Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers
. Biomarkers may facilitate identification of these ...responding tumors
. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer
. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
The MAJA study compared vinflunine (VFL) plus best supportive care (BSC) maintenance therapy versus BSC alone in advanced urothelial carcinoma responsive to first-line chemotherapy. The primary end ...point of progression-free survival was achieved. We present the final overall survival (OS) and long-term follow-up safety analyses.
Patients were enrolled, and a subsequent post hoc analysis was performed on the basis of radiologic response or stabilization to first-line cisplatin/gemcitabine (CG) chemotherapy (4-6 cycles), according to Response Evaluation Criteria in Solid Tumors (RECIST). VFL + BSC versus BSC alone were randomly assigned until disease progression.
At final analysis, 58 patients (66.7%) had died while 29 (33.3%) had survived; the BSC arm had higher mortality (VFL + BSC, n = 26, 59.1% vs. BSC, n = 32, 74.4%). Median follow-up of surviving patients was 38.8 months (interquartile range, 23.8-61.6). Median OS was 16.7 months (95% confidence interval, 0-34.5) in VFL and 13.2 months (95% confidence interval, 6-20.4) in the BSC groups (hazard ratio, 0.736; 95% confidence interval, 0.44-1.24, P = .182). Post hoc group division did not affect median OS in either study arm.
Final analysis supported a benefit of VFL in maintenance therapy in patients with disease control after first-line treatment with CG, with no unexpected long-term adverse effects. The study was insufficiently powered to show a significant OS advantage.
Current first-line treatment for advanced urothelial carcinoma has a limited duration of response. The MAJA study aimed to compare vinflunine (VFL) plus best supportive care (BSC) maintenance therapy versus BSC alone in 88 patients after first-line treatment with cisplatin/gemcitabine. Results demonstrated a progression-free survival benefit and a positive OS trend (with limited power due to the small sample size) with VFL in maintenance therapy with no unexpected long-term adverse effects.
Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC).
To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and ...circulating tumor DNA (ctDNA) in the ABACUS trial.
ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy.
Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected.
The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements.
The median follow-up time was 25 mo (95% confidence interval CI 25-26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21-41). Two-year DFS and OS were 68% (95% CI 58-76) and 77% (95% CI 68-85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65-94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio HR 0.60 95% CI 0.24-1.5, p = 0.26, and 0.72 95% CI 0.31-1.7, p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 95% CI 0.09-0.68, p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 95% CI 1.3-13, p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work.
Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future.
We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy.
Purpose: The purpose of this study is to assess the correlation between metabolic response with fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and pathological ...response in patients with locally advanced esophageal cancer treated with neoadjuvant chemoradiotherapy and to study FDG-PET parameters for the prediction of pathological response and outcome. Methods: Twenty-five patients with locally advanced esophageal cancer underwent two FDG-PET/CT scans for initial staging and after neoadjuvant chemoradiotherapy. FDG uptake in the primary tumor was calculated in both scans (SUVmax, SULpeak, and TLG). Metabolic response was assessed according to the reduction of PET parameters: complete response (mCR = 100%), partial response (mPR ≥50%), and no response (mNR ≤50%). Pathological response was also classified as complete (pCR), partial (pPR), or no response (pNR). Patients were followed up (range, 8-99 months) determining free-disease interval (FDI) and overall survival (OS). Results: Two patients were excluded due to exitus for nonesophageal-related causes. The metabolic response was observed in 18/23 remaining patients (3mCR, 15 mPR), of which 12/18 patients showed a pathological response (3 pCR, 9 pPR). A major discrepancy was observed in 2 mNR patients who achieved pPR. FDI and OS were longer in patients with metabolic response than nonresponders, but no statistical difference was found. No significant correlation was found between PET parameters and pathological response, FDI, and OS. Conclusions: FDG-PET/CT is a useful technique to assess response to neoadjuvant chemoradiotherapy in esophageal cancer. Although in this preliminary study, no correlation between metabolic and pathologic response was found and no statistical differences between responders and nonresponders were observed, a tendency of longer FDI and OS was apparently found in responders patients.
5090 Background: The androgen receptor (AR) plays a predominant role in prostate cancer (PC) biology and it represents a cornerstone of PC treatment strategies, including androgen deprivation therapy ...(ADT) and androgen receptor selective inhibitors (ARSI). However, the androgen receptor splice variant 7 ( ARV7) has emerged as a biomarker for resistance to AR target therapies. In this study we aim to investigate a signature of AR-regulated genes and the ARV7 in a cohort of metastatic hormone-sensitive prostate cancer (mHSPC) patients (pts). Methods: This is a multicenter retrospective biomarker study performed in mHSPC pts treated with ADT, ADT+Docetaxel (D) and ADT+ARSI (abiraterone/enzalutamide). A customized panel of 184 genes was tested in from FFPE tumor samples by nCounter platform (Nanostring Technologies). AR signature was comprised of 31 AR-related genes. Single-sample GSEA (ssGSEA) was used to calculate a gene-set enrichment score per patient. RNA expression levels were correlated with castration resistance-free survival (CRPC-FS) (primary endpoint) and overall survival (OS) by Kaplan Meier and multivariate Cox modeling. Analyses were performed with R software (v.4.3.2). Results: A total of 326 pts were included: 93 treated with ADT, 125 with ADT+D, and 108 with ADT+ARSI. Baseline PSA was 44 ng/ml (range 0.2–7448), Gleason score was ≥ 8 in 72.7% of pts, 15.3% had visceral metastasis, 64.6% had high volume disease and 77.9% were de novo stage IV disease. Median follow-up was 39.5 months (m) (95%CI 4.4–223.5). Median time to CRPC was 21.7 m (95%CI 19.4–25.9) and median OS 49.1 m (95%CI 43.9–57.1). Among the 326 pts, 108 (33.1%) were classified as high AR signature, while 81 of them (24.8%) were considered high ARV7. High AR signature expression levels were associated with less frequency of visceral metastasis ( p=0.01) and high ARV7expression correlated with higher Gleason scores ( p=0.009). High AR signature expression independently correlated with longer CRPC-FS (33 vs 19.3 m; HR 0.7, p=0.011). Considering AR signature individual genes as continuous variables in the multivariate analysis, the high expression of four genes was independently associated with longer CPRC-FS: KLK3 (HR 0.9, p=0.024), KLK2 (HR 0.9, p=0.027), CD200 (HR 0.8, p=0.028), and GNMT (HR 0.9, p=0.013). Besides, the high expression of these genes was independently associated with longer OS: KLK3 (HR 0.8, p<0.001), KLK2(HR 0.9, p=0.014), CD200(HR 0.8, p=0.014), ACSL3(HR 0.8, p=0.015), and PTGER4 (HR 0.8, p=0.04). Focusing in the ARV7gene, a high expression of ARV7 was independently associated with shorter OS (43.2 vs 52.2 m; HR 1.4, p=0.028). Conclusions: High expression of the AR signature correlates with a better prognosis in mHSPC pts, while high expression of ARV7is associated with adverse clinical outcomes. This may be useful as a potential biomarker to personalize treatment strategies.
TPS238
Background: Metastatic prostate cancer is usually dependent on the androgen receptor (AR) pathway. However, around 20% of metastatic prostate cancers are AR independent with an aggressive ...behavior. Aggressive Variant mCRPC (AVPC) is considered a distinct entity and it has been defined by seven clinical-pathological criteria (AVPC-C). These tumors have poor response rates to conventional treatments and increased sensitivity to platinum-based combinations. Carboplatin (CBDCA) and cabazitaxel is a recommended regime in this scenario (Corn PG. Lancet Oncol 2019). These tumors are excluded from many mCRPC clinical trials and treatment options remain an unmet medical need. Methods: This is a multicentre, single-arm, phase 2 study that will investigate the activity of the combination of CBDCA, cabazitaxel and pembrolizumab in patients with AVPC. Patients will receive an induction phase consisting of 6 cycles of CBDCA area under the curve (AUC) 4 plus cabazitaxel 25mg/m
2
plus pembrolizumab 200mg on day 1 of each 3-week cycle. After induction, a maintenance phase will follow, with pembrolizumab 400mg administered every 6 weeks for 15 cycles or a total of 2 years. An initial cohort of 6 patients will be treated for an initial safety assessment. If ≤ 1 DLTs are observed an additional 36 patients will be enrolled at the same doses. Key eligibility criteria include at least 1 of the AVPC-C: histologically proven small cell or neuroendocrine differentiation, exclusive visceral metastases, predominantly lytic bone metastases (investigator criterion), bulky lymph nodes (≥ 5 cm in longest dimension) or high grade pelvic/prostatic masses, low PSA (≤10 ng/ml) at diagnosis in the presence of extensive disease (≥20 metastases), elevated serum LDH (≥2 x ULN) or CEA (≥2 x ULN) and time to castration resistance ≤6 months. Prior therapy with docetaxel and/or novel hormonal agents is allowed. The primary endpoint is 6-months radiographic progression-free survival (rPFS), by Prostate Cancer Working Group 3 (PCWG3) criteria and secondary endpoints are 12-months rPFS; response rate and PSA response by PCWG3, PSA PFS, overall survival and safety. A sample size of 42 patients achieves 80% power at a 0.05% significance level to detect an improvement of 20% in 6m-PFS. Imaging tumor assessments with CT scans and bone scintigraphy, and PSA will be done every 6 weeks in the first 24 weeks, every 12 weeks after first 24 weeks and at the end of treatment (EOT). Correlative studies will evaluate exploratory biomarkers as potential predictive/prognostic factors. Assessments include blood samples at baseline, 12 weeks after starting treatment, at the end of chemotherapy and at the EOT. Baseline FFPE tissue will be collected if obtained in the previous 12 months, or newly obtained tumor biopsy. This study was approved by a Central Institutional Review Board. Clinical trial information: NCT05563558 .
198
Background: Genomic alterations in PTEN are associated with an aggressive disease and treatment resistance in patients (pts) with castration-resistant prostate cancer (PC). The aim of the present ...study is to characterize the molecular alterations associated to tumor PTEN-low mRNA expression in different cohorts of metastatic hormone-sensitive PC (mHSPC) pts and its prognostic value. Methods: This is an ongoing multicenter ambispective study enrolling mHSPC pts receiving different treatment strategies. PTEN status was assessed in FFPE tumor samples by mRNA expression by nCounter and RNA-seq. PTEN expression was correlated with castration resistance-free survival (CRPC-FS) and overall survival (OS) by Kaplan Meier and multivariate Cox analysis. Results: 297 pts were included: 125 treated with ADT + docetaxel (ADT+D), 79 with androgen deprivation therapy (ADT) + abiraterone or enzalutamide (A/E) and 93 with ADT alone. Median follow-up of 46.3 months (m) (6.7-223). Median age was 66.4 years, 75.7% of pts presented de novo stage IV and 67.9% had high-volume disease. RNA-seq analysis was performed to assess differences in gene expression between low vs. high/medium PTEN expression tumors in 66 pts. There was a significant correlation between PTEN expression detected by nCounter and by RNASeq (p=8.7e
-11
). Differential expression analysis found 13 genes differentially expressed (padj<0.05 &abs(LFC)>0.26) in PTEN-low (25.8%) vs the rest, including PTEN and 2 novel transcripts (Table). In the functional analysis PTEN-low tumors had overexpression of several pathways including cell cycle, DNA repair, metabolism and immune regulatory response, and infraexpression of the androgen-response hallmark. In the whole cohort (n=297 pts), PTEN-low (30.5%) was independently associated with low CRPC-FS (HR 1.8 (95% CI, 1.3 – 2.4), p=8.7e
-5
) and OS (HR 1.7 (95% CI, 1.2 – 2.2), p=0.0038). Conclusions: Lower expression of PTEN correlates with a distinct molecular profile and a more aggressive disease in pts with mHSPC, supporting the development of new therapeutic strategies in pts. Table: see text
5083
Background: Alterations on the tumor suppressor genes (TSG) RB1, PTEN and TP53 are associated with treatment resistance and aggressive clinical evolution of prostate cancer patients (pts). Here, ...we developed and validated a TSG gene expression signature in mHSPC pts. Methods: This is a multicenter retrospective biomarker study in mHSPC pts. Mutations on TSG were assessed by targeted sequencing, mRNA expression by nCounter platform and protein by IHC in FFPE tumor samples. Expression data of the training cohort were used to establish the cut-off applied to the other cohorts. TSGlow was considered when ≥2 out of 3 TSG presented low expression and TSGwt in the remaining cases. CHAARTED trial pts with microarray data (Hamid, Ann Oncol, 2021) were analyzed as an independent validation cohort. TSG signature was correlated with castration resistance-free survival (CRPC-FS) (primary endpoint) and overall survival (OS) by Kaplan Meier and multivariate Cox analysis. Results: 218 pts were included: 125 treated with ADT + docetaxel (ADT+D) and 93 with ADT. 160 pts from the CHAARTED dataset were analyzed (84 with ADT+D and 76 with ADT). ADT+D pts with available TSG gene expression and targeted sequencing were considered as the training cohort (n=54). Pts with low PTEN and RB1 gene expression had lower IHC expression (p<0.01). Low PTEN pts had a higher frequency of PTEN mutations (p<0.05). TSGlow (25.9%) pts had a worse CRPC-FS (14.3 vs 21.7 months (m); HR 2.2 (95% CI, 1.1 – 4.4) p=0.022). In the internal validation cohort of ADT+D-treated pts (n=71), TSGlow (9.9%) correlated with a worse CPRC-FS (11.7 vs 20 m, p=0.027) and OS (27.6 vs 58.1 m, p=0.012). TSGlow was independently associated with CPRC-FS (HR 2.7 (95% CI, 1.2 – 6.1) p=0.02) and OS (HR 3.7 (95% CI, 1.3 – 10.1) p=0.012). In the ADT cohort (TSGlow 21.5%), no differences in either CRPC-FS or OS were observed. When analyzed together the ADT+D and ADT cohorts, we observed that TSGwt pts treated with ADT+D had the largest CRPC-FS (21.6 m; p=0.014) and OS (58.1 m; p=0.029), while TSGlow pts receiving ADT+D had a CRPC-FS and OS similar to ADT-treated pts. Similarly, in the CHAARTED dataset, TSGlow (20.2%) pts treated with ADT+D had a worse CPRC-FS (14.8 vs 29.4 m, HR 2.2 (95% CI, 1.1 – 4.3) p=0.023) and OS (32.9 vs 57.4 m, HR 2.2 (95% CI, 1 – 4.5) p=0.04). TSGlow (35.5%) was not predictive of either CRPC-FS or OS in ADT-treated pts. Analyzing together ADT+D and ADT pts, TSGwt pts treated with ADT+D had the best CRPC-FS and OS (p<0.01). Conclusions: Our results suggest that a TSGlow expression may predict the lack of benefit to taxanes in mHSPC pts, which may be useful to personalize the treatment. Table: see text
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