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Novartis' Targeted Radio-Ligand Therapy Highlighted at ASCO as Potential New mCRPC Option

NEW YORK – Novartis' targeted radio-ligand therapy, 177Lu-PSMA-617, in combination with standard-of-care treatments prolonged metastatic castration-resistant prostate cancer patients' lives and delayed their risk of cancer progression compared to just standard-of-care treatments, a Phase III trial has shown.

The VISION trial, highlighted as late-breaking research at the American Society of Clinical Oncology's virtual annual meeting on Sunday, explored the activity of 177Lu-PSMA-617, which is an example of a new type of precision cancer therapy that relies on a phenotypic biomarker to improve administration of a radioactive agent to cancer cells while sparing normal cells.

Oncologists at the meeting agreed that if approved by the US Food and Drug Administration and other regulators, 177Lu-PSMA-617 would be a promising new option for refractory mCRPC patients who lack treatment options. In mCRPC patients, the cancer spreads to bones and other organs and stops responding to hormone treatment. Around 30 percent of patients with metastatic prostate cancer survive five years following diagnosis.

In the VISION trial, researchers randomized mCRPC patients to receive either 177Lu-PSMA-617 with the best standard-of-care treatment or just a standard-of-care treatment. Patients had PSMA-positive disease determined using a PET scan. They also had to have received and progressed on androgen receptor inhibitors and chemotherapies.

The co-primary endpoints in the study were overall survival, evaluated in around 830 patients, and radiographic progression-free survival, determined in around 580 patients. Patients receiving 177Lu-PSMA-617 had a median overall survival of 15.3 months compared to 11.3 months for those receiving just the standard of care. Median radiographic progression-free survival was 8.7 months in the 177Lu-PSMA-617 arm and 3.4 months in the comparator arm.

This translates to a 38 percent reduction in the risk of death and a 60 percent lowering of the risk of progression for patients receiving Novartis' radio-ligand therapy. "These findings do warrant adoption of 177Lu-PSMA-617 as a new treatment option in this patient population, pending FDA review," said Michael Morris, an oncologist at Memorial Sloan Kettering specializing in prostate cancer and a VISION trial investigator.

177Lu-PSMA-617 combines a targeting compound and therapeutic radioisotope. The treatment is injected into patients' bloodstream, at which point it binds to PSMA, an antigen expressed on tumor cells, and delivers a radioactive payload. In a statement, Novartis described PSMA as a phenotypic biomarker that distinguishes more than 80 percent of prostate cancer cases and is expressed mostly on tumor cells.

"Expression on normal tissue is limited, making PSMA an excellent target for PET imaging and targeted systemic radiation treatment," said Morris. Since PSMA isn't typically expressed on tumor cells, the radioactive component of 177Lu-PSMA-617 is able to home in on the cancer and avoid damaging surrounding normal cells.

Although there were no new safety issues seen with 177Lu-PSMA-617 in the VISION trial, Morris said it did cause more treatment-related side effects and there were five deaths.

Novartis in March had announced that the VISION trial had met its overall survival primary endpoint and that based on the results it would file for regulatory approval for 177Lu-PSMA-617 in the US and Europe later this year.

There are limited treatment options for mCRPC to which patients have enduring responses. ASCO President Lori Pierce, who is a radiation oncologist and vice provost for academic and faculty affairs at the University of Michigan, recognized that patients in this trial benefited from 177Lu-PSMA-617 despite progressing on anti-androgen treatments and prior taxane therapies. "This trial shows an alternative to traditional therapies by using radiation targeted to the prostate-membrane antigen, so it could be delivered directly to the prostate cancer cells," she said, "and by doing that, survival was significantly improved."

If approved by the FDA, the radio-ligand treatment could become an important option for mCRPC patients with refractory disease, Pierce said.

The theme of this year's ASCO annual meeting is equity in cancer care, and in reviewing the VISION trial data at the meeting, Mary-Ellen Taplin, director of clinical research at the Dana-Farber Cancer Institute's Lank Center for Genitourinary Oncology, pointed out that the study lacked racial representation. In the trial, 6.6 percent of patients were Black and 2.4 percent were Asian. "Prostate cancer is both more common and more lethal in Blacks, and it's time as a community we commit to concrete steps to understand the effects of therapies in minority populations," she said.

The fact that the VISION trial used PET imaging to enroll PSMA-positive patients also raised questions about access disparities should 177Lu-PSMA-617 be approved in the US and other countries. Meeting attendees pointed out that PET imaging is costly and may not be widely accessible in low-resource locations.

Patients had to have at least one PSMA-positive metastatic lesion and no PSMA-negative lesions in order to be eligible for the study, and 87 percent of screened patients met these criteria. Even though 177Lu-PSMA-617 is a targeted treatment, Taplin wondered whether the imaging requirement is needed since most mCRPC patients appear to have PSMA-positive lesions.

This may be the most important question for the further development of this drug, Morris reflected, noting that researchers may explore this retrospectively. VISION investigators purposely set a lax PSMA-positivity standard to enable access to the drug and trial.

"We'll have to look at the predictive value of those PSMA scans in terms of how they are associated with overall survival and radiographic progression-free survival to know whether indeed those scans are predictive and can further optimize the patient population," he said. "If there is no relationship, then certainly it does beg the question as to whether they are necessary."

Ultimately, the FDA will decide whether to require PSMA PET imaging as a companion diagnostic for 177Lu-PSMA-617. The agency has approved other PSMA imaging agents but for determining if prostate cancer patients are experiencing recurrence or metastasis. "The use of PSMA imaging here … is to identify PSMA-positive disease in preparation for PSMA-directed therapy," Morris said. "We'll have to see how that regulatory ruling plays itself out."