ESMO: Survival data mars Pluvicto prostate cancer trial

Novartis’ highly-touted radionuclide therapy Pluvicto met its primary endpoint in a phase 3 trial as a second-line therapy for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC), but may not be the home run the company is hoping for.

The PSMAfore trial met its primary objective of improving radiographic progression-free survival (rPFS) in patients previously treated with androgen receptor pathway inhibitor (ARPI) therapy, with a 59% reduction on that endpoint compared to a change in ARPI – currently the main treatment strategy.

That difference was seen at 7.3 months of follow-up, and the benefit was confirmed in a second analysis carried out at 15.9 months when the median rPFS was just over 12 months with Pluvicto (lutetium [lu177] vipivotide tetraxetan) and 5.6 months in the control group.

Presenting the data at the ESMO congress, co-principal investigator Dr Oliver Sartor of Tulane University School of Medicine in the US described the benefit as “impressive” and in line with Novartis’ open-label VISION trial of Pluvicto in the same treatment setting that was reported last year.

The results could “change the treatment paradigm for advanced prostate cancer by allowing patients to potentially avoid or delay taxane-based chemotherapy, which carries a heavy burden of side effects,” said Novartis’ head of oncology development, Jeff Legos.

There was one issue in the PSMAfore trial, however, in that its ability to give a reading on overall survival was stymied by a high rate of crossover from the ARPI group to Pluvicto before the second interim analysis.

After correcting for that crossover, there was a trend towards improvement and Novartis is still following up the survival data, but isn’t expecting an update on that until next year. The company has indicated it will hold off on filing for approval of the drug as a second-line therapy until it is available.

“The results from the PSMAfore trial are interesting, but their impact on clinical practice will be limited without confirmation of an overall survival (OS) benefit,” remarked Professor Nicholas James from the Institute of Cancer Research and Royal Marsden Hospital in the UK, ESMO’s discussant for the data.

“We also need to consider cost and the possibility that treatment in the comparator arm was suboptimal,” added James. “Switching from one ARPI to an alternative is known to be a strategy with limited efficacy compared to switching to chemotherapy.”

Pluvicto is viewed as the most promising drug in Novartis’ radionuclide arsenal, and is already approved as a later-line treatment for PSMA-positive mCRPC after both ARPI and taxane-based chemotherapy have been tried. It is growing quickly, with annual sales already approaching blockbuster levels in its first full year on the market, coming in at $707 million in the first nine months of this year.

The drug was added to Novartis’ portfolio through a $2.1 billion acquisition of Endocyte in 2018, and the drugmaker has said it thinks sales could eventually top $2 billion if it expands into earlier lines of therapy in mCRPC, as well as metastatic hormone-sensitive prostate cancer.