Biospace: Novartis Breaks Through with Radioligand Therapy for Prostate Cancer - BioSpace

Dr. Oliver Sartor, Medical Director, Tulane Cancer Center and trial co-principal investigator/Photo courtesy of Tulane University

Novartis has a lot to be excited about going into this year's American Society of Clinical Oncology (ASCO) meeting, and the highlight is the company's targeted radioligand therapy (RLT) platform, ¹⁷⁷Lu-PSMA-617, which has demonstrated considerable promise in PSMA-positive metastatic castration-resistant prostate cancer.

Today, the Swiss pharma titan announced the results of its Phase III VISION study where 177Lu-PSMA-617 plus best standard of care (SOC) met both of its primary endpoints, significantly reducing the risk of death by 38% and reducing the risk of radiographic disease progression or death by 60%. The therapy led to a median improvement in overall survival of four months. Novartis will present the findings at ASCO on June 6.

"I think this is the most significant advance that I've been a part of in my 31-year career. This therapy is effective both in prolonging survival and retaining health-related quality of life for patients that are extremely difficult to treat, those individuals who have failed multiple other therapies and really have few other options," Dr. Oliver Sartor, Medical Director and C. E. and Bernadine Laborde Professor of Cancer Research at Tulane University Cancer Center told BioSpace.

Sartor was the trial's co-principal investigator along with Dr. Bernd J. Krause of the University of Rostock in Germany.

Prostate cancer is the second most common cancer diagnosed in men. This particular manifestation, which occurs when patients stop responding to testosterone-reducing and androgen deprivation therapy, is particularly lethal as it allows the cancer to spread to other regions of the body. The average 5-year survival rate is just 30%, with only 3 in 10 patients being alive at the end of five years.   

The VISION study was comprised of 831 patients who were randomized 2:1 to receive either ¹⁷⁷Lu-PSMA-617 plus standard of care, or SOC alone, and received up to six cycles of eligible therapy.

To be eligible for the trial, patients must have exhausted at least one treatment of androgen or hormone deprivation therapy, along with at least one taxane based chemotherapy regimen. They were also required to be PSMA positive as detected by PET CT imaging with Gallium 68-labeled PSMA-11.

The ¹⁷⁷Lu-PSMA-617 platform combines a targeting compound, or ligand, with a therapeutic radioisotope, which is a radioactive particle.

At a media briefing on Tuesday, Novartis Oncology president Susanne Schaffert credited the approach with being "precision medicine at its best." 

"What is unique about the radioligand therapy is the ability to target the tumor and deliver radiation directly to the cancer cells in a very precise way with a minimal effect on healthy cells, which allows for greater efficacy and a very, very safe profile," Schaffert said. "It's almost like a guided missile in your cancer cells." 

The therapy targets the PSMA receptor, which is found in approximately 80% of all prostate cancer cells.

"If you think about this PSMA ligand, or peptide as a GPS, it allows us to actually deliver this high dose radioactive lutetium directly to a cancer cell. We basically are delivering it to a precise address, based on the PSMA expression on the prostate cancer cells," added Jeff Legos, SVP and Global Head of Oncology Development at Novartis, on the call.

The ligand then binds with the receptor, is internalized, and the high dose radioactive lutetium disrupts the target's ability to replicate, thereby triggering the death of the cancer cells. 

Besides delivering a powerful payload of radiation directly to the diseased cells and avoiding off-target toxicity, the therapy allows for patient quality of life during treatment.

"This molecule is actually very well-tolerated. In terms of impacting the way that patients feel during the side effects of therapy, they're really quite minimal, and that's so key in these patients, many of whom are relatively frail," Sartor said. "These are men, perhaps in the autumn of life in general, typically men in their 70s and often 80s, and they really do prioritize the time that they have remaining. This allows them to have more quality of time."

The platform's comprehensive patient coverage makes it a standout in the precision medicine space.

Sartor stated that based on a PSMA-positive PET scan, patients were eligible for inclusion in the trial 87% of the time.

"This is unlike some of the other precision therapies that have been recently introduced where only a significant minority of the patients could benefit," he said.

In what Sartor refers to as molecularly-targeted radiation, the platform also enables a new level of visualization for physicians.

"One of the cool things about ¹⁷⁷Lu-PSMA-617 is that it has a gamma emission in addition to the beta. First of all, you can visualize uptake of PSMA with molecules. In addition, you have a gamma that comes off, so you can scan these patients and see exactly where the radiation is delivered. It actually is a nice way to manage patients," he said.

Novartis stated that regulatory submissions to both U.S. and EU health authorities are on track for the second half of 2021. The company also hopes to use the therapy to halt metastatic prostate cancer earlier and expects to initiate two pivotal studies in earlier lines of treatment by the end of 1H 2021.