Earlier use of a targeted radionuclide therapy delays metastatic prostate cancer progression when administered as part of a trio of drugs, according to a phase 3 clinical trial led by Weill Cornell Medicine, NewYork-Presbyterian, Memorial Sloan Kettering Cancer Center and investigators at several other institutions worldwide.
The results, published in The Lancet on Aug. 6, may change the standard of care for many patients with prostate-specific membrane antigen (PSMA)-positive metastatic prostate cancer. The most standard backbone of therapy had been an androgen receptor pathway inhibitor (ARPI) paired with androgen deprivation therapy (ADT). But the trial showed that adding a targeted radionuclide therapy drug called 177Lu-PSMA-617 or lutetium PSMA 617 vipivotide tetraxetan to backbone therapy in patients with PSMA-positive cancer reduces the risk of disease progression as determined by scans or death by 28% when given soon after the diagnosis of metastatic cancer. Results of the study and ongoing analyses led the U.S. Food and Drug Administration to approve early use of the drug for PSMA-positive metastatic prostate cancer in late July.
"About 9 out of 10 patients with metastatic prostate cancer have tumors that are positive for PSMA," said lead author Dr. Scott Tagawa , the Gebroe Family Professor of Hematology-Oncology in honor of Morton Coleman, M.D. at Weill Cornell Medicine and director of the Genitourinary Oncology Program at NewYork-Presbyterian/Weill Cornell Medical Center. "Now, we have a new therapy that, when added to the backbone therapy, extended radiographic progression-free survival for almost all patients with metastatic prostate cancer."
The PSMAddition trial, funded by Novartis, enrolled more than 1100 patients with minimally treated or untreated PSMA-positive prostate cancer across 169 sites in 20 countries, including NewYork-Presbyterian/Weill Cornell Medical Center and MSK. Half the participants received intravenous 177Lu-PSMA-617 every six weeks, with ADT and ARPI; the other half received the previous standard of care, ADT and ARPI only. Patients who were in the control arm were allowed to crossover to the triple therapy group if disease progression occurred.
More adverse events occurred in the patients who received 177Lu-PSMA-617, an expected result with triple therapy, said Dr. Tagawa, who is also a member of the Sandra and Edward Meyer Cancer Center and the Englander Institute of Precision Medicine at Weill Cornell Medicine. The most common was dry mouth, which occurred in 46% of patients. Fatigue, a typical side effect of radiation and hormonal therapy, was also common.
In addition to delayed progression, 177Lu-PSMA-617 increased the amount of time until a patient developed resistance and needed to switch to a new therapy and delayed symptoms of cancer spread to the skeleton. Previous trials by Dr. Tagawa and his colleagues had shown the drug was effective in patients with treatment-resistant metastatic prostate cancer, and it was approved for that purpose in 2022.
"Now our patients can get 177Lu-PSMA-617 at diagnosis and don't have to wait until they develop resistance to the backbone therapies," Dr. Tagawa said.
The drug's success is the result of more than two decades of collaboration between a multidisciplinary team of Weill Cornell Medicine investigators and the team's colleagues at MSK. It consists of an agent that targets the PSMA protein on the surface of prostate cancer cells linked with a molecule that contains a dose of radiation. The combination helps find and destroy prostate cancer with relative sparing of normal tissue.
"The PSMA gene was first discovered at MSK, and the first therapeutics targeting it were developed and tested at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center," Dr. Tagawa said.
Dr. Tagawa and his team are continuing to analyze the data from the PSMAddition trial to assess longer-term outcomes, such as overall survival and potential safety concerns with longer-term use. He noted that the therapy may not be the best choice for every patient. Only nuclear medicine physicians or radiation oncologists can administer the drug, and specialized imaging scans are needed to identify eligible patients. Such care is usually available at academic medical centers, but patients from areas with few specialists may have to travel long distances. Additionally, he noted there are some additional safety precautions to consider with radiotherapies to prevent exposure to others in the household.
But Dr. Tagawa noted there are now multiple options for targeted therapies available to add to the backbone therapy for metastatic prostate cancer depending on the patient's tumor biomarkers and preferences. Several new imaging agents can help physicians detect cancers earlier and help select the right drug for the patient.
"We can find tumors we couldn't see before," he said. "We now have multiple drugs that delay metastatic prostate cancer progression," he said. "It is unclear yet if they delay death from all causes, but the data on all of them is trending in that direction."
Dr. Scott Tagawa serves as a paid consultant for Novartis, the study funder.
