Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: Results of cohort 6 of the COSMIC-021 study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5564-5564 ◽  
Author(s):  
Neeraj Agarwal ◽  
Yohann Loriot ◽  
Bradley Alexander McGregor ◽  
Robert Dreicer ◽  
Tanya B. Dorff ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lymph Node ◽  
High Risk ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Recist 1.1 ◽  
High Risk Disease ◽  
Node Metastases ◽  
Ecog Ps ◽  
Baseline Psa

5564 Background: Cabozantinib (C) may enhance response to immune checkpoint inhibitors (ICIs) by promoting an immune-permissive microenvironment and has shown encouraging activity in combination with ICIs in tumor types including RCC and HCC. C and atezolizumab (A) have shown low objective response rates as monotherapy in metastatic castration-resistant prostate cancer (mCRPC) (Smith JCO 2012; Kim JCO 2018). COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating the combination of C + A in various solid tumors. We report results for Cohort 6 in mCRPC. Methods: Eligible patients (pts) were required to have radiographic progression in soft tissue after enzalutamide and/or abiraterone, measurable disease, and an ECOG PS of 0 or 1. Prior chemotherapy for mCSPC was permitted. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for the first year and Q12W thereafter. The primary endpoint is ORR per RECIST 1.1. Other endpoints include safety, ORR per irRECIST, duration of response (DOR), PFS, and OS. Results are presented for the first 44 pts enrolled. Results: Median follow-up as of Dec 20, 2019 was 12.6 mo (range 5, 20) for the 44 mCRPC pts. Median age was 70 y (range 49, 90), 50% had ECOG PS 1, 34% had visceral metastases, and 61% had extrapelvic lymph node metastases. 27% had prior docetaxel and 52% had 2 prior novel hormonal therapies. The most common any grade treatment-related adverse events (TRAEs) were fatigue (50%), nausea (43%), decreased appetite (39%), diarrhea (39%), dysgeusia (34%), and PPE (32%). One grade 5 TRAE of dehydration was reported in a 90 y/o. Median duration of treatment was 6.3 mo. ORR per RECIST 1.1 among all 44 pts was 32% (2 CRs [4.5%] and 12 PRs [27%]); 21 (48%) pts had SD resulting in a disease control rate of 80% in all pts. One pt with PD per RECIST 1.1 had an irPR per irRECIST. ORR per RECIST 1.1 was 33% in 36 pts with high-risk disease (visceral and/or extrapelvic lymph node metastases). Median DOR for all pts with response per RECIST 1.1 was 8.3 mo (range 2.8, 9.8+). 17 (50%) of 34 pts with post-baseline PSA evaluation had a decrease in PSA. In 12 responders with post-baseline PSA evaluation, 8 (67%) had a PSA decrease ≥50%. Tumor PD-L1 expression will also be reported. Conclusions: The combination of C + A had a tolerable safety profile and demonstrated clinically meaningful activity with durable responses in men with mCRPC. Given the encouraging activity in these pts, especially in those with high-risk disease, further evaluation of C + A in men with mCRPC is being pursued. Clinical trial information: NCT03170960 .

Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of Cohort 6 of the COSMIC-021 Study.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 139-139 ◽  
Author(s):  
Neeraj Agarwal ◽  
Yohann Loriot ◽  
Bradley Alexander McGregor ◽  
Robert Dreicer ◽  
Tanya B. Dorff ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Node Metastases ◽  
Checkpoint Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Duration Of Treatment ◽  
Recist 1.1 ◽  
Mri Scans ◽  
Node Metastases ◽  
Hormonal Therapies ◽  
Ecog Ps

139 Background: C may enhance response to immune checkpoint inhibitors by promoting an immune-permissive microenvironment. COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating the combination of C with A in various solid tumors. We report interim results from Cohort 6 in mCRPC. Methods: Eligible pts were required to have radiographic progression in soft tissue after enzalutamide and/or abiraterone, measurable disease, and an ECOG PS of 0 or 1. Prior chemotherapy for mCSPC was permitted. Pts received C 40 mg PO qd and A 1200 mg IV q3w. CT/MRI scans were performed q6w for 52w and q12w thereafter. Bone scans were performed q12w. The primary endpoint is ORR per RECIST 1.1. Other endpoints include safety, ORR per irRECIST, duration of response (DOR), PFS, and OS. Results: As of Oct 2019, 44 mCRPC pts were enrolled with a median follow-up of 10.6 mo (range 3.4+, 17.9). Median age was 70 y (range 49, 90), 50% had ECOG PS 1, 34% had visceral metastases, and 61% had extrapelvic lymph node metastases. 27% of pts had prior docetaxel and 52% had ≥2 prior novel hormonal therapies. The most common any grade TEAEs were fatigue (57%), nausea (48%), decreased appetite (45%), diarrhea (39%), PPE (32%), and vomiting (32%). One Grade 5 TRAE of dehydration was reported in a 90 y/o. Median duration of treatment was 5.3 mo. The ORR per RECIST 1.1 among all pts was 32% (2 CRs [4.5%] and 12 PRs [27%]); 21 (48%) pts had SD giving a disease control rate of 80% in all pts. One pt with initial PD per RECIST 1.1 had an irPR per irRECIST. ORR per RECIST 1.1 was 33% in 36 pts with high-risk clinical features (visceral and/or extrapelvic lymph node metastases). Median DOR for all pts with response per RECIST 1.1 was 8.3 mo (range 1.38+, 9.76+). In 12 responders with at least 1 post-baseline PSA evaluation, 8 (67%) had a PSA decline ≥50%. Conclusions: The combination of C+A had a tolerable safety profile and demonstrated clinically meaningful activity with durable responses in men with mCRPC. Given the encouraging activity in these pts, especially in those with visceral and/or extra pelvic lymph node metastases, further evaluation of C+A in men with mCRPC is being pursued. Clinical trial information: NCT03170960.

scholarly journals Abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: a systematic review of ‘real-life’ studies

2018 ◽  
Vol 10 (10) ◽  
pp. 305-315 ◽  
Author(s):  
Michele Marchioni ◽  
Petros Sountoulides ◽  
Maida Bada ◽  
Sebastiano Rapisarda ◽  
Cosimo De Nunzio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Meta Analysis ◽  
Real Life ◽  
Castration Resistant Prostate Cancer ◽  
The Real ◽  
Castration Resistant ◽  
Real Life Setting ◽  
Grade 3 ◽  
Baseline Psa

Background: To assess the efficacy and safety of treatment with abiraterone acetate (AA) in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC) in the ‘real-life’ setting. Methods: Data acquisition on the outcomes of the use of AA in chemotherapy-naive patients with mCRPC was performed by a MEDLINE comprehensive systematic literature search using combinations of the following key words: ‘prostate cancer’, ‘metastatic’, ‘castration resistant’, ‘abiraterone’, ‘real life’, and excluding controlled clinical trials (phase II and III studies). Identification and selection of the studies was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria. Outcomes of interest were overall survival (OS), progression-free survival (PFS), 12-week 50% reduction in prostate-specific antigen (PSA), and grade 3 and higher adverse events. Data were narratively synthesized in light of methodological and clinical heterogeneity. Results: Within the eight identified studies that fulfilled the criteria, a total of 801 patients were included in the meta-analysis. Baseline PSA ranged between 9.5 and 212.0 ng/ml. Most of the patients had bone metastases. Duration of treatment with AA was longer in the studies with lower baseline PSA levels. The median OS ranged between 14 and 36.4 months. The PFS, assessed according to different definitions, ranged from 3.9 to 18.5 months. A 50% PSA reduction at 12 weeks was reached by a variable percentage of patients ranging from 36.0% to 62.1%. Finally, the rate of grade 3 and higher adverse events was reported in three studies and ranged from 4.4% to 15.5%. Conclusions: Despite the high grade of heterogeneity among studies, treatment with AA seems to ensure good survival outcomes in the ‘real-life’ setting. However, prospective studies based on patients’ characteristics being more similar to ‘real-life’ patients are necessary.

Use of the Prostate Health Index for the Detection of Aggressive Prostate Cancer at Radical Prostatectomy

2015 ◽  
Vol 95 (4) ◽  
pp. 390-399 ◽  
Author(s):  
Luigi Mearini ◽  
Elisabetta Nunzi ◽  
Carla Ferri ◽  
Guido Bellezza ◽  
Carolina Lolli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lymph Node ◽  
High Risk ◽  
Radical Prostatectomy ◽  
Gleason Score ◽  
Health Index ◽  
Final Pathology ◽  
High Risk Disease ◽  
Prostate Health Index ◽  
Prostate Health

Introduction: In current study, we compared the accuracy of the PSA isoform p2PSA and its derivatives, the percentage of p2PSA to free PSA (%p2PSA) and the Prostate Health Index (PHI) in the detection of prostate cancer (PC) characteristics at the final pathology with respect to reference standards. Materials and Methods: This was an observational prospective study evaluating 43 consecutive PC patients treated with laparoscopic/robotic radical prostatectomy (RP). Logistic regression models were fitted to test the predictors of pT3 stage, pathologic Gleason score ≥8 or Gleason score upgrading, margin status, lymph node invasion, and the presence of high-risk disease (pT3 disease and/or Gleason score ≥8 and/or positive lymph node). The comparative base model included tPSA, clinical stage, biopsy Gleason score, and percentage of positive core. Results: Seventeen patients (39.5%) were affected by pT3 disease or had a pathologic Gleason score ≥8; positive margins were detected in 12 patients (27.9%), lymph node invasion was found in 2 patients (4.7%), and 15 patients (34.8%) harbored high-risk disease. In the univariate analysis, p2PSA, %p2PSA, and PHI were significant predictors of pT3 disease, pathologic Gleason score, and the presence of high-risk disease (all p < 0.05), whereas only PHI was an independent predictor of pT3 disease, margin status, and presence of high-risk disease, increasing the accuracy of a base multivariable model by 6.3% (p < 0.05) and 4.2% (p < 0.05) for the prediction of pT3 and high-risk disease, respectively. Conclusions: p2PSA and its derivatives, primarily PHI, were significant predictors of unfavorable PC characteristics as detected at the final pathology, thus improving the clinical performance of standard prognostic factors for aggressive disease.

scholarly journals Resolution of the Expert Council on the New Approach to Drug Therapy for Non-Metastatic Castration-Resistant Prostate Cancer

2021 ◽  
Vol 59 (1) ◽  
pp. 8-11
Author(s):  
Dilyara Kaidarova ◽  
Oxana Shatkovskaya ◽  
Zaure Dushimova ◽  
Bakytzhan Ongarbayev
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Treatment Efficacy ◽  
Doubling Time ◽  
Distant Metastases ◽  
Diagnostic Methods ◽  
Efficacy And Safety ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psa Doubling Time

Relevance: Prostate cancer (PC) is one of the most common malignant neoplasms in the male population. The widespread introduction of modern diagnostic methods and the determination of prostate-specific antigen (PSA) levels have increased the number of detected cases of localized and locally advanced PC forms. However, in some patients treated with radical methods and long-term androgen deprivation therapy (ADT), the disease continues to progress in the form of an increase in PSA levels with castration testosterone values and with no distant metastases. Such a course of the disease is referred to as non-metastatic castration-resistant prostate cancer (nmCRPC). Purpose: The article reports the results of a meeting of the Expert Council arranged by the Kazakh Research Institute of Oncology and Radiology on December 25, 2020, on non-metastatic castration-resistant prostate cancer diagnostics and treatment. Results: Large clinical studies highlight the critical importance of controlling the PSA doubling time as the main prognostic factor for an unfavorable outcome to increase patient survival and prevent the development of distant metastases. Based on the results of large randomized studies, experts recommended using new-generation androgen receptor antagonists in combination with ongoing ADT to improve the clinical outcomes in nmCRPC patients at high risk of metastatic progression. The Expert Council was presented with the data of a registration clinical study on darolutamide efficacy and safety. The advantages of introducing this drug into clinical practice to expand the choice of therapeutic options were identified. Personalized adjustment of a treatment regimen will increase the treatment efficacy and ensure higher survival in this category of patients. Conclusion: Increasing survival as the main objective in treating nmCRPC patients requires improved diagnostics through regular controlling of testosterone and PSA levels, calculation of PSA doubling time, and the use of radiological diagnostic methods to rule out distant metastases. The choice of therapy in patients at high risk of metastasis shall consider the patient’s status and the treatment efficacy and safety balance.

ENZA-p: A randomized phase II trial using PSMA as a therapeutic agent and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS177-TPS177
Author(s):  
Louise Emmett ◽  
Shalini Subramaniam ◽  
Alison Yan Zhang ◽  
Andrew James Martin ◽  
Sonia Yip ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Fdg Pet ◽  
Predictive Biomarkers ◽  
Receptor Expression ◽  
Receptor Blockade ◽  
Castration Resistant Prostate Cancer ◽  
Concurrent Administration ◽  
Castration Resistant ◽  
Psma Pet

TPS177 Background: 177Lu‐PSMA‐617 (LuPSMA) is a novel radionuclide with promising activity and tolerability in metastatic, castration-resistant prostate cancer (mCRPC). Pre-clinical studies have shown that androgen receptor blockade with enzalutamide upregulates PSMA-receptor expression, and that PSMA-receptor blockade increases treatment response to enzalutamide. We hypothesise that concurrent administration of LuPSMA and enzalutamide will be synergistic in mCRPC. The aims of ENZA-p are to determine the activity and safety of LuPSMA and enzalutamide in men with mCRPC at high-risk of early progression on enzalutamide alone; and to identify potential prognostic and predictive biomarkers from imaging, blood, and tissue. Methods: This open-label, randomised, multicentre, phase 2 trial will recruit 160 men with mCRPC. Key eligibility criteria include progression on androgen deprivation therapy, 2 or more high-risk features for early (LDH ≥ULN; ALP ≥ULN; albumin <35 g/L; M1 disease at diagnosis; <3 years from initial diagnosis to randomisation; >5 bone metastases; visceral metastases; PSA doubling time <84 days; pain requiring opiates >14 days; prior abiraterone), no prior treatment with a novel androgen signalling inhibitor (except abiraterone), no prior chemotherapy for mCRPC, and PSMA-avid disease on positron emission tomography (PET) with 68Ga-PSMA. Participants are randomly assigned (1:1) enzalutamide 160 mg daily or enzalutamide 160 mg daily plus LuPSMA 7.5 GBq on days 15 and 57. Two subsequent doses of Lu-PSMA will be administered if the 68Ga-PSMA PET on day 92 shows persistent PSMA expression in the tumour. Imaging assessments include CT and technetium bone scan at baseline, day 99, then every 12 weeks; 68Ga-PSMA-11 PET at baseline, days 15, 92, and first progression; and 18F FDG PET at baseline and first progression. Translational samples including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA) and biopsies (optional) will be collected at baseline, day 92, and first progression. The primary endpoint is PSA progression-free survival (PSA-PFS). Secondary endpoints include radiological-PFS, PSA-response rate, pain response and PFS, clinical-PFS, overall survival, health related quality of life, adverse events, and cost-effectiveness. Correlative studies include identification of prognostic and predictive biomarkers from 68Ga-PSMA, 18F FDG PET/CT, CTCs, and ctDNA. A sample size of 160 provides 80% power with a 2-sided type 1-error rate of 5% to detect a HR of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone. Accrual was 5 on 13 October 2020. ENZA-p is an investigator-initiated, academic trial led by ANZUP in collaboration with the NHMRC Clinical Trials Centre, University of Sydney. Clinical trial information: NCT04419402.

Detection of Lymph Node Metastases in Patients With Prostate Cancer: Comparing Conventional and Digital [18F]-fluorocholine PET-CT Using Histopathology as Reference

2021 ◽  
Author(s):  
Mimmi Bjöersdorff ◽  
Christopher Puterman ◽  
Jenny Oddstig ◽  
Jennifer Amidi ◽  
Sophia Zackrisson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lymph Node ◽  
High Risk ◽  
Lymph Nodes ◽  
Lymph Node Metastases ◽  
Reconstruction Algorithms ◽  
High Risk Prostate Cancer ◽  
Pet Ct ◽  
Risk Prostate Cancer ◽  
Node Metastases

Abstract Background: Positron emission tomography-computed tomography (PET-CT) can be used to detect and stage metastatic lymph nodes in intermediate to high-risk prostate cancer. Improvements to hardware, such as digital technology, and to software, such as reconstruction algorithms, have recently been made. We compared the capability of detecting regional lymph node metastases using conventional and digital silicon photomultiplier (SiPM)-based PET-CT technology for [18F]-fluorocholine (FCH). Extended pelvic lymph node dissection (ePLND) histopathology was used as the reference method.Methods: Retrospectively, a consecutive series of patients with prostate cancer who had undergone staging with FCH PET-CT before ePLND were included. Images were obtained with either a conventional or a SiPM-based PET-CT and compared. FCH uptake in pelvic lymph nodes beyond the uptake in the mediastinal blood pool was considered to be abnormal.Results: One hundred eighty patients with intermediate or high-risk prostate cancer were examined using a conventional Philips Gemini PET-CT (n = 93) between 2015 and 2017 or a digital GE Discovery MI PET-CT (n = 87) from 2017 to 2018. Images that were obtained using the Philips Gemini PET-CT system showed 19 patients (20%) with suspected lymph node metastases compared with 40 patients (46%) using the GE Discovery MI PET-CT. Sensitivity, specificity, and positive and negative predictive value (PPV and NPV) were 0.30, 0.84, 0.47, and 0.72, respectively, for the Philips Gemini and 0.60, 0.58, 0.30, and 0.83, respectively for GE Discovery MI. Area under the curve (AUC) in a receiver operating characteristics (ROC) analysis was similar between the two PET-CT systems (0.58 and 0.58, P = 0.8).Conclusions: A marked difference in sensitivity and specificity was found for the different PET-CT systems, although similar overall diagnostic performance. This is probably due to differences in both hard- and software, including reconstruction algorithms, and should be considered when new technology is introduced.

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