Radiological Progression-free Survival Research Articles

Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial.

For patients with metastatic hormone-sensitive prostate cancer (mHSPC), delaying progression to castration-resistant disease is important not only for overall survival (OS) but also for patients' quality of life . Darolutamide plus androgen-deprivation therapy (ADT) with docetaxel improved OS versus ADT and docetaxel in patients with mHSPC. The ARANOTE trial evaluated darolutamide and ADT without chemotherapy in patients with mHSPC. In this global phase 3 trial, patients were randomized 2:1 to receive darolutamide 600 mg twice daily or placebo, with concomitant ADT. The primary endpoint was radiological progression-free survival (rPFS). From March 2021 to August 2022, 669 patients were randomized (darolutamide n=446; placebo n=223). At the primary cutoff date (June 7, 2024), darolutamide plus ADT significantly improved rPFS by 46% versus placebo plus ADT (hazard ratio [HR] 0.54; 95% confidence interval [CI], 0.41-0.71; P<0.0001), with consistent benefits across subgroups, including high- and low-volume disease. OS results were suggestive of benefit with darolutamide versus placebo (HR 0.81; 95% CI, 0.59-1.12) and clinical benefits were seen across all other secondary endpoints, including delayed time to castration-resistant prostate cancer (HR 0.40; 95% CI, 0.32-0.51) and time to pain progression (HR 0.72; 95% CI, 0.54-0.96). Adverse events were similar in the two groups. Notably, the incidence of fatigue was lower in patients receiving darolutamide (5.6%) versus those receiving placebo (8.1%), and fewer patients receiving darolutamide (6.1%) versus placebo (9.0%) discontinued treatment due to adverse events. These results confirm the efficacy and tolerability of darolutamide plus ADT in patients with mHSPC, demonstrating clinically and statistically significant improvement in rPFS and a favorable safety profile consistent with prior phase 3 darolutamide trials.

Low-dose abiraterone plus Olaparib as a late-line treatment for mCRPC patients without BRCA1/2 mutations: a multicenter retrospective pilot study

Although overall survival data are still premature, the PROpel study found radiological progression-free survival (PFS) benefits of abiraterone and olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC). However, for patients who have not been genetically tested or lack BRCA1/2 mutations (BRCAm), this combination therapy has been questioned as a first-line conventional treatment for mCRPC, mainly due to significant health economics and side effects. In our retrospective study, we found that treatment with low-dose abiraterone plus olaparib as a late-line treatment for mCRPC could lead to prostate-specific antigen (PSA) and symptom PFS in selective cases even without BRCAm. The median PSA–PFS was 8 months (IQR: 6.5–11.5), with a median follow-up duration of 39.0 months (IQR: 27.5–64.5). Gene tests were conducted in all patients, identifying non-BRCA mutations through ctDNA testing (24%), tumor tissue testing (12%), or both (64%). Adverse events occurred in 72% of patients, with 16% experiencing Grade ≥ 3 events. Common adverse events included anemia (64%), decreased appetite (48%), and fatigue (25%). Our findings support low-dose abiraterone plus olaparib as a potential option for mCRPC patients without BRCAm, offering manageable safety and efficacy profiles.

The Contribution of 68 Ga-FAPI-04 PET/CT to Staging and Prognosis in Gastric Cancer.

This study aimed to compare the diagnostic capabilities of 18 F-FDG PET/CT and 68 Ga-FAPI-04 PET/CT imaging in staging gastric carcinoma, exploring the impact of 68 Ga-FAPI-04 PET/CT on treatment planning and its prognostic significance. The research included 31 patients undergoing staging for gastric cancer, who received both 18 F-FDG PET/CT and 68 Ga-FAPI-04 PET/CT scans. We compared the SUV max and SUV mean of the primary tumor and lymph nodes, the count of organ metastases, tumor-to-background ratios, and overall staging accuracy. Additionally, the study evaluated radiological progression-free survival and overall survival rates. The 68 Ga-FAPI-04 PET/CT demonstrated superior efficacy in identifying the primary tumor compared with 18 F-FDG PET/CT, particularly in cases of poorly cohesive, signet-ring cell, and mucinous subtypes, with detection rates of 96.7% versus 77.4% ( P = 0.006 and P = 0.008, respectively). Analysis of lymph nodes showed a significantly higher detection of positive nodes with 68 Ga-FAPI-04 ( P = 0.026), although no significant differences were observed in SUV max and tumor-to-background ratio on a patient basis ( P > 0.05). SUV max and tumor-to-background ratios for peritoneal involvement were notably higher with 68 Ga-FAPI-04 PET/CT compared with 18 F-FDG PET/CT ( P = 0.04 for both). No significant differences were found in the detection of organ metastases and disease stage between the 2 imaging modalities ( P > 0.05). Primary tumor uptake did not significantly impact radiological progression-free survival or overall survival in either modality. 68 Ga-FAPI-04 PET/CT imaging surpasses 18 F-FDG PET/CT in detecting the primary tumor, especially in poorly cohesive and signet-ring cell gastric cancer types, and offers improved accuracy in disease staging. This indicates its potential to enhance treatment management and prognostic assessment in gastric cancer patients.

Durable Response to Pembrolizumab and Lenvatinib in a Patient with Chemotherapy-refractory Cholangiocarcinoma

Cholangiocarcinoma (CCA), a rare malignancy originating from bile duct epithelial cells, often presents a challenging prognosis due to its rarity, delayed diagnosis, and early recurrence post-curative-intent treatments. Additional complexities include difficulties in achieving R0 resection during surgical intervention and the lack of effective second-line treatments following the failure of first-line regimens, particularly in unresectable advanced cases. In this case study, we demonstrate a durable response to a combination regimen of pembrolizumab and lenvatinib in a patient with distal CCA. Despite the regimen’s interim median Progression-Free Survival (PFS) of 6.1 months (95% CI, 2.1-6.4), our patient achieved a clinical and radiological PFS of approximately two years. The underlying mechanisms, potentially involving the upregulation of immune response pathways through undisclosed means or influenced by lenvatinib’s activation of T cells, might augment the sensitivity to PD-1 antibodies like pembrolizumab, contributing to the patient’s sustained response over two years. This case also highlights the significance of the patient’s initial good health condition, multidisciplinary care, and the potential impact of molecular subtyping on treatment selection in a patient with distal CCA who underwent numerous diagnostic procedures, intricate surgical interventions, and subsequent treatment regimens over seven years. Additionally, we underscore significant landmark trials and emerging combination therapies, including chemotherapies, immunotherapy, and targeted treatments in this report.

Metastasis-Directed Stereotactic Body Radiotherapy in Prostate Cancer Patients Treated with Systemic Therapy and Undergoing Oligoprogression: Report on 11 Consecutive Cases

Background: Stereotactic body radiotherapy (SBRT) targeted at metastatic sites of disease progression is emerging as a potential therapeutic approach for managing oligoprogressive prostate cancer. However, a definitive benefit has yet to be demonstrated. Herein, we present our institution’s experience with this treatment approach. Methods: From April 2018 to March 2023, 11 patients affected by oligoprogressive prostate cancer were treated with SBRT targeting the nodal or bone sites of progression while maintaining the ongoing systemic therapy. Three patients were undergoing single-agent ADT (Androgen Deprivation Therapy), while the remaining eight were receiving a subsequent line of systemic therapy. All patients were evaluated with a pre-treatment 68Ga-PSMA-11 or 18F-fluorocholine PET/CT, which demonstrated between one and five localizations of disease. All the active sites were treated with SBRT in one (15–24 Gy) or three (21–27 Gy) fractions, except for one patient, who was treated in five fractions (35 Gy). PSA serum levels were tested at baseline, one month after RT and at least every three months; all patients underwent a post-treatment 68Ga-PSMA-11 or 18F-fluorocholine PET/CT. The evaluated endpoints were PSA response, defined as a post-treatment decrease &gt;50% from baseline measured within 6 months, time to next-line systemic treatment (NEST), local control (LC), biochemical progression-free survival (bPFS), radiological progression-free survival (rPFS) and freedom from polymetastatic progression (FPP). Results: Nineteen lesions were treated (seven nodal and twelve bone). At a median follow-up of 19 months (7–63), 9 of the 11 patients had a PSA response; all patients had local control of the treated metastases. A total of six patients switched to a next-line systemic treatment, with a median NEST of 13 months. Six patients had polymetastatic progression with an FPP median time of 19 months. No patients died during the follow-up period. The SBRT-related toxicity was negligible. Conclusions: Our data support the use of SBRT targeting the sites of oligoprogressive disease before moving to a subsequent line of systemic treatment in patients with metastatic prostate cancer. Prospective studies to evaluate the potential impact of this approach on overall survival are warranted.

Impact of Circulating Tumor Cell-Expressed Prostate-Specific Membrane Antigen and Prostate-Specific Antigen Transcripts in Different Stages of Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer micrometastases. This study evaluated whether a circulating tumor cell (CTC)-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in prostate cancer. We prospectively enrolled 21 healthy individuals and 247 patients with prostate cancer [localized prostate cancer (LPCa), n = 94; metastatic hormone-sensitive prostate cancer (mHSPC), n = 44; and metastatic castration-resistant prostate cancer (mCRPC), n = 109]. The mRNA expression of six transcripts [PSMA, prostate-specific antigen (PSA), AR, AR-V7, EpCAM, and KRT 19] from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. CTC detection rates were 75.5%, 95.3%, and 98.0% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA [hazard ratio (HR), 3.35; P = 0.028) and PSA mRNA (HR, 1.42; P = 0.047] expressions were associated with BCR. Patients with mHSPC with high PSMA (HR, 4.26; P = 0.020) and PSA mRNA (HR, 3.52; P = 0.042) expressions showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expressions were significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. PSMA and PSA mRNA expressions are associated with BCR in LPCa. In advanced prostate cancer, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance.

Abstract LB110: Impact of circulating tumor cell-expressed prostate-specific membrane antigen and prostate-specific antigen transcripts in various stages of prostate cancer

Abstract PurposeProstate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer (PCa) micrometastases. This study evaluated whether a circulating tumor cell (CTCs-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in PCa. Experimental design We prospectively enrolled 21 healthy individuals and 247 patients with PCa (localized PCa [LPCa]: 94; metastatic hormone-sensitive PCa [mHSPC]: 44; and metastatic castration-resistant PCa [mCRPC]: 109). The mRNA expression of six transcripts (PSMA, prostate-specific antigen [PSA], AR, AR-V7, EpCAM, and KRT 19) from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. Results CTC detection rates were 75.5%, 95.3%, and 98% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA (hazard ratio [HR]: 3.35; P=0.028) and PSA mRNA (HR: 1.42; P=0.047) expression was associated with BCR. mHSPC patients with high PSMA (HR: 4.26; P=0.020) and PSA mRNA (HR: 3.52; P=0.042) expression showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expression was significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. Conclusion PSMA and PSA mRNA expression is associated with BCR in LPCa. In advanced PCa, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance. Citation Format: Hyungseok Cho, Seok-Soo Byun, Nak-Hoon Son, Jae Il Chung, Won Ik Seo, Chan Ho Lee, Todd M Morgan, Ki-Ho Han, Jae-Seung Chung. Impact of circulating tumor cell-expressed prostate-specific membrane antigen and prostate-specific antigen transcripts in various stages of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB110.

Abstract CT231: Identification of a novel agnostic predictive multiomic signature via Elastic Net/Machine Learning in TALAPRO-2 (TP-2), a phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: TP-2 (NCT03395197) demonstrated significantly improved radiologic progression-free survival (rPFS) regardless of homologous recombination repair (HRR) gene alteration status for pts with mCRPC who received 1L TALA + ENZA (n=402) vs PBO + ENZA (n=403; Agarwal et al. Lancet. 2023. PMID: 37285865). We explore potential associations of ctDNA genomics and tumor gene expression with efficacy in TP-2. Methods: The analysis was based on the safety population (n=799). Two data sets were used: a FoundationOne®Liquid CDx data set (Azad et al. ASCO 2023, #5056) of prospectively collected/retrospectively analyzed plasma samples (n=681); and a tumor transcriptomic data set generated via HTG’s Oncology Biomarker Panel (with 10 additional genes implicated in PARP inhibitor sensitivity; n=304). Correlations between baseline molecular biomarkers and rPFS were assessed via a Cox proportional hazards model. Multivariate elastic net regression analysis incorporated 151 pts in the TALA + ENZA arm with 2,868 molecular features (ctDNA: 309 genes [only short variant alterations incorporated]; HTG: 2,559 tumor transcripts). Results: Positively predictive candidate tumor biomarkers for TALA + ENZA included androgen response signature and individual androgen receptor (AR) target genes such as PSA, ALDH1A3, and CAMKK2. These expression signatures/transcripts had no/minimal predictive value for PBO + ENZA. A 33-feature (3 genes, 30 transcripts) elastic net signature was identified that was predictive of rPFS with TALA + ENZA: TP53 and AR short variant alteration status were each prognostic and associated with worse rPFS. Expression of multiple AR target genes, including ALDH1A3 (top selected feature) and CAMKK2, was positively associated with rPFS. For TALA + ENZA, this multiomic signature was predictive of rPFS in pts regardless of HRR gene alteration status, and to a lesser extent for PBO + ENZA. None of the 12 HRR genes used for stratification in TP-2 were included in the signature. Conclusions: Our exploratory analysis identified candidate gene expression signatures, including AR pathway elements, potentially associated with differential benefit from TALA + ENZA, reinforcing the potential for exploitable crosstalk between AR and DNA repair pathways. Though validation is necessary, a predictive multiomic signature for benefit from TALA + ENZA regardless of HRR alteration status was identified that included alterations in genes previously implicated in prognosis and expression of multiple AR target transcripts. Strikingly, it did not include any of the 12 HRR genes used in prospective stratification for TP-2, reinforcing the potential benefit for TALA + ENZA beyond HRR-deficient tumors. Citation Format: Glenn Liu, Xinmeng Jasmine Mu, Karim Fizazi, A. Douglas Laird, Nobuaki Matsubara, Steven M. Yip, Jie Pu, Joan Carles, Andre P. Fay, Robert J. Jones, Stefanie Zschäbitz, Josep M. Piulats, Jae Young Joung, Whijae Roh, Jijumon Chelliserry, Nicola Di Santo, Michelle Saul, Arun A. Azad, Neeraj Agarwal. Identification of a novel agnostic predictive multiomic signature via Elastic Net/Machine Learning in TALAPRO-2 (TP-2), a phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT231.

Abstract 3238: Therapeutic targeting of the genome guardian sirtuins in metastatic prostate cancer

Abstract Introduction: The effective treatment paradigm for the lethal form of metastatic prostate cancer (mPCa) remains challenging. Almost all mPCas eventually develops therapy resistance against androgen receptor (AR) inhibitors (e.g., Enzalutamide, Abiraterone) or to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors (Olaparib, Niraparib, Talazoparib) (HRRd) when used as monotherapy. Although the patients in the ARSi+PARPi combination produced significantly longer radiologic progression-free survival (rPFS), a substantial number had attained therapy resistance by the end of the study tenure. So, a newer therapy is urgently needed. In recent years, a new targetable therapeutics development domain has been unfolding with an expanding understanding of the role of SIRTuins in prostate cancer cell survival, invasion, and progression to an aggressive metastatic state. Here, we will investigate the therapeutic efficacy of SIRT1/7 inhibitor (SIRT1/7i) and determine synergy with DNA-damaging PARP inhibitor combinations through a battery of cell and molecular assays using various prostate cancer cellular models. Methods: We have treated the mPCa cell lines 22Rv1, LAPC4, PC3 and LnCAP as well as prostate epithelial cell line RWPE1 with SIRT1 inhibitor SIRT1-IN-2 (MedChemExpress, HY-146689), SIRT7 inhibitor 97491 (MedChemExpress, HY-135899) and AR inhibitor Enzalutamide individually as well as in combination of PARP inhibitor Olaparib. The treatment of the SIRT1 and SIRT7 monotherapy arm was 72 hours long, and combination therapy continued for 7 days. The cell viability was assessed with CellTiter-Glo® 2.0 Cell Viability Assay (Promega). The cell cycle progression and proliferation analysis were done using flow cytometry through Propidium iodide staining and AnnexinV-FITC apoptosis detection chemistry. Cell survival was orthogonally assessed using colony counting assays. We adopt RAD51 foci counting assays and COMET assays for evaluating treatment-induced genome instability. Results: The preliminary result suggested that the SIRT1i+Olaparib and SIRT7i+Olaparib combination significantly sensitized the mPCa cell lines 22Rv1, PC3, and LnCAP for cell death compared to the prostate epithelial cell RWPE1. Upon the combination treatment, the mPCa cell lines showed elevated apoptotic cell death, reconfirmed through colony counting assay. Conclusion: Therapeutic combination treatment of SIRT1 and SIRT7 inhibition with Olaparib could be an effective treatment option for aggressive metastatic prostate cancer. Citation Format: Subhajit Giri. Therapeutic targeting of the genome guardian sirtuins in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3238.

A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer

BackgroundInhibition of the adenosine 2A receptor (A2AR) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs. This phase 2 study evaluated the A2AR antagonist AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer.MethodsPatients with histologically/cytologically confirmed disease progressing within 6 months on ≥ 2 therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab). Primary endpoints were objective response rate per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival, safety, and pharmacokinetics.ResultsFifty-nine patients were treated (Module 1, n = 29; Module 2, n = 30). Median number of prior therapies was 4. One confirmed complete response by RECIST (Module 1) and 2 confirmed PSA responses (1 per module) were observed. The most frequent adverse events (AEs) possibly related to AZD4635 were nausea (37.9%), fatigue (20.7%), and decreased appetite (17.2%) in Module 1; nausea (50%), fatigue (30%), and vomiting (23.3%) in Module 2. No dose-limiting toxicities or treatment-related serious AEs were observed. In Module 1, AZD4635 geometric mean trough concentration was 124.9 ng/mL (geometric CV% 69.84; n = 22); exposures were similar in Module 2. In Modules 1 and 2, median (95% CI) rPFS was 2.3 (1.6 –3.8) and 1.5 (1.3– 4.0) months, respectively. Median PFS was 1.7 versus 2.3 months for patients with high versus low blood-based adenosine signature.ConclusionIn this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity with a manageable safety profile. Clinical Trial.gov identifier: NCT04089553.

P104 - Stereotactic body radiation therapy and abiraterone acetate for patients affected by oligometastatic castrate-resistant prostate cancer: Freedom from biochemical, radiological progression free survival and freedom from following treatment approaches within a randomized phase II trial (ARTO – NCT03449719)

P104 - Stereotactic body radiation therapy and abiraterone acetate for patients affected by oligometastatic castrate-resistant prostate cancer: Freedom from biochemical, radiological progression free survival and freedom from following treatment approaches within a randomized phase II trial (ARTO – NCT03449719)

Natural killer cell activity in metastatic castration resistant prostate cancer patients treated with enzalutamide

Metastatic castration resistant prostate cancer (mCRPC) is still the lethal stage for the whole spectrum of prostate cancer disease. Even though different treatment options have been introduced in the last decade with a significant survival improvement for this population, a lack of more reliable prognostic and predictive markers is still one of the main clinical challenges in management of mCRPC. The aim of this study was to investigate the correlation between Natural Killer cell activity (NKA) and both treatment effect and outcomes in patients with mCRPC treated with enzalutamide. A total of 87 patients with mCRPC treated with enzalutamide as the first line treatment were enrolled. NKA was estimated at baseline and prior to each treatment cycle. Endpoints included both treatment effect with biochemical response (BR), biochemical progression (BP) and radiological progression (RP), as well as outcome data with overall survival (OS), radiologic progression free survival (rPFS), and time to next treatment (TTT). At the time of BR, interferon-gamma (IFNγ) decreased significantly compared to levels detected at baseline (z-score = 2.33, p = 0.019). Regarding outcome data, the whole cohort was divided into four groups according to the change of IFNγ level during the first 3 cycles of enzalutamide treatment. In group 1 (n = 42) the IFNγ level remained within a normal range (≥ 250 pg/mL),while in group 2 (n = 7) it increased from an abnormal (< 250 pg/mL) to a normal level. In group 3 (n = 13) it dropped to an abnormal level, and it remained at an abnormal level during treatment in group 4 (n = 17). Patients in group 2 showed the worst prognosis with shorter both rPFS and TTT (HR 4.30, p = 0.037; and HR 6.82, p = 0.011, respectively). In this study inverse correlations between NKA and both treatment response and outcomes was observed in mCRPC patients receiving enzalutamide, suggesting an unfavourable role of NK cells in the late stage of PCa.

Disitamab vedotin in combination with immune checkpoint inhibitors for locally and locally advanced bladder urothelial carcinoma: a two-center's real-world study.

Objective: Our study aims to assess the effectiveness and safety profile of Disitamab Vedotin (DV, RC48-ADC), an innovative humanized anti-HER2 antibody conjugated with tubulin-disrupting antimitotic drug monomethyl auristatin E (MMAE) via a cleavable peptide linker. This treatment combined immune checkpoint inhibitors as part of the bladder sparing approach for selected patients suffering from locally and locally advanced bladder urothelial carcinoma. Patients and methods: We conducted a two-center, real-world study involving locally advanced urothelial carcinoma (UC) patients. Patients were classified based on HER2 expression (IHC 3+/2+/1+) or lack of HER2 expression (IHC 0). The primary endpoint was the objective response rate (ORR), assessed by the investigator following the criteria of RECIST V1.1. Secondary endpoints encompassed the pathological complete response rate (pCR), pathological partial response rate (pPR), and pathological stable disease (pSD), along with recurrence-free survival (RFS), the pathological downstaging rate, and the safety profile of the treatment. Results: In this study, nine patients were enrolled, with a median follow-up duration of 12.0months. The overall confirmed ORR was 88.9%, Five patients achieved a complete response (CR), and three patients achieved a partial response (PR). The radiological complete response (rCR) aligned perfectly with pCR. The median radiological progression-free survival (rPFS) spanned 12.0months (range from 8.0 to 17.0months). One patient diagnosed with disease progression (PD) underwent a radical cystectomy. The pathological stage evolved from T2N0M0 to T3aN2M0, followed by adjuvant chemotherapy with a gemcitabine-cisplatin (GC) combination radiotherapy. At the 9-month follow-up, neither recurrence nor metastasis was observed. The rate and intensity of complications were manageable among these patients, with no evidence of grade 4 and 5 adverse events. Conclusion: The combination of DV and PD-1 demonstrated considerable activity in the objective response rate (ORR) in patients with HER2 IHC 0/1+/2+/3+ muscle-invasive bladder cancer (MIBC), along with the longest reported median radiological progression-free survival (rPFS) to date. With an extended duration of treatment, the safety profile of DV plus PD-1 was also confirmed to be manageable.

Clinical aspects of prostate cancer in patients with germinal and somatic mutations in DNA homologous recombination repair genes

Background. In clinical practice, there is a need to predict clinical behavior of prostate cancer with germinal and somatic mutations in DNA homologous recombination repair (HRR) genes due to an atypical response to standard treatment methods. Also, the expediency of testing the mutational status of HRR genes is dictated by the possibility of using the PARP-inhibition strategy in metastatic castration-resistant prostate cancer (mCRPC). In addition to expanding the possibilities for targeted therapy the necessity to inform the relatives of mutation carriers is underestimated. It is also important to realize the fact of accumulation of somatic changes both in the primary tumor and in the metastatic lesion during tumor evolution and under treatment, which dictates the possibility of repeated biopsy with exhausted therapy possibilities.Aim. Evaluation of prostate cancer clinical behavior features and response to drug therapy depending on the identified mutations in the HRR genes.Materials and methods. The study was performed at the Clinical Oncological Dispensary No. 1 (Krasnodar). Clinical and morphological data of 27 patients with prostate cancer and identified germinal and somatic mutations in HRR genes (BRCA1, BRCA2, ATM, BARD, BRIP1, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD54L, FANCL) were retrospectively analyzed. Statistical analysis was performed using the IBM SPSS Statistics v.22 statistical package.Results and conclusion. The median age of patients was 61 years. The most frequent were mutations in the BRCA2 (37 %), CHEK2 (18.5 %), ATM (14.8 %) genes. More than half of the patients (69 %) had primary metastatic disease. The differentiation grade of G2 and G3 according to the classification of the International Society of Urological Pathologists (ISUP) with Gleason score of 7 (3 + 4) and 7 (4 + 3) were both detected in 27 % of cases. The type of mutation did not affect the time of castration resistance development (p = 0.216). The time to castration resistance increased close to statistical significance in the case of primary stage of T3–4N0M0 compared to other stages (log-rank p = 0.092). Progression-free survival (PFS) with docetaxel monochemotherapy was significantly longer when prescribed for metastatic hormone-sensitive prostate cancer with mutations in HRR genes compared to mCRPC (p = 0.061) and to primary metastatic disease (p = 0.04). At the same time, the risk of progression during therapy was higher for presence of regional lymph node metastases with primary advancement (p = 0.005; hazard ratio 1.167; 95 % confidence interval 2.765–267). There was also an advantage in PFS when prescribing docetaxel for BRCA1/2 and ATM mutations in comparison with other mutations (p = 0.038). When prescribing therapy with 2nd generation antiandrogens or abiraterone, progression-free survival is higher in the group of patients with prostate cancer with Gleason score of 7 (4 + 3) compared to cohort with other morphological types, and this difference is almost statistically significant (log-rank p = 0.091, Breslow p = 0.076, Taron-Ware p = 0.074). Targeted therapy with the PARP inhibitor Olaparib in the performed trial was received by 10 patients with HRR mutations. At the same time, according to the data of the PROfound trial, the advantage of Olaparib in radiological PFS was shown in germinal and somatic mutations in group A (BRCA1, BRCA2, ATM) and in the general group (A and B – other HRR mutations).

Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study.

Despite the existence of various treatment options, the prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unfavorable. One potential therapeutic approach is the use of [225Ac]Ac-PSMA-617, a targeted alpha therapy (TAT) that administers alpha-particle radiation specifically to prostate cancer cells expressing PSMA. In this study, we report the long-term survival outcomes of this novel therapy in a series of patients with mCRPC who have exhausted all standard treatment options. The study enrolled patients with mCRPC who had shown resistance to standard lines of therapies, including next-generation anti-androgen therapies and taxane-based chemotherapies. These eligible patients received treatment with [225Ac]Ac-PSMA-617 at 100-150 kBq/kg doses administered every 8 weeks. The primary objective of the study was to assess overall survival (OS), while secondary objectives included evaluating radiological progression-free survival (rPFS), monitoring serum prostate-specific antigen (PSA) levels as a measure of biochemical response, and assessing adverse events using the CTCAE v5.0 grading system. Among the 63 initially enrolled patients, a total of 56 patients who had completed at least two cycles of [225Ac]Ac-PSMA-617 were included in this study. The mean age was 67 years (range, 39-87) and patients received a total of 204 cycles of [225Ac]Ac-PSMA-617 TAT. 91% of patients exhibited any PSA decline, with 67.8% experiencing a decline of 50% or more. The median follow-up was of 22 months (range: 6-59 months). Imaging-based disease progression was observed in 68% of patients, and 66% of patients succumbed to the disease. The median OS was 15 months (95% CI: 10-19). In univariate analysis, factors such as lack of >50% PSA decline (P=0.031), Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher (P=0.048), and radiological progression (rPD) (P<0.001) were found to be predictors of poor OS. However, in multivariate analysis, only rPD emerged as an independent prognostic factor with a hazard ratio (HR) of 8.264 (95% CI: 1.429-16.497, P=0.004). The estimated median rPFS was 9 months (95% CI: 7-15). Moreover, patients who demonstrated any PSA decline had a median rPFS of 10 months compared to only 3 months in patients without any PSA decline (multivariate HR: 6.749; 95% CI: 1.949-23.370; P=0.002). Fatigue was one of the most common treatment-emergent adverse events, with grades 1/2 occurring in 70% of patients and grades 3 or higher in 3.5% of patients. This fatigue was transient and resolved before the next treatment cycle. Additionally, approximately one-third of patients experienced xerostomia (grades 1/2: 32.1%). [225Ac]Ac-PSMA-617 targeted alpha therapy, was found to be well-tolerated with acceptable adverse events and effective in the treatment of patients with end-stage mCRPC.

Impact of prostate radiotherapy on survival outcomes in clinically node-positive prostate cancer: A multicentre retrospective analysis

PurposeTo evaluate clinical outcomes for cN1M0 prostate cancer treated with varied modalities. Materials and methodsMen with radiological stage cN1M0 prostate cancer on conventional imaging, treated from 2011-2019 with various modalities across four centres in the UK were included. Demographics, tumour grade and stage, and treatment details were collected. Biochemical and radiological progression-free survival (bPFS, rPFS) and overall survival (OS) were estimated using Kaplan Meier analyses. Potential factors impacting survival were tested with univariable log-rank test and multivariable Cox-proportional hazards model. ResultsTotal 337 men with cN1M0 prostate cancer were included, 47% having Gleason grade group 5 disease. Treatment modalities included androgen deprivation therapy (ADT) in 98.9% men, either alone (19%) or in combinations including prostate radiotherapy (70%), pelvic nodal radiotherapy (38%), docetaxel (22%), or surgery (7%). At median follow up of 50 months, 5-year bPFS, rPFS, and OS were 62.7%, 71.0%, and 75.8% respectively. Prostate radiotherapy was associated with significantly higher bPFS (74.1% vs 34.2%), rPFS (80.7% vs 44.3%) and OS (86.7% vs 56.2%) at five years (log rank p < 0.001 each). On multivariable analysis including age, Gleason grade group, tumour stage, ADT duration, docetaxel, and nodal radiotherapy, benefit of prostate radiotherapy persisted for bPFS [HR 0.33 (95% CI 0.18–0.62)], rPFS [HR 0.25 (0.12–0.51)], and OS [HR 0.27 (0.13–0.58)] (p < 0.001 each). Impact of nodal radiotherapy or docetaxel was not established due to small subgroups. ConclusionAddition of prostate radiotherapy to ADT in cN1M0 prostate cancer yielded improved disease control and overall survival independent of other tumour and treatment factors.

LuPARP: Phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC).

5005 Background: 177Lu-PSMA-617, a PSMA-directed, radionuclide therapy improves progression free survival (PFS) and overall survival (OS) in patients (pts) with mCRPC. Although many pts benefit from treatment, approximately a third have primary resistance, median PFS is 5.1 months and all pts inevitably relapse. Poly (ADP-ribose) polymerase (PARP) is implicated in repairing radiation-induced DNA single-strand breaks (SSBs). The potent PARP inhibitor (PARPi) olaparib results in the conversion of DNA SSBs to lethal double-strand breaks. Multiple preclinical studies have shown enhanced anti-tumor activity from combined PARPi and radiotherapy. LuPARP aims to evaluate the safety and efficacy of the combination of 177Lu-PSMA-617 and olaparib. Methods: 48 pts with mCRPC and high PSMA expression (SUVmax 15 at a site of disease, and SUVmax ≥ 10 at other measurable sites) without discordant FDG positive/PSMA negative disease will be enrolled in two stages: dose-escalation (standard 3+3 design) and dose-expansion at the recommended phase 2 dose (RP2D). 177Lu-PSMA-617 is administered at 7.4 GBq IV on day 1, every 6 weeks for up to 6 cycles in conjunction with 9 prespecified dose schedules of olaparib. The dose-limiting toxicity (DLT) period is 6 weeks. The primary objectives are establishing the DLTs and RP2D. Secondary objectives are toxicity, radiological PFS (rPFS), PSA response rate (PSA50-RR), PSA-PFS, objective response rate (ORR) and OS. Responses are assessed by 3-weekly PSA and conventional and PSMA PET/CT imaging every 12 weeks. Results: 29 pts (median age 70 years: range: 52-84; prior docetaxel: 97%; prior androgen receptor pathway inhibitor: 100%) received 177Lu-PSMA-617 on day 1 with escalating doses of olaparib (cohorts 1-6: 50mg - 300 mg BD days 2-15) or alternate olaparib schedules (cohort 7: 200 BD days - 4 to 14; cohort 8: 300 BD days - 4 to 14; cohort 9: 300 mg BD days -4 to 18) for up to 6 cycles. No DLTs were reported. Common treatment related adverse events (TRAE) (≥10%) were Grade (G) 1-2 and included xerostomia (83%), nausea (62%), fatigue (34%), constipation (31%), anorexia (17%), vomiting (14%) and diarrhea (10%). Hematologic TRAE included anemia (G1: 14%; G2: 7%; G3: 7%), thrombocytopenia (G1: 14%; G2: 7%; G3: 3%) and neutropenia (G1: 3%; G3: 7%) that were transient and without clinical sequelae. Across cohorts 1-9, the PSA50-RR was 62% (18/29) and PSA90-RR was 48% (14/29). Five of the 7 pts (71%) with RECIST measurable disease had a partial response. Conclusions: The combination of 177Lu-PSMA-617 and olaparib is well tolerated and has promising activity. Three further patients are being enrolled to cohort 9 to confirm the RP2D ahead of dose-expansion. Clinical trial information: NCT03874884 . [Table: see text]

Circulating ether lipids in prostate cancer.

e17009 Background: Decreased circulating levels of ether lipids (glycerophospholipids with an ether-linked fatty alcohol, e.g. plasmalogens) have been observed in obesity, diabetes and cardiovascular disease. In vitro and in vivo studies suggest that ether lipids are anti-inflammatory and protective against obesity. A recent landmark study revealed that ether lipids can kill cancer cells through ferroptosis. However, the role of ether lipids in prostate cancer has not been thoroughly investigated despite the known association of dysregulated lipid metabolism with poorer clinical outcomes. The aim of this study was to assess the relationship between the circulating profiles of ether lipids and clinical outcomes in localised and metastatic prostate cancer. Methods: The profiles of ~150 ether lipids (8 lipid classes) in plasma lipidomic data from localised prostate cancer (389 men in Australia) and metastatic castration-resistant prostate cancer (mCRPC)(2 cohorts –147 men in USA, 128 men in Australia) were analysed for associations with disease progression or overall survival (OS). Open-access genomic data of mCRPC tumours (108 men, CbioPortal) were analysed for aberrations in genes associated with ether lipid metabolism in relation to clinical outcome. Results: Previously in these study cohorts, we had identified men with poorer prognosis based on their plasma lipidome and our validated sphingolipid signature. These men with poorer prognosis have lower plasma levels of ether lipids than those with better prognosis (t-test p &lt; 0.05, localised disease – 110 ether lipids, mCRPC – 54 ether lipids). Decreased plasma levels of up to 46 ether lipid species were associated with higher rates of clinical relapse in localised disease (hazard ratio (HR) range 0.37-0.73, p-value range 0.006-0.049), shorter radiological progression-free survival in mCRPC (HR range 0.35-0.73, p-value range 0.00009-0.049), and shorter OS in mCRPC (HR range 0.33-0.79, p-value range 0.000004-0.0497). Chromosomal loss of tumour GNPAT, an essential gene in ether lipid synthesis, was associated with shorter OS in mCRPC (HR = 1.36, 95% CI 1.02-1.81, p = 0.03). Conclusions: Lower circulating levels of ether lipids were associated with worse prognosis in localised and metastatic prostate cancer, suggesting that these lipids are protective against disease progression. Further research is required to understand the role of ether lipids in disease progression, and to determine if modulation of ether lipid levels through supplementation is beneficial.

Abstract 2137: Clinical utility of circulating tumor DNA in patients with advanced KRAS G12C-mutated NSCLC treated with sotorasib

Abstract Introduction: The CodeBreaK 200 trial showed that in patients (pts) with advanced KRAS G12C mutated (KRAS+) NSCLC sotorasib, a KRAS G12C-specific inhibitor, is superior to docetaxel for progression free survival (PFS) (HR 0.66) with a one-year PFS of 25%. We hypothesized that the detection of circulating tumor DNA (ctDNA) in plasma could allow for treatment response prediction and longitudinal monitoring. We analyzed serial plasma samples at baseline and within 3 months of start of sotorasib to evaluate ctDNA changes and correlation with clinical response. Methods: Pts with sotorasib treated KRAS+ NSCLC were prospectively enrolled in our biomarker START-TKI study (NCT05221372) after written informed consent. Plasma samples were collected prior to treatment (T0) and at first response evaluation (T1). The TruSight Oncology 500 ctDNA panel was used for mutation detection in cell-free DNA (cfDNA). cfDNA KRAS/TP53/STK11/KEAP1 status was determined and compared to tumor tissue pathology reports to filter out false positives. Radiological response and PFS was assessed per RECIST 1.1. Results: Between May 2021 and August 2022, 35 pts were included (table 1). Of these, 29 (83%) had detectable ctDNA KRAS G12C at T0, and 24 had both T0 and T1 samples. A decrease in variant allele frequency (VAF) at T1 compared to T0 was observed in 88% (n=21); 42% (n=10) showed complete clearance of ctDNA KRAS G12C. Six-months PFS was 83% in T0 negative pts (n=6) versus 43% in T0 positive pts (n=29); and 65% in pts with complete clearance (n=10) versus 14% in pts with incomplete clearance (n=11). VAF increase was seen in 3 pts, of which 1 had progression at T1. Conclusions: In pts with KRAS+ NSCLC treated with sotorasib, baseline ctDNA and ctDNA clearance within 3 months of treatment correlated with treatment response. Pts with undetectable KRAS ctDNA at baseline, or with complete clearance at first evaluation, had superior PFS. PFS will be updated as follow-up duration extends. Table 1. Patient cohort Liver metastasis KRAS p.G12C ctDNA at T0, median VAF % (range) KRAS p.G12C ctDNA at T1, median VAF % (range) Median change in VAF % (range) TP53/STK11/KEAP1 ctDNA T0 T1 response Reason EOT ꝉ Time on treatment (months) * Negative at T0 (n=6) No = 6 0 NE NE NE 1x PR; 4x SD; 1x PD 2x PD; 4x ongoing &amp;gt;8 months 6 (1 - 11) Positive at T0 (n=29) No = 20; Yes = 9 2.6 (0.1 - 46.7) 0.6 (0.1 - 38.9) -95% (-100 - +39) 4x TP53; 2x STK11; 1x STK11●; 2x KEAP1; 2x KEAP1●; 2x TP53 + KEAP1; 1x TP53 + STK11● 4x PR; 21x SD; 2x PD; 2x NE 19x PD; 3x toxicity; 6x ongoing &amp;gt;4 months; 1x loss to follow up 3 (1 - 15) Complete clearance at T1 (n=10) No = 6; Yes = 4 1.4 (0.1 - 8.4) 0 100% 2x TP53; 1x TP53 + KEAP1; 1x KEAP1; 1x KEAP1● 1x PR; 9x SD 6x PD; 1x toxicity; 2x ongoing &amp;gt;6 months; 1x loss to follow up 5 (1 - 11) Incomplete clearance at T1 (n=11) No = 7; Yes = 4 3.6 (1.3 - 46.7) 0.4 (0.1 - 29.4) -89% (-23 - -99) 2x TP53; 1x STK11; 1x STK11●; 2x TP53 + STK11●; 1x TP53 + STK11 + KEAP1; 1x STK11 + KEAP1 3x PR; 7x SD; 1x PD 8x PD; 2x toxicity; 1x ongoing &amp;gt;4 months 3 (1 - 8) Increase in VAF at T1 (n=3) No = 2; Yes = 1 1.0 (0.5 - 35.2) 1.1 (0.6 - 38.9) +11% (+10 - +39) 1x TP53●; 1x TP53 + KEAP1; 1x STK11● + KEAP1● 1x PD; 2x SD 3x PD 3 (1 - 15) Positive T0, no T1 available (n=5) No = 5 6.2 (0.3 - 24.6) NE NE 1x TP53; 1x TP53●; 1x KEAP1; 1x STK11 + KEAP1 3x SD; 2x NE 2x PD; 3x ongoing &amp;gt;3 months 2 (1 - 3) NE = Not evaluated; ● = Positive cell-free DNA (cfDNA), not tested in tumor tissue; PR = Partial response; SD = Stable disease; PD = Progressive disease; EOT = End of treatment; ꝉ for PFS analysis patients who discontinued treatment due to toxicity were censored at treatment discontinuation, and patients with ongoing sotorasib treatment were censored at data cut off (16-Nov-2022); * = excluding ongoing patients. Citation Format: Sophie M. Ernst, Ronald van Marion, Peggy N. Atmodimedjo, Evert de Jonge, Ron H. Mathijssen, Marthe S. Paats, Peter de Bruijn, Ron H.N. van Schaik, Hendrikus J. Dubbink, Anne-Marie C. Dingemans. Clinical utility of circulating tumor DNA in patients with advanced KRAS G12C-mutated NSCLC treated with sotorasib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2137.

A phase II randomized trial of metastasis-directed therapy with alpha emitter radium-223 in men with oligometastatic castration-resistant prostate cancer (MEDAL)

BackgroundThe significance of metastasis-directed therapy for oligometastatic prostate cancer has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multidisciplinary treatment for castration-resistant prostate cancer (CRPC). When oligometastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases. The progression of oligometastatic CRPC after targeted therapy may be due in part to the presence of micrometastatic lesions that, though undetected on imaging, were present prior to targeted therapy. Thus the systemic treatment of micrometastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect. Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays. Therefore, for oligometastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases.MethodsThis phase II, randomized trial of Metastasis-Directed therapy with ALpha emitter radium-223 in men with oligometastatic CRPC (MEDAL) is designed to assess the utility of radium-223 in combination with metastasis-directed radiotherapy in patients with oligometastatic CRPC confined to bone. In this trial, patients with oligometastatic CRPC with three or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone. The prior use of androgen receptor axis-targeted therapy and prostate-specific antigen doubling time will be used as allocation factors. The primary endpoint will be radiological progression-free survival against progression of bone metastases on WB-DWI.DiscussionThis will be the first randomized trial to evaluate the effect of radium-223 in combination with targeted therapy in oligometastatic CRPC patients. The combination of targeted therapy for macroscopic metastases with radiopharmaceuticals targeting micrometastasis is expected to be a promising new therapeutic strategy for patients with oligometastatic CRPC confined to bone.Trial registration Japan Registry of Clinical Trials (jRCT) (jRCTs031200358); Registered on March 1, 2021, https://jrct.niph.go.jp/latest-detail/jRCTs031200358