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Introduction & Objectives: The incidence of prostate cancer, both in the world and in the Russian Federation, tends to increase. In the Republic of Bashkortostan in 2021, 699 patients with this diagnosis were registered. 19.6% of patients had stage IV disease at the time of diagnosis. 5818 patients were registered, of which 361 died within a year. The effectiveness of hormonal treatment of common prostate cancer has time limitations, after which there is a development of resistance to castration and progression of the disease. To date, drugs such as kabazitaxel, sipuleucel-T vaccine, abiraterone, enzalutamide and radium-223 have been approved for use in metastatic CRPC. The purpose of the work: analysis of the experience of systemic radiotherapyand Radium - 223 patients with mCRPC in the Republic of Bashkortostan in 2021. Material(s) and Method(s): Analysis of patients who received systemic radiotherapy Radium - 223 in the Republic of Bashkortostan according to medical documentation and research data. In 2021, Radiy-223 radiotherapy was performed on 7 patients diagnosed with mCRPC. Median age 63.14 years. All patients met the criteria for treatment, i.e. had castration-resistant prostate cancer with bone metastases, without visceral metastases. All patients had concomitant pathology from the cardiovascular system, respiratory tract, endocrine system. According to the previous surgical treatment, patients were distributed as follows: orchidectomy - 4, prostatectomy - 1 and 2 patients underwent tumor biopsy. By morphology: Glisson 6 - 2 patients, Glisson 7 - 1, Glisson 8 - 3, Glisson 10 - 1. 4 patients were referred to Xofigo for radiologically confirmed progression, 3 patients were progressingin height at PSA levels. Result(s): 1 patient previously received 1 line of systemic therapy, 5 patients received 2 lines, 1 patient received 3 lines of therapy. 6 patients received all 6 courses of radiotherapy, 1 patient did not complete treatment due to COVID 19. He is expected to complete therapy. All patients are currently alive with no signs of disease progression. Serious side effects were not registered. Conclusion(s): The "therapeutic window" for the prescription of radium-223 is the period before the appearance of visceral metastases and decline of the somatic status. To achieve the maximum benefit from the appointment of radium-223, it is necessary to conduct >=5 cycles of therapy, which is possible in 1-2 treatment lines. It is necessary to select patients carefully for radiotherapy - Radium 223.Copyright © 2022 European Association of Urology. Published by Elsevier B.V.
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Background: Lorigerlimab (MGD019) is an investigational, bispecific Fc-bearing (IgG4) DART molecule designed to enhance CTLA-4 blockade on dual expressing, tumor infiltrating lymphocytes, while maintaining maximal PD-1 blockade on PD-1 expressing cells. Lorigerlimab has approximate dose proportional PK across 1-10 mg/kg IV dosing Q3W, with sustained PD-1 receptor occupancy evident at doses >=1 mg/kg Q3W. MGD019-01 is a global first-in-human dose finding and activity estimating study of lorigerlimab in advanced solid tumors (AST). Method(s): The exp phase of MGD019-01 evaluates single agent safety, PK, and antitumor effects of lorigerlimab at the recommended dose for exp of 6 mg/ kg IV Q3W in 4 tumor specific cohorts. Confirmed responses were noted in each cohort. Preliminary results of the mCRPC cohort are reported here. Response evaluable pts received >=1 dose and had >=1 postbaseline imaging evaluation. Measurable lesions were evaluated per RECIST v1.1 and skeletal metastases assessed by bone scan. Prostate specific antigen (PSA) response was defined as a >=50% (PSA50) or>=90% (PSA90) PSA decline from baseline with confirmation>=3 weeks later. Expression of proliferation marker, Ki67, and inducible costimulator (ICOS) by peripheral T cells was assessed by flow cytometry. Result(s): At data cutoff (9/10/22), 127 pts with AST received >=1 dose of lorigerlimab 6 mg/ kg. Median exposure was 10 weeks (range, 0.1, 94.4) with median of 4 infusions. 6 pts remain on therapy;36 discontinued for PD (n=13), AEs (n=17), or patient/physician decision (n=6). Treatment related adverse events (TRAE) occurred in 109/127 (85.8%) pts. TRAEs occurring in>=15% of pts were fatigue, pruritus, hypothyroidism, pyrexia. Rates of grade >=3 TRAEs and immune-related AEs were 32.3% and 7.9%, respectively. AEs leading to drug discontinuation occurred in 22.8% of pts. There were no fatal AEs related to lorigerlimab. In the mCRPC exp cohort (n=42), pts had a median of 2 prior lines of therapy for CRPC, >80% received prior ART or taxanes;88% had visceral (liver, 26%;lung, 26%) or nodal disease and 95% had bone metastases. 42 pts were PSA response evaluable;35 were RECIST evaluable. ORR was 25.7% (9/35;9 confirmed PRs). Median duration of response was 16.1 weeks (range 6-25+ weeks). 5 responders remain on study, 4 discontinued for unrelated fatal AEs: COVID-19 (2) cardiac arrest (1) C. difficile infection (1). Confirmed PSA50 and PSA90 response rates were 28.6%(12/42) and 21.4% (9/42), respectively. Increased frequencies of Ki67+ and ICOS+ T cells were observed on day 8 posttreatment compared to pretherapy per the flow cytometry analyses from 35 pts. Conclusion(s): Lorigerlimab demonstrates a manageable safety profile with evidence of encouraging and durable antitumor activity in a chemotherapy refractory mCRPC population. Randomized evaluation of lorigerlimab in mCRPC is warranted.
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Ongoing research into the use of messenger RNA (mRNA) vaccines for the treatment of cancer has been expediated by the coronavirus pandemic because similar technology was used in the development of mRNA COVID-19 vaccines. So how close are we now to the widespread clinical use of mRNA anti-cancer vaccines?.Copyright © 2023 Wiley Interface Ltd.
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Background: The RECORD Study is a real world data, prospective evaluation of clinical outcomes in patients with nmCRPC treated with Darolutamide. This study will increase the understanding of treatment response and management and in particular informregarding use of next generation imaging in this setting. Method(s): Patient data from 9 UK centres was collected based on the recommendation of NICE for Darolutamide as an option for the treatment of non-metastatic castrate resistant prostate cancer (nmCRPC) from November 2020. Data cut-off was 15 September 2022. The study is ongoing. Result(s): 87 patients were analysed with a median age of 78 (range 61-92). Median pre-treatment PSA and PSA doubling time (PSAdT) were 13 (range 1.99-110.6) mg/L and 5.05 (range 0.6 -10) months. 42 patients (49.4%) had pre-treatment PSAdT of <6 months and 43 (50.6%) patients had PSAdT of >=6 months (2 patients had no pre-treatment PSAdT data). 6 patients (6.90%) had next generation imaging prior to initiation of Darolutamide. Median duration of treatment on Darolutamide was 17 months for patients with pre-treatment PSAdT <6 months but median duration had not been reached for patients with pre-treatment PSAdT >=6 months after 24 months of treatment, a significant difference p=0.018 (HR=0.385, 95% CI 0.17-0.88). 30 patients have come off treatment so far (34.5%);21 (70%) for disease progression, 5 (16%) for a medical cause unrelated to the drug (e.g. COVID infection, reduced performance status secondary to pre-existing Parkinson's), 3 (10%) for unacceptable toxicity (rash, Grade3 fatigue, muscle aches, memory issues), and 1 patient died (unrelated). Conclusion(s): In the RECORD study, predominantly the diagnosis of nmCRPC is based on conventional imaging. The majority of patients respond and tolerate Darolutamide well, comparable with the ARAMIS trial. There is a significant difference between time on Darolutamide for those with pre-treatment PSAdT of<6 months compared with>=6 months. Further long-term toxicity, MFS and OS data will continue to be collected prospectively within the study.
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BACKGROUND: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. OBJECTIVE: To present the voting results of the APCCC 2022. DESIGN, SETTING, AND PARTICIPANTS: The experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. RESULTS AND LIMITATIONS: The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. CONCLUSIONS: These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. TWITTER SUMMARY: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. TAKE-HOME MESSAGE: At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here.
Subject(s)
COVID-19 , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Prostatic Neoplasms, Castration-Resistant/pathology , Diagnostic Imaging , HormonesABSTRACT
Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options. Trial Registration Clinical Trial Registration: NCT04446117 (ClinicalTrials.gov) Registered on 24 June 2020.
Subject(s)
Adenocarcinoma/drug therapy , Anilides/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Pyridines/therapeutic use , Adenocarcinoma/pathology , Androstenes/therapeutic use , Benzamides/therapeutic use , Humans , Male , Neoplasm Metastasis , Nitriles/therapeutic use , Phenylthiohydantoin/therapeutic use , Prostatic Neoplasms, Castration-Resistant/pathology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitorsABSTRACT
Background: The Phase III PROpel (NCT03732820) trial demonstrated at interim analysis a statistically significant clinical benefit from combining ola + abi in the first-line (1L) mCRPC setting vs placebo (pbo) + abi. Benefit was seen irrespective of a pt's homologous recombination repair mutation (HRRm) status;median radiographic progression-free survival (rPFS) 24.8 for ola + abi vs 16.6 months for pbo + abi (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54-0.81;P<0.0001). The safety profile of ola + abi was shown to be consistent with that for the individual drugs. We report additional interim safety analysis from PROpel. Methods: Eligible pts were ≥18 years with mCRPC, had received no prior chemotherapy or next-generation hormonal agent treatment at mCRPC stage, and were unselected by HRRm status. Pts were randomized 1:1 to abi (1000 mg qd) plus prednisone/prednisolone with either ola (300 mg bid) or pbo. Primary endpoint was investigator-assessed rPFS. Safety was assessed in all pts receiving ≥1 dose of study treatment by adverse event (AE) reporting (CTCAE v4.03). Results: 398 pts received ola + abi and 396 pbo + abi (safety analysis set). At data cut-off (July 30, 2021), median total duration of exposure for ola was 17.5 vs 15.7 months for pbo, and for abi 18.2 months in the ola + abi arm and 15.7 in the pbo + abi arm. Anemia (n=183) was the most common AE in the ola + abi arm, and 34% of these 183 events were managed by dose interruption, 23% by dose reduction, and 8% resulted in treatment discontinuation. Anemia and pulmonary embolism (PE) were the only Grade ≥3 AEs in ≥5% of pts (anemia: ola + abi, 15.1% vs pbo + abi, 3.3%;PE: 6.5% vs 1.8%, respectively). Most PEs were detected incidentally on radiographic imaging (69.2% and 71.4% in the ola + abi and pbo + abi arms, respectively) and no pts discontinued. More pts in the ola + abi arm experienced venous thromboembolism (Table). Arterial thromboembolism and cardiac failure AEs were balanced between the treatment arms. No AE of myelodysplastic syndrome/acute myeloid leukemia was reported in either treatment arm. COVID-19 was reported more frequently with ola + abi (8.3% vs 4.5%). Conclusions: PROpel demonstrated a predictable safety profile for ola + abi given in combination to pts with 1L mCRPC unselected by HRRm status. AEs of cardiac failure and arterial thromboembolism were reported at similar frequency in both treatment arms. The majority of PEs were asymptomatic. The safety profile of abiraterone was not adversely impacted by its combination with olaparib.
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Introduction A global trial is currently investigating the impact of high-intensity interval training (HIIT) on survival in advanced prostate cancer (the INTERVAL trial). To ensure greater accessibility, we designed a parallel trial (EXACT), to determine the feasibility of exercise in those contraindicated to HIIT. Methods Men with metastatic castrate-resistant prostate cancer being actively treated with androgen deprivation therapy and a novel hormone therapy (abiraterone acetate or enzalutamide) are eligible to participate in 12- weeks of home-based walking and strengthening. Participants complete physical (e.g. 6-min walk test and timed sit-to-stand) and quality of life (e.g. BPI-SF;EQ-5D-5L;FACIT-fatigue;FACT-P) outcomes at baseline (T1), 12 (T2) and 24 weeks (T3). This trial was adapted to enable remote recruitment and delivery during the COVID-19 pandemic. Results To date, 118 patients have been screened, with 33 approached by their clinician to participate. 25 patients have consented, with 12 completing the trial without any intervention-related adverse events and 6 withdrawn. Recruitment and trial delivery was operational throughout the COVID-19 pandemic. Currently positive trends are evident for physical and quality of life outcomes at T2 and T3. Conclusions Although this trial is ongoing, early trends suggest this intervention is safe and feasible for men with advanced castration resistant prostate cancer and could improve physical capacity and quality of life.
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PURPOSE: This article summarizes current androgen receptor (AR)-directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC). SUMMARY: PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone-releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR gene overexpression, and mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism, possess a higher affinity for AR, and are postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects. CONCLUSION: Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Receptors, Androgen , Androgen Antagonists/therapeutic use , Androgen Receptor Antagonists/therapeutic use , Androgens/metabolism , Gonadotropin-Releasing Hormone/agonists , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Humans , Male , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Signal Transduction , TestosteroneABSTRACT
The goal of this project is to develop a novel chimeric antigen receptor natural killer cell (CAR NK cell) therapy for the treatment of highly aggressive androgen receptor negative prostate cancer by targeting the cell surface antigen CD133. The CAR NK cells were going to be made from primary NK cells isolated from the peripheral blood of healthy donors using adeno associated virus (AAV) and CRISPR/cas9. The objective was to create these CAR NK cells and then subsequently test them using in vitro and in vivo models of highly aggressive prostate cancer. Thus far we have encountered much difficulty manipulating the primary NK cells to successfully express CARs. Coupled with the COVID-19 pandemic, little progress has been made on this project thus far.
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BACKGROUND: Patients with cancer are at increased risk of complicated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, but it is still unclear if the risk of mortality is influenced by cancer type or ongoing anti-cancer treatments. An interesting debate concerning the potential relationship between androgen deprivation therapy (ADT) and SARS-CoV-2 infection has recently been opened in the case of prostate cancer (PC), and the aim of this multi-centre cohort study was to investigate the incidence and outcomes of SARS-CoV-2 infection in patients with metastatic castration-resistant prostrate cancer (mCRPC). PATIENTS AND METHODS: We retrospectively reviewed the clinical records of patients with mCRPC who developed SARS-CoV-2 infection, and recorded their baseline clinical characteristics, their history of PC and SARS-CoV-2 infection, and their oncological status and treatment at the time of infection. The primary study end point was the death rate and the possible impact of the patients' PC-related history and treatments on mortality. RESULTS: Thirty-four of the 1433 patients with mCRPC attending the participating centres (2.3%) developed SARS-CoV-2 infection, 22 (64.7%) of whom were hospitalised. Most of the patients were symptomatic, the most frequent symptoms being fever (70.6%), dyspnoea (61.8%), cough (52.9%) and fatigue (38.2%). After a median follow-up of 21 days (interquartile range: 13-41), 13 patients had died (38.2%), 17 recovered (50.0%) and four (11.7%) were still infected. The number of treatments previously administered for mCRPC had a significant impact on mortality (p = 0.004). CONCLUSIONS: Our findings contribute additional data to the current debate concerning the postulated protective role of ADT, which seems to be less in patients with metastatic PC.