 / 2 clinical trials within the Bladder BRIDGister study group with the ultimate goal of bladder preservation after pCR to neoadjuvant combination therapies.
Real world toxicity profile of enfortumab vedotin (EV) with or without pembrolizumab (P) in ultra elderly urothelial carcinoma (UC) patients (pts).
734 Background: EV is an antibody drug conjugate that was approved in the United States as monotherapy for pretreated advanced UC and, then, in combination with P in untreated pts. However, EV is associated with multiple toxicities, which are mostly non-overlapping with those of P. In the EV-302 study, grade (G) 3 or higher treatment-related adverse events (TRAEs) occurred in 55.9% of pts and led to treatment discontinuation in 35.0% of those on EV+P. Pts aged 80 years or older (i.e. the ultra elderly) are a special population, who may be particularly vulnerable to EV toxicity. Methods: This is a retrospective analysis of UC pts, who received EV monotherapy or EV+P at 2 academic institutions in Southern California from 12/2019 to 9/2024. Pts had to be aged 80 years or older at EV start to qualify and must have received at least 1 EV dose. Toxicity was graded using the CTCAE version 5 criteria. Results: A total of 26 pts were included, with 83.6% being male. Median age was 86.5 years [range, 80 to 97], with 38.5% of pts aged 80-84 years (group 1), 46.2% aged 85-89 years (group 2), and 15.4% aged over 90 years (group 3). 53.8% identified as Caucasian, 23.1% as Asian, 15.4% as Hispanic, and 7.7% as “other”. 69.2% received EV monotherapy and 30.8% EV+P. In those on EV alone, 88.9% had a prior PD-1/PD-L1 inhibitor. At time of data cut off, 27.0% of pts were still receiving EV. Median number of EV infusions given was 10.5 [range, 2 to 25], while median number of weeks on EV was 19.5 [range, 1 to 52]. In group 1, starting EV dose was 1.25 mg/kg in 30.0% of pts and 1.0 mg/kg in 70.0%. In group 2, starting EV dose was 1.25 mg/kg in 16.7% of pts, 1.0 mg/kg in 25.0%, 0.75 mg/kg in 41.7%, and 0.5 mg/kg in 16.7%. In group 3, starting EV dose was 1.25 mg/kg in 25.0% of pts, 1.0 mg/kg in 50.0%, and 0.5 mg/kg in 25.0%. After EV start, 50.0% had at least 1 EV dose reduction, 42.3% had at least 1 dose delay, and 30.8% had EV discontinued due to TRAEs. Toxicity severity in the overall study population was as follows: G0 in 26.9%, G1 in 30.8%, G2 in 26.9%, and G3 in 15.4%. No G4/5 toxicities were noted. Starting EV dose and associated toxicity are outlined in the table. Specific TRAEs included neuropathy in 34.6% of pts, ocular symptoms in 19.2%, rash/pruritus/fatigue/abnormal electrolytes in 15.4% each, nausea and diarrhea in 3.8% each. Conclusions: Despite its small sample size and retrospective nature, this dataset did not identify any excessive or unexpected toxicity in the ultra elderly population. More pts in groups 2/3 received up-front EV dose reduction, with less G2/3 TRAEs noted at lower starting EV doses. Up-front dose reduction of EV may be a good strategy to mitigate TRAE risk. Starting EV dose and associated EV-related TRAEs. Dose (mg/kg) % of pts % of pts with G0 TRAEs % of pts with G1 TRAEs % of pts with G2 TRAEs % of pts with G3 TRAEs 1.25 23.1 16.7 0 66.7 16.7 1.0 46.2 25.0 33.3 25.0 16.7 0.75 19.2 40.0 40.0 0 20.0 0.5 11.5 33.3 66.7 0 0
Early detection of recurrent prostate cancer using 18F-DCFPyL PET/CT PET/CT in patients with minimal PSA levels.
344 Background: PSMA PET imaging is a highly sensitive and specific imaging tool for detecting prostate cancer, especially in biochemical recurrence (BCR). This has led to growing interest in utilizing PSMA PET for patients with minimally detectable PSA levels following definitive treatment as conventional imaging rarely localizes recurrent disease in this range, potentially delaying diagnosis and appropriate management. However, there is limited literature on the detection rate of 18F-DCFPyL at very low PSA levels in the BCR setting. Methods: This is a pooled retrospective analysis of patients from investigator-initiated trials at West Los Angeles Veterans Affairs and the phase III CONDOR trial with minimal PSA levels. Patients included had 18F-DCFPyL PET/CT at minimal PSA values (0.05 to 0.5 ng/ml). BCR was defined as rising PSA and patients were included irrespective of prior conventional imaging findings. The PET/CT scan reads were assisted by the automated Prostate Cancer Molecular Imaging Standardized Evaluation (aPROMISE) platform. The results were verified by an experienced and independent nuclear medicine physician. Primary analysis focused on the detection rate defined as the number of patients with positive PSMA lesions relative to total number of patients with BCR. Results: In total 129 patients were identified, 36 with PSA levels ranging from 0.05 to 0.2 ng/ml, and 93 with PSA levels >0.2 to 0.5 ng/ml. The site of positive findings, the intensity and volume of uptake in the 18F-DCFPyL PET/CT scan are detailed in the table below. Conclusions: 18F-DCFPyL PET/CT demonstrates high detection rate for recurrent prostate cancer even in patients with minimally detectable PSA levels, highlighting its potential as a valuable tool in early identification of metastatic disease. These findings suggest that current thresholds for initiating PSMA PET/CT imaging in BCR patients may need reconsideration to optimize early detection and subsequent clinical management. Further studies are necessary to refine guidelines and assess the cost-effectiveness of incorporating PSMA imaging at very low PSA levels. 0 – 0.2 (N=36) 0.2 – 0.5 (N=93) Total Detection Rate 13 (36%) 47 (51%) Prostate Bed 3 (8%) 4 (4%) Lymph Node Only 5 (14%) 29 (31%) Lymph Node and Bone 12 (33%) 39 (42%) Bone Only 8 (22%) 14 (15%) Visceral (Lung or Liver) 1 (3%) 10 (11%) Total SUVmean 3.8 4.2 Total SUVmax 10.9 12.4 Total disease volume (mean) 4.9 ml 1.9 ml
Analysis of gene expression signatures in prostate cancer prior to liver metastases.
206 Background: It has been recognized that as a prostate cancer (PCa) metastasizes to bone, it begins to express bone-specific proteins such as osteopontin, bone sialoprotein, and osteocalcin. This process is known as osteomimicry. Liver metastases (LM) are associated with the poorest clinical outcomes and affect 25% of PCa patients at autopsy. We hypothesized that PCa that metastasize to the liver express liver-specific genes prior to liver metastasis – a process we have named “hepatomimicry”. Methods: We have curated a list of 23 putative genes that are both primarily expressed in the liver and found in RNA-seq data from over 3000 PCa samples. Initial sources included the PCa transcription atlas (n = 2115), West Coast/SU2C Dream Team (n = 210), neuroendocrine PCa from cBioPortal (n = 49), and TEMPUS RNA-seq data generated specifically for Cedars-Sinai (n = 88). In each dataset, for the 23 hepatomimicry genes, we used recursive feature elimination and a t-test to discriminate between PCa LM and non-liver visceral metastases. In datasets with count-level data, we performed differential gene expression analysis with DeSeq2 and gene set enrichment analysis (GSEA) on identified differentially expressed genes. Results: In three different datasets, MAT1A, ELF3, and WEE1 were found to be either optimal genes for discriminating between these two groups or significantly different by t-test and were more highly expressed in LM. 270 genes were downregulated and 437 genes were upregulated in liver metastases (FDR q-value < 0.05, log2 fold change > 1 for upregulated and < -1 for downregulated). Subsequent GSEA found that liver-specific gene sets are highly enriched in the genes upregulated in LM, and endothelial cell genes are strongly downregulated. Conclusions: The initial results indicate that a three-gene subpanel of our initial set have predictive power for LM against other visceral metastases in PCa.While hepatocyte infiltration may impact the characterization of these samples by yielding a strong signal for liver-specific gene expression signature, confirmation of this finding remains important. Ongoing work is directed at confirming this signature in single-cell RNA-seq from PCa LM. Our work may be adaptable to developing diagnostic technologies such as liquid biopsies that may enhance the identification of patients who may have occult LM or that may develop LM as part of their natural history so that interventions may be enacted in a more timely manner.
Patient characteristics and survival in primary prostate sarcomas: An analysis of the SEER database.
271 Background: Primary prostate sarcoma (PPS) is a rare neoplasm of prostate and is associated with poor survival outcome. Methods: We conducted an analysis of patients with PPS in the Surveillance, Epidemiology, End Results (SEER) database from year 2000 to 2020. Patients were identified by using the primary cancer site codes for prostate as well as histological codes (ICD-O-3) that matches the list of sarcoma histology found in the NCCN soft tissue sarcoma and bone cancer guidelines. Data for demographics, disease extent and median overall survival (OS) were obtained. Sarcomas mixed with carcinomas, so-called carcinosarcomas, were included in the analysis. OS data of prostate adenocarcinoma from same database were obtained for a comparison. Results: During the period analyzed, a total of 1,120,527 patients with primary prostate neoplasms were identified. Among them, 239 patients (0.0002%) had PPS. Majority were Caucasian (67.8%) followed by Hispanics (13.4%) and African Americans (8.8%). The most common histology was rhabdomyosarcoma (28.5%), followed by leiomyosarcoma (21.8%), carcinosarcoma (16.7%), and unspecified sarcomas (8.8%).Among 221 patients with known extent of disease, 29.4%, 37.1% and 33.5% had localized, locoregional and distant metastatic disease, respectively. Overall, PPS was associated with worse OS than prostate adenocarcinoma (28 months vs. 183 months, P<0.01). OS for patients with localized, regional, and distant diseases were 54, 39, and 18 months, respectively (P=0.04). Patients with carcinosarcomas had worse OS than those with pure sarcomas (15 months vs. 34 months, P<0.001). Among patients with locoregional disease, 19 (14.2%) received chemotherapy only, 84 (62.7%) received surgery only, and 31 (23.1%) received both chemotherapy and surgery. Median OS was not reached in those with locoregional disease who did not receive surgery while it was 44 months in those who received surgery (P=0.055). As for those with distant metastasis, 37 (56.1%) received chemotherapy only, 13 (19.7%) received surgery only, and 16 (24.2%) received both chemotherapy and surgery. Median OS for those with metastatic disease who received chemotherapy versus no chemotherapy was 9 months versus 19 months (P=0.063). Conclusions: PPS was rare and associated with worse survival outcome compared with prostate adenocarcinomas. Carcinosarcomas were less common than pure sarcomas and were associated with worse survival than pure sarcomas.
A phase 2 study of cabozantinib in combination with atezolizumab as neoadjuvant treatment for muscle-invasive bladder cancer, (HCRN GU18-343) ABATE study.
800 Background: Atezolizumab (A) has demonstrated single agent activity as neoadjuvant therapy (NAT) for muscle invasive urothelial carcinoma (MIUC) (ABACUS trial). Cabozantinib (C) has a unique immunomodulatory profile that may foster anti-tumor immunity and has demonstrated clinical activity as monotherapy and in combination with A. We hypothesized that the combination of C and A as NAT for MIUC would improve pathologic response rate (pRR) compared to single-agent A. Methods: This open-label, single arm, multi-center study investigated the efficacy and safety of C 40 mg PO daily with A 1200mg every 3 weeks for 9 weeks as NAT for cT2-T4aN0/xM0 MIUC. Eligibility required patients (pts) to be cisplatin-ineligible or decline cisplatin, with UC as the predominant histology (≥ 50%). Primary endpoint was pRR defined as no residual muscle-invasive cancer in the surgical specimen (< ypT2); patients with progression prior to cystectomy were counted as non-responders. pRR was to be compared to the 39% response rate with the single agent A using a Bayesian evaluation with a Beta (0.5, 0.5) prior. Secondary endpoints were safety and toxicity, pathologic complete response rate (pCR, ypT0N0M0) and event-free survival (EFS). Exploratory end points included patient-reported outcomes and outcome associations with biomarkers. Results: From Feb 2021 to July 2024, 46 pts enrolled at 5 sites. 2 pts were deemed ineligible, and 6 pts did not proceed with cystectomy for reasons other than progression (4 pts opted for bladder preservation, 1 pt died from causes unrelated to tx and 1 pt still undergoing tx). Median follow up is 14 mo. At study entry median age was 71 yrs, 21% were female, 98% Caucasian and 71% were cisplatin ineligible, with T2, T3 and T4 disease in 73%, 18% and 9% respectively. Histology included pure urothelial cancer (56%), squamous (18%), glandular (3%), micropapillary (18%) and plasmacytoid (5%) differentiation. Among 35 pts who underwent cystectomy, 32 (91%) / 3 (9%) completed 3 and 2 doses of A and 15 (43%) / 32 (91%) completed 9 and at least 6 weeks of C. Adverse events are being analyzed. The estimated pRR was 29.5% (95% CrI 16.5% - 44.5%) and the pCR was 20.8% (95% CrI 9.4% - 35.3%). The pCR was lower in pts with variant histology compared to pure UC (13 vs 25%; p=0.39). 2-year EFS was 68.4% (95% CI, 47.7-82.3%). Conclusions: C+A has modest activity as NAT in MIUC and did not meet the pre-specified primary endpoint for pRR. Biomarkers studies are planned. Clinical trial information: NCT04289779 .
OCOG-RATIONAL: A phase II randomized trial of optimal recurrence-directed therapy (RDT) without or with androgen-deprivation therapy (ADT) in radio-recurrent oligo-metastatic castrate sensitive prostate cancer (romCSPC).
TPS305 Background: This is a Canadian, multi-center study that investigates whether addition of ADT to RDT improves oncological outcomes in early romCSPC. The primary outcome is a 36-month composite Progression-free survival (cPFS). Secondary outcomes include metastasis-free survival, time to salvage therapy, time to castrate-resistant PC, OS, Quality of Life and toxicity. Methods: Population: Patients with biochemical recurrence after definitive or adjuvant/salvage radiotherapy for localized prostate cancer (PC) with oligo-metastatic disease (≤5 sites) without or with local recurrence. All patients will be staged with conventional imaging (CT/BS), mpMRI, PSMA-PET and biopsy of the prostate if in situ. Randomization: Patients are randomized 1:1 to RDT versus RDT+ADT for 12 months and stratified for, i) presence of local recurrence (Y/N), ii) volume of metastatic disease [0 (local recurrence alone) versus 1-3 versus 4-5 metastases]. iii) treatment centre, and iv) metastasis detected on conventional imaging (Y/N). Interventions: RDT options include Stereotactic Body Radiotherapy (SBRT), hypo-fractionated radiotherapy (HFRT), brachytherapy and surgical resection. Concurrent and adjuvant ADT involves four 3-month leuprolide acetate injections. Statistics: A clinically meaningful improvement for the use of ADT is defined as an improvement in the 30-month cPFS of ≥20% (from 50% to 70%). With an expected accrual period of 3 years, an additional 1 year of follow-up, a 1-sided log-rank test with α=0.05 would have over 80% power to distinguish between the two group with 73 patients in each arm. This number is inflated by 10% for stratification factors and patients lost-to-follow-up, for a total of 162 patients. Coordination: The study is coordinated by the Ontario Clinical Oncology Group (OCOG) and is expected to open in 10-12 institutions across Canada. This trial will provide evidence on the impact of ADT in romCSPC managed with optimal recurrence directed therapy. Findings will support phase III trial design to help define the optimal management of romCSPC in the future. Clinical trial information: NCT06654336 .
A phase III study testing the role of proactive coaching on patient reported outcome in advanced or metastatic renal cell carcinoma treated with sunitinib or a combination of axitinib + pembrolizumab or avelumab in first line therapy (PREPARE; AIO-NZK-0115/ass).
523 Background: Tyrosine kinase (TKI) and immune checkpoint inhibitors (CPI) are first-line options in metastatic renal cell carcinoma (mRCC). Most patients (pts) experience adverse events (AE) and 20-30% discontinue therapies due to AEs. We tested whether proactive onco-coaching (POC) improved quality of life (QoL) in patients with medical treatment. Methods: Adult treatment-naïve mRCC pts who were candidates for sunitinib (SU), axitinib + avelumab (AA) or axitinib + pembrolizumab (AP) were eligible. Treatment and modifications were at the physician's discretion. Pts were 1:1 randomized to POC by a trained nurse (8 visits of structured interviews educating on preventive, preemptive and supportive measures, and phone call follow-up for a total of 24 wks) or standard of care (SOC). Primary endpoint was the fraction of pts with QoL improvement (QOLI) by ≥3 points (minimal important difference: MID) of the FKSI-15 score. Secondary endpoints consisted of patient reported outcomes (PRO: FACT-G, EQ-5D), time to QOLI, efficacy, survival and safety (CTCTAE 4.03). The planned sample size was 430 pts. Log rank analyses were employed for time to event endpoints and Fisher exact tests for categorical data. Results: Between 2016 and 2023, 113 pts were included. Median age was 72 and 68y (POC vs. SOC). 44% had a Charlson Comorbidity Index (CCI) ≥2. MSKCC good/intermediate/poor risk were 21/61/12%. 86% had clear cell histology. Of 110 treated patients, 39% and 61% received SU or AXI-CPI (AA or AP). FKSI-15-completion rate was 85%. 80 pts (73%) had ≥2 PRO assessments and were evaluable for the primary endpoint. There was no difference in QOLI between POC and SOC (43.6% vs. 41.5%; p=0.95). Mean baseline FKSI-15 score was similar between arms, as were ORR (38.2 [95% CI 25.4-52.3] vs. 34.5% [95% CI 22.2-48.6]; p=0.96) and PFS (11.1 [95% CI 8.3- 18.9] vs. 9.2 mo [95% CI 5.6-14.6]; p=0.21). Overall survival was favored by POC (median 49.6 [95% CI 30.6- 61.6] vs. 25.4 mo [95% CI 17.8-NC]; p=0.11). Stratification by CCI had no relevant effect on OS in the POC arm (p=0.26), while pts. with CCI ≥2 had poorest OS in the SOC arm (15.7 vs. 33.4 mo; p=0.002). Treatment related AEs of any or ≥3 grade affected 96.4% and 52.7% with POC and 85.5% and 36.4% with SOC. Discontinuation due to toxicity between POC vs. SOC occurred for TKI in 7.3 vs. 9.1% and for CPI in 18.2 vs. 5.5% pts. Conclusions: Target patient accrual was not reached, and POC did not improve the rate of QoL responders or treatment efficacy. However, there was a trend towards a considerable extension of OS in the POC group, suggesting an overall beneficial impact of proactive coaching compared to standard reactive therapy management. Comorbid patients putatively benefit most from pro-active coaching, which warrants further studies. Clinical trial information: NCT03013946 .
Population-adjusted network meta-analyses (NMA) to evaluate the efficacy of treatment alternatives for metastatic hormone-sensitive prostate cancer (mHSPC).
267 Background: Existing NMA in mHSPC compare treatments assuming homogeneity in treatment effect modifiers across study populations. However, evidence suggests that these effects vary in mHSPC. This study employs the recent methods of multilevel network meta-regression (ML-NMR) and network meta interpolation (NMI) to adjust for population differences and predict relative effect estimates for an ARASENS-like target population. Methods: We used a systematic literature review to identify studies for our NMA on overall survival (OS) in mHSPC. We applied ML-NMR to adjust for imbalances in treatment effect modifiers by integrating individual patient data (IPD) regression from the ARASENS trial across the covariate distributions of comparator studies. The IPD was reconstructed from Kaplan-Meier curves for aggregate data studies, incorporating covariates age, ECOG performance status, Gleason score, and disease volume. Utilizing the same set of variables, NMI was employed to analyze subgroup data from comparator studies using reported hazard ratios. Results: Twelve studies were identified for inclusion in our analyses. The ML-NMR demonstrated a significant benefit for the darolutamide (daro) triplet compared to enzalutamide + ADT, apalutamide + ADT, abiraterone + ADT, and the abiraterone triplet in the ARASENS-like population. However, in the NMI analysis, the daro triplet was significantly favored over abiraterone + ADT when compared to other commonly utilized alternatives (Table). A key strength of the ML-NMR over NMI is that it only requires baseline characteristics to be reported, rather than subgroups which were relatively poorly reported or not powered to detect statistically significant differences. The NMI method suffered due to incomplete subgroup data, with full data for effect modifiers available in 8/12 studies. Conclusions: Both ML-NMR and NMI analyses support triplet benefit with ADT + docetaxel + daro in improving OS for patients with mHSPC. The evidence from ML-NMR is particularly robust, benefiting from the better covariate data and the attendant decrease in uncertainty. Hazard ratio from ML-NMR and NMI. Daro + docetaxel + ADT versus ML-NMR: OSHR (95% CrI) NMI: OSHR (95% CrI) SNA+ADT 0.28 (0.17, 0.46)* 0.36 (0.23, 0.56)* ADT 0.43 (0.32, 0.60)* 0.51 (0.39, 0.65)* Docetaxel + ADT 0.57 (0.42, 0.77)* 0.68 (0.57, 0.80)* Enzalutamide + ADT 0.64 (0.44, 0.96)* 0.80 (0.57, 1.11) Apalutamide + ADT 0.68 (0.46, 1.00)** 0.75 (0.55, 1.03) Abiraterone + ADT 0.65 (0.45, 0.92)* 0.65 (0.52, 0.81)* Abiraterone acetate + docetaxel + ADT 0.66 (0.47, 0.93)* 0.89 (0.59, 1.34) CrI: credible interval, SNA: standard nonsteroidal antiandrogen, ADT: androgen deprivation therapy, *upper CrI did not cross the line of no effect, **rounding, upper CrI limit treated as below 1.00.
Phase I dose-escalation study of the next-generation nectin-4 targeting antibody–drug conjugate CRB-701 (SYS6002) in US and UK patients with urothelial cancer and other solid tumors.
807 Background: Linker conjugation chemistry is a key determinant of antibody–drug conjugate (ADC) activity and tolerability. Linkers must be stable in the systemic circulation and allow efficient drug release at the target site for maximal intra-tumoral drug delivery. CRB-701, a next-generation nectin-4 targeted ADC, has third-generation linker technology that is specifically designed to reduce the dose-limiting toxicities (DLTs) reported with ADCs (e.g. enfortumab vedotin [EV]). In nonclinical studies, CRB-701 demonstrates preferential internalization-mediated payload release and a longer half-life than EV, which may reduce free monomethyl auristatin E (MMAE)-related toxicities and enable less frequent dosing. Following the first-in-human study (SYS6002-01), we present results of a phase I dose-escalation study conducted in a Western population. Methods: A Bayesian Optimal Interval design with 4 dose groups (1.8, 2.7, 3.6 and 4.5 mg/kg; each once every 3 weeks) was used to determine the maximum tolerated dose and the optimal doses for phase II evaluation (CRB-701-01; ClinicalTrials.gov identifier, NCT06265727). Patients with advanced solid tumors who failed or were intolerant to standard treatment were enrolled. Retrospective H-scores were obtained to confirm nectin-4 positivity. Safety, tolerability, pharmacokinetics (PK) and preliminary antitumor activity were assessed. Results: Patients with metastatic urothelial cancer, cervical cancer, endometrial cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer or triple-negative breast cancer were enrolled (N = 31). Patients had failed all potentially available, appropriate prior therapies. All 4 dose cohorts were enrolled; maximum patient follow-up was 23 weeks. No DLTs occurred. Most adverse events (AEs) were grade 1 or 2 in severity. Grade 1 or 2 treatment-related AEs reported in >20% of patients included corneal epithelial lesions, hematuria, hypertriglyceridemia, hyponatremia, proteinuria, anemia and dry eye. Skin rash (grade 1 or 2), neutropenia, fatigue and peripheral neuropathy were less frequent than expected for an MMAE-based ADC; longer-term data will be reported at the congress. CRB-701 demonstrated linear PK across all doses with limited accumulation. Antitumor responses were observed at multiple doses, with the first partial response at the lowest 1.8 mg/kg dose (confirmed responses will be presented). Conclusions: PK, safety andefficacy observations are consistent with those from a previous study in Han Chinese patients. CRB-701 was well tolerated and, relative to EV at similar doses, demonstrated signs of a differentiated PK profile, including a longer half-life and lower free MMAE levels. CRB-701 development will continue to dose expansion. Clinical trial information: NCT06265727 .