ASCO 2022

ASCO 2022: Association of RB1 Mutational Status with Overall Genomic Landscape in Neuroendocrine Prostate Cancer (NEPC)

(UroToday.com) Neuroendocrine prostate cancer (NEPC) is an increasingly common and particularly aggressive subtype of prostate cancer. The molecular program that gives rise to development of NEPC remains incompletely understood. Among the genomic alterations associated with NEPC is alterations in RB1, although this is known to not be necessary nor sufficient for transformation. Here Dr. Grivas and colleagues sought to evaluate the impact of RB1 in NEPC cases.

ASCO 2022: Circulating Tumour Cells (CTCs) and PSMA PET Correlates in the Phase I PRINCE Trial of 177Lu-PSMA-617 plus Pembrolizumab for Metastatic Castration Resistant Prostate Cancer (mCRPC)

(UroToday.com) As now increasingly appreciated, PSMA-targeted radionuclides are safe and effective therapies in metastatic castration resistant prostate cancer (mCRPC). Despite this, there are approximately half of patients in the published large studies (e.g. TheraP, VISION) who do not experience a significant PSA decline. Whether due to patient selection, mechanism of targeting, or radionuclide, ongoing work is active to enhance the efficacy of PSMA-TRTs for more patients. To this goal, the phase I PRINCE study was launched to evaluate the safety and efficacy of 177Lu-PSMA-617 in combination with an immune checkpoint inhibitor (pembrolizumab) in mCRPC.

ASCO 2022: A Randomized Phase Ib/II Study of Intermittent Androgen Deprivation Therapy Plus Nivolumab With or Without Interleukin-8 Blockade in Men With Hormone-Sensitive Prostate Cancer (MAGIC-8)

(UroToday.com) Thus far the revolution of immune checkpoint inhibitors (ICI) has largely passed by prostate cancer. Despite the past success of autologous cellular therapy (Sipuleucel-T), immunotherapy has had limited efficacy in prostate cancer. Advancing the use of immune-based therapies for prostate cancer is an actively pursued goal and a space in which successful use of ICI would be a breakthrough.

ASCO 2022: Introduction - Panel Question and Answer

(UroToday.com) As an introduction to this case based session, Dr. VanderWeele laid the groundwork for a discussion primarily around T-cell redirection in advanced prostate cancer to prevent cancer progression and death. This is an interesting and important topic as immunotherapy has not been as effective in prostate cancer as opposed to other solid tumor malignancies. There are putative tumor antigens in prostate cancers that could be exploited for immunotherapy purposes. However, challenges in this field have included the relative immune-excluded microenvironment of prostate cancer, potential unique difficulties in immunotherapy targeting primarily bone metastases, and the comorbidities of this patient population.

ASCO 2022: Future Targets for Cellular Therapy in Prostate Cancer

(UroToday.com) In his portion of this case-based discussion, Dr. Narayan discussed some of the barriers to the efficacy of CAR-T therapies. These include limited T-cell expansion or persistence once infused, dysfunction of infused T-cells, tumor immune escape by down-regulation of the targeted tumor antigen, and inflammatory toxicities such as CRS or neurotoxicity.

ASCO 2022: CAR T for Prostate Cancer: Current Strategies to Improve Efficacy

(UroToday.com) In her portion of this case-based panel, Dr. Dorff described chimeric antigen receptor T-cell (CAR-T) therapy and its potential use in prostate cancer. She indicated that CAR-Ts are especially exciting given their potential to induce long-term disease responses, such as have been seen in leukemias and lymphomas. CAR-T cells are a flexible platform, where in addition to introducing a chimeric receptor against a tumor antigen into T-cells, they can be engineered to have immune-co-stimulatory domains and even secrete cytokines to help support T-cell proliferation. Future generations of CARs may also have a conditional expression or be able to be targeted against multiple tumor antigens.

ASCO 2022: T-Cell Engagers for Prostate Cancer: Efficacy and Toxicity Management

(UroToday.com) Dr. Schweizer began the case-based discussion of T-cell redirection against prostate cancers using the context of the case shown below.

 

ASCO 22_Michael Thomas Schweizer_0 

 

Despite progress on multiple lines of therapy for metastatic castration resistant prostate cancer, this patient has good performance status and organ function, and would be a reasonable candidate for clinical trials. Dr. Schweizer discussed that he may consider this patient for a trial testing the efficacy of bi-specific T-cell engagers (BiTEs).

 

BiTEs are immunotherapies that engage both T-cells as well as a tumor-specific antigen to induce cytotoxic cell death as well as immune cell compartment expansion. An example of a BiTE that is undergoing clinical testing in prostate cancer is AMG160, which engages T-cells and PSMA-expressing cells including prostate cancer cells. Other BiTEs are being developed against other tumor antigens like PSCA, KLK2, and other proteins.

 

ASCO 22_Michael Thomas Schweizer_1 

 

Dr. Schweizer summarized data around a few BiTEs that are in clinical development. He summarized data originally presented at ESMO 2020 of the first in human study of AMG160 monotherapy as part of a dose-exploration cohort in patients who had progressed on second-generation androgen pathway inhibitors as well as taxane (or ineligible for taxane). Of the 43 patients presented, the majority of patients had received four or more prior lines of therapy. Over 90% of patients had clinical evidence of cytokine release syndrome (CRS), with 11 patients sustaining grade 3 CRS, though no grade 4 or 5 events were reported. About a third of patients had PSA responses of more than 50%, and 8 patients had stable disease with two patients having partial responses by RECIST criteria.

 

ASCO 22_Michael Thomas Schweizer_2 

 

He then summarized phase 1 data for the HPN424 BiTE which has a similar structure to AMG160 but also has an albumin linker between the CD3 and PSMA domains to extend half life. Data first presented at ASCO 2021showed stable disease in over 50% of the heavily-pretreated patients on study, and PSA50 responses in 5.4% of patients. A large majority of patients had CRS, though only 4% of patients had grade 3 or higher symptoms. Dr. Schweizer cautioned against comparing the AMG160 and HPN424 efficacy results given they were data from various stages of non-equivalent dose escalations.

 

ASCO 22_Michael Thomas Schweizer_3 

 

The patient in this case was enrolled on a BiTE immunotherapy trial. This required weekly infusions and inpatient hospitalization for monitoring until the 2nd infusion at the target dose was administered. With the priming dose, dexamethasone premedication was given, and the patient sustained rigors, tachycardia and low grade fever for several hours. A week later at the target dose with premedication, the patient again had rigors and tachycardia as well as hypotension requiring IV fluids and brief treatment with pressors. CRP rose from 8 to 188. Tocilizumab, an IL-6 receptor antibody, was administered in response to the pressor-dependent hypotension with rapid resolution of symptoms.

 

Dr. Schweizer offered a primer on cytokine release syndrome (CRS), which is a non-antigen specific toxicity reflecting high levels of immune activation and release of cytokines, resulting in fever and potentially multi-organ system dysfunction. One clinically important cytokine mediator of CRS is IL-6. The table below lists some of the symptoms that are associated with CRS.

 

ASCO 22_Michael Thomas Schweizer_4 

 

Standard for clinical grading of CRS are shown below.

 

ASCO 22_Michael Thomas Schweizer_5 

 

Clinical management of CRS is aimed at ruling out other etiologies that can mimic CRS such as sepsis, and should include a broad laboratory panel (CBC, metabolic panel, inflammatory markers such as CRP and ferritin, coagulation panel, infectious work-up, consideration of cardiac and CT imaging). As shown in the data above, the CRS observed with BiTE therapy is usually low grade, ameliorated by dexamethasone premedication, and can be managed with IV fluids and anti-pyretics. Other measures that can reduce the severity of CRS include a dose step-up method starting with a lower priming dose before giving the target dose of the agent, and subcutaneous administration which may reduce cytokine levels, though this has been hampered by the development of anti-drug antibodies.

 

To wrap up this case presentation, the patient sustained a PSA decline of greater than 50% and had stable disease on conventional imaging at three months. At six months his PSA returned to his baseline, but his disease was stable on imaging. The patient discontinued therapy due to the side effects of dry mouth and anorexia.

 

 

Presented by: Michael Thomas Schweizer, MD, University of Washington, Fred Hutchinson Cancer Research Center

Written by: Alok K. Tewari, MD, PhD, medical oncologist at the Dana-Farber Cancer Institute, @aloktewar on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022. 

 

 

ASCO 2022: Genomic Alterations and Evolution in Patients With Prostate Cancer With Histologic Evidence of Neuroendocrine Differentiation

(UroToday.com) Increasingly neuroendocrine prostate cancer (NEPC) is both looked for and diagnosed, matching the rise of awareness of the potential treatment-emergent transdifferentiation and the earlier clinical use of highly potent AR targeted therapies. Histological, clinical, and genomic markers are associated with the presence of NEPC, yet the specific program that results in the development of treatment-emergent NEPC (tNEPC) is yet to be codified.

ASCO 2022: Bone Biomarkers and Overall Survival in Men with Advanced HSPC: Results from SWOG S1216, a Phase III Trial of ADT +/- Orteronel

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a presentation by Dr. Lucky Lara discussing data from the SWOG S1216 trial of ADT +/- orteronel assessing bone biomarkers and overall survival in men with advanced HSPC. Skeletal metastasis is common in men with advanced prostate cancer and is a frequent source of morbidity, and the homeostatic balance between bone formation and resorption is disrupted in these men. This disruption is clinically assessable with bone metabolism in the serum. Circulating bone biomarkers are strongly prognostic for OS in castration-resistant prostate cancer (CRPC). Dr. Lara and colleagues prospectively evaluated bone biomarkers in men with HSPC in S1216, a trial that established new OS benchmarks. They sought to identify patient subsets with differential OS outcomes as defined by bone biomarkers.

ASCO 2022: BRCAAway: A Randomized Phase 2 Trial of Abiraterone, Olaparib, or Abiraterone + Olaparib in Patients with mCRPC with DNA Repair Defects

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a presentation by Dr. Maha Hussain discussing BRCAAway, a randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with mCRPC with DNA repair defects. The PARP-inhibitor olaparib is approved for mCRPC patients with deleterious germline or somatic homologous recombination repair gene mutations. PARP1 interacts with androgen signaling, and castration-resistant tumor cells exhibit increased PARP1 activity. Preclinically, PARP1-inhibition synergizes with androgen receptor targeted therapy. BRCAAway is a biomarker selected, randomized, open-label, multicenter phase 2 trial evaluating efficacy of targeting androgen receptor vs PARP vs combination in first line mCRPC patients with germline and/or somatic homologous recombination repair gene mutations in BRCA1, BRCA2, or ATM.

ASCO 2022: A Phase 2 Randomized Study of Oral Docetaxel plus Ritonavir (ModraDoc006/r) in Patients with mCRPC

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a presentation by Dr. Ulka Vaishampayan discussing a phase 2 randomized study of oral docetaxel plus ritonavir (ModraDoc006/ritonavir) in patients with mCRPC. Intravenous docetaxel and oral prednisone is a standard of care regimen in patients with mCRPC. ModraDoc006 is an oral formulation of docetaxel and to enhance bioavailability of ModraDoc006 it is co-administered with ritonavir, an inhibitor of cytochrome P450 3A4 and P-glycoprotein. The ModraDoc006 and ritonavir combination is active in multiple docetaxel and cabazitaxel-resistant prostate cancer cell-lines. This combination has potential advantages in terms of patient convenience, elimination of infusion-related reactions, as well as other safety benefits regarding typical dose-limiting toxicities for taxanes. In this trial, the oral combination (ModraDoc006/ritonavir) was compared to IV docetaxel in a randomized phase 2b study of patients with mCRPC evaluating two doses of ModraDoc006/ritonavir (30-20/200-100 mg and 20-20/200-100 mg). At ASCO 2022, data on outcomes in the larger cohort, receiving the lower dose, were presented.

ASCO 2022: Defining More Precisely the Effects of Docetaxel plus ADT for Men with mHSPC: Meta-Analysis of Individual Participant Data from Randomized Trials

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a presentation by Dr. Claire Vale discussing a meta-analysis of individual participant data (IPD) from randomized trials to more precisely define the effects of docetaxel plus ADT for men with mHSPC. Adding docetaxel to ADT improves survival in mHSPC, but uncertainty remains about who benefits most. To investigate this thoroughly and reliably, the STOPCAP M1 collaboration conducted a meta-analysis of IPD from relevant trials.

ASCO 2022: Discussant: AR and PARP: Partners in Crime

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a discussant presentation by Dr. Heather Cheng discussing important abstracts incorporating inhibition of AR + PARP in advanced prostate cancer. Dr. Cheng discussed the following abstracts “BRCAAway: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with mCRPC with DNA repair defects” presented by Dr. Maha Hussain, “Tolerability of abiraterone combined with olaparib in patients with mCRPC: Further results from the phase III PROpel trial” presented by Dr. Antoine Thiery-Vuillemin, and “Gene-by-gene analysis in the MAGNITUDE study of niraparib with abiraterone acetate and prednisone in patients with mCRPC and HRR gene alterations” presented by Shahneen Sandhu.

ASCO 2022: Discussant: Familiar Faces and New Directions for Prostate Cancer

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a discussant presentation by Dr. Bradley Carthon discussing familiar faces and new directions for prostate cancer. Dr. Carthon started his presentation by highlighting the complexity of the prostate cancer treatment landscape:

ASCO 2022: Eight-Year Survival Rates by Baseline Prognostic Groups in Patients with mHSPC: An Analysis from the ECOG-ACRIN 3805 (CHAARTED) Trial

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a presentation by Dr. Abhishek Tripathi discussing 8-year survival rates by baseline prognostic groups in patients with mHSPC from the CHAARTED trial. Treatment intensification with docetaxel improves overall survival (OS) in mHSPC when added to testosterone suppression. To date there is no prospective survival data beyond 5 years for patients treated with ADT with or without docetaxel when analyzed by well-defined baseline prognostic risk groups and treatment arms. In this updated analysis of the CHAARTED trial.1,2 Dr. Tripathi and colleagues report the 8-year survival rate based on disease volume and metachronous versus de novo metastatic disease status with ADT without or with docetaxel.

ASCO 2022: Gene-by-Gene Analysis in the MAGNITUDE Study of Niraparib with Abiraterone Acetate and Prednisone in Patients with mCRPC and HRR Gene Alterations

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a presentation by Dr. Shahneen Sandhu discussing gene-by-gene analysis in the MAGNITUDE study of niraparib + abiraterone acetate + prednisone in patients with mCRPC and HRR gene alterations. Niraparib + abiraterone acetate + prednisone significantly improved outcomes in patients with mCRPC and HRR gene alterations in the phase 3 MAGNTUDE study. However, there is a paucity of data supporting the use of PARP inhibitors in patients with HRR gene alterations other than BRCA1/2. At ASCO 2022, Dr. Sandhu and colleagues reported on the efficacy of niraparib + abiraterone acetate and prednisone in patients with mCRPC and a  cc other than BRCA1/2.

ASCO 2022: PSMA PET Tumor-to-Salivary Glands Ratio (PSG Score) to Predict Response to Lu-177 PSMA Radioligand Therapy: An International Multicenter Retrospective Study

(UroToday.com) Despite the promise of PSA50 responses in about half of the patients treated on the phase III VISION study of 177Lu-PSMA, it cannot be overlooked that the balance of patients garnered little to no benefit from this emerging agent. One possible explanation for non-uniform response rates could arise from insufficiently specific patient selection. The authors of this study proposed that use of the parotid gland, an organ with typically higher PSMA expression on PSMA PET (as compared to liver) could serve as a better reference organ for more selective patient stratification.

ASCO 2022: Local and Focal: What’s Next in Salvage Therapy? - Discussion

(UroToday.com) Following three abstract presentations in the poster discussion session focused on Prostate, Testicular, and Penile at the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, Dr. Mark Garzotto provided a discussion of salvage therapies in patients with prostate cancer.

ASCO 2022: Cohort Study of Patients With Oligorecurrent Prostate Cancer: Oncological Outcomes of Patients Treated With Salvage Lymph Node Dissection via PSMA Radioguided Surgery

(UroToday.com) At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster session focused on Prostate, Testicular, and Penile cancers on Monday afternoon included a presentation from Dr. Sophie Knipper discussing prostate-specific membrane antigen (PSMA)-guided radiosurgery for oligorecurrent prostate cancer.

ASCO 2022: Outcome of Patients with PSMA PET/CT Screen Failure by VISION Criteria and Treated with 177Lu-PSMA Therapy: A Multicenter Retrospective Analysis

(UroToday.com) As it has been well-covered in this publication and others, the VISION trial demonstrated prolonged survival and improve quality of life for patients with advanced mCRPC who received 177Lu-PSMA as compared to a chemotherapy-free standard of care alternative. To enroll, patients must have demonstrated on PSMA PET-CT (68Ga-PSMA-11) at least one positive lesion and zero negative lesions. Positivity was defined as uptake greater than the liver parenchyma background. The authors here investigated the outcome of those patients deemed ineligible by inadequate PSMA PET imaging alone. In the phase III study, screen failure due to PSMA PET findings was 12.6% (126/1003). The authors deployed a registry compiled of patients treated with at least 1 cycle of 177Lu-PSMA, all retrospectively studied. Using a dual certified nuclear medicine and radiology reader, baseline PSMA PET-CT studies were reviewed and classified as either eligible (VISION=PET-E) or ineligible (VISION-PET-SF, i.e. Screen Failure). The mechanism of screen failure included absence of a metastatic lesion with SUV greater than liver or the presence of one or more lesion measurable by CT but with uptake less than liver background.

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