Castration-resistant metastatic prostate cancer: new targeted radioligand therapy reduces risk of death by 38%
Advances in the treatment of metastatic castration-resistant prostate cancer. A new targeted radioligand therapy. Novartis today announces the results of the Phase III VISION study which he rated 177Lu-PSMA-617 in addition to best standard of care (SOC) demonstrating a significant improvement in overall survival (OS) over standard of care (SOC) alone, in patients with metastatic castration-resistant progressive prostate cancer (mCRPC) 1, antigen positive specific membrane of the prostate (PSMA).
177Lu-PSMA-617 is able to reduce the risk of death by 38 %1. The difference in overall survival between the study arms was statistically significant (p <0.001 unilateral), with an estimated 38% reduction in the risk of death in the 177Lu-PSMA-617 arm (n = 551) compared to the arm with best standard of care only (n = 280) (hazard ratio: 0.62 with 95% confidence interval (CI): (0.52, 0.74)) 1. The results will be presented on June 6 during the plenary session of the American Society of Clinical Oncology (ASCO) 2021 Congress.
Patients treated with 177Lu-PSMA-617 also demonstrated a statistically significant (p <0.001 unilateral) 60% reduction in the risk of radiographic progression (rPFS) compared to the best standard of care arm alone (hazard ratio: 0, 40 with confidence interval (CI) 99.2% CI: (0.29 0.57)) 1. There was a higher rate of therapy-related adverse events (85.3%) than standard of care alone (28.8%) in the 177Lu-PSMA-617 treatment arm.
In both arms of the study, treatment discontinuation rates associated with adverse events resulting from therapy presented as follows: In the 177Lu-PSMA-617 plus standard of care (SOC) arm, 11.9% of patients had discontinued 177Lu-PSMA-617 and 8.5% discontinued SOC; while in the SOC alone arm, 7.8% of patients discontinued treatment.
“We are entering the era of precision medicine in prostate cancer with the VISION study – he says Giuseppe Procopio, Head of Genitourinary Medical Oncology of the IRCCS Foundation National Cancer Institute of Milan -. For the first time, the selective antitumor action of a radiopharmaceutical, Lutetium, is demonstrated in patients with disease in the phase of resistance to castration. The anticancer efficacy of Lutetium induced a significant advantage in progression-free and overall survival in patients selected on the basis of an innovative diagnostic test such as PET PSMA ”.
“In 2020, about 36 thousand new cases of prostate cancer were estimated in Italy – he explains Sergio Bracarda, Director of the Oncology Department and of the Complex Structure of Medical and Translational Oncology of the Santa Maria di Terni Hospital -. The impact of metastatic prostate cancer on the daily life of patients who develop symptoms related to the disease can be important, in some cases limiting the possibility of sleeping or walking due to pain. The new targeted therapy with radioligand, in addition to showing very promising clinical efficacy, represents an innovative and non-cross-reactive therapeutic approach with other drugs already available, in a ‘complex’ disease to be treated. 177Lu-PSMA-617 is directed against prostate specific membrane antigen (PSMA), which is overexpressed in most prostate cancer cells. In particular, it has the ability to act only on diseased tissues, saving everything around “.
“Nuclear medicine uses radioactive substances to target cancer cells – he stresses Ettore Seregni, Director of the Nuclear Medicine Complex Structure of the IRCCS National Cancer Institute of Milan -. The approach to a pathology such as prostate cancer must necessarily be multidisciplinary. In fact, the nuclear doctor works in a team with the oncologist and assesses whether the patient is a candidate for treatment with 177Lu-PSMA-617 by analyzing the results of the diagnostic PET performed previously. It is foreseeable that this therapy can be performed in many cases also on an outpatient basis, therefore without the need for hospitalization of the patient. The radiation emitted by the patient, in fact, is limited and the radioactivity disappears in a short time, so, following the appropriate precautions and indications, no risks for caregivers and family members are foreseeable “.
Two further studies of 177Lu-PSMA-617 radioligand therapy in the first lines of metastatic prostate cancer are planned to start in the first half of 2021, for the study of the potential clinical utility in the pre-taxane setting (PSMAfore) of the mCRPC and in the metastatic hormone-sensitive setting (PSMAddition).
Further data from the VISION study
In the VISION study, the median overall survival (95% CI) in the 177Lu-PSMA-617 adjunct standard of care arm was 15.3 months (14.2 – 16.9), compared with 11.3 months ( 9.8 – 13.5) in the one with only the best standard of care1. Radiographically detected progression-free survival (rPFS) (99.2% CI) was 8.7 months (7.9 – 10.8) for the 177Lu-PSMA-617 arm compared with 3.4 months (2, 4 – 4.0) for the arm with only the best standard of care.
Major secondary endpoints were also met. The mean time to development of the first symptomatic skeletal event was 11.5 months (95% CI: 10.3 -13.2) in the 177Lu-PSMA-617 arm compared to 6.8 months (95% CI: 5, 2 – 8.5) in the one with only the best standard of care (hazard ratio: 0.50 (95% CI: 0.40 – 0.62)); bilateral p-value: <0.0011. In addition, significant differences were observed in the overall response rate of patients with measurable disease at baseline (51.1% partial or complete response in the 177Lu-PSMA-617 arm versus 3.1% partial response in the best-alone arm. standard of care (bilateral p-value: <0.001) and disease control rate (86.4% in the 177Lu-PSMA-617 arm versus 50.0% in the best standard of care only (p- bilateral value: <0.001).
Grade ≥3 therapy-related adverse events occurred in 28.4% in the 177Lu-PSMA-617 arm compared with 3.9% in the best standard of care arm alone1. The most common events (greater than 2% for 177Lu-PSMA-617 and best standard of care, respectively) were anemia (12.9% vs. 4.9%), thrombocytopenia (7.9% vs. 1%), lymphopenia (7.8% vs 0.5%), fatigue (7.0% vs 2.4%), urinary tract infection (3.8% vs 0.5%) neutropenia (3.4% vs 0, 5%), hypertension (3.2% vs 1.5%), acute kidney injury (3.0% vs 2.4%), leukopenia (2.5% vs 0.5%), bone pain (2 , 5% vs. 2.4%), and hematuria (2.5% vs. 0.5%).
Therapy-related serious adverse events were observed in 9.3% of patients in the 177Lu-PSMA-617 arm compared with 2.4% in the best standard of care alone.
Advanced prostate cancer
Prostate cancer is a form of cancer that develops in the prostate gland, a small, walnut-shaped gland in the pelvis of men. In castration resistant prostate cancer (CRPC), the cancer shows signs of growth, such as increased prostate specific antigen (PSA) levels, despite the use of hormone treatments that lower testosterone7. In castration-resistant metastatic prostate cancer (mCRPC), the cancer spreads to other sites in the body such as adjacent organs or bones and does not respond to hormone treatment7. The 5-year survival rate of patients with metastatic prostate cancer is approximately 30% 2.
Phenotypic precision medicine in advanced prostate cancer
Despite advances in prostate cancer treatment, there is a strong unmet need for new targeted treatment options to improve outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC). More than 80% of prostate cancers express in high quantities a phenotypic biomarker6 called Prostate Specific Membrane Antigen (PSMA) 3-5,8-9, making it a promising diagnostic target (via positron emission tomography (PET)) and potential therapeutic target for radioligand therapy10. It differs from “genotypic” precision medicine which deals with the specific genetic alterations of cancer cells.
Therapy with 177Lu-PSMA-617
177Lu-PSMA-617 is an experimental PSMA-directed ligand therapy in castration-resistant metastatic prostate cancer. It is a precision anticancer treatment that combines a targeted compound (ligand) with a therapeutic radioisotope (a radioactive particle) 11-13. After administration into the bloodstream, 177Lu-PSMA-617 binds to prostate cancer cells expressing PSMA14, a transmembrane protein, with high tissue uptake from tumor to normal11,15,16. Once bound, radioisotope emissions damage cancer cells, disrupting their ability to replicate and / or triggering cell death17-19. Radiation from the radioisotope acts over very short distances to limit damage to surrounding cells10,11,15.
The VISION study
VISION is a prospective, randomized, open-label Phase III multicenter international study to establish the efficacy and safety of 177Lu-PSMA-617 (7.4 GBq administered by intravenous infusion every 6 weeks for up to 6 cycles) plus the best standard of care chosen by the investigator in the experimental arm, compared to the best standard of care in the control arm20. Patients with PET scan positive mCRPC for PSMA and progression after previous taxane and second generation antiandrogen (ARSI) therapy were randomized in a 2: 1 ratio in favor of the experimental arm. The primary alternative endpoints were radiographically verified progression-free survival (rPFS) and overall survival (OS) 20. The study enrolled 831 patients.
Novartis states that its media update contains forward-looking statements as defined by the United States Private Securities Litigation Reform Act of 1995.