Novartis has high hopes for its radiotherapy Pluvicto. But as the Swiss pharma aims to move the drug into an earlier treatment setting in prostate cancer, it has posted a mixed bag of trial data that cast a cloud of uncertainty over its regulatory path forward.
In an impressive showing, Pluvicto slashed the risk of disease worsening or death by 57% compared with a change of androgen receptor inhibitor in patients with PSMA-positive, metastatic castration-resistant prostate cancer who hadn’t received taxane-based chemotherapy.
The result, from the phase 3 PSMAfore trial, was shared at the European Society for Medical Oncology 2023 Congress.
A 50%-plus improvement in progression-free survival should be cause for celebration in the oncology world. But Pluvicto’s readout was tempered by a concerning sign regarding patients’ life expectancy.
In contrast to the big tumor progression showing, Pluvicto’s use showed a trend, which currently suggested a 16% increased risk of death in PSMAfore, investigators reported. The overall survival readout, captured at 45% data maturity, was not conclusive at this point.
The overall survival results are confounded and influenced by the fact that 84% of patients whose disease progressed in the control arm actually went on to receive Pluvicto, Jeff Legos, Ph.D., Novartis’ global head of oncology and hematology development, said in an interview.
After adjusting for crossover treatments, Pluvicto posted a 20% reduction in the risk of death compared with the control group. That result was once again immature.
The large number of crossover patients means that the overall survival analysis basically compared pre-taxane Pluvicto with the radiotherapy itself used later, although the trial wasn’t prospectively designed to test that sequencing scenario, Legos said.
But the reality is, Pluvicto is already approved by the FDA as a later-line, post-taxane therapy. So the crossover-adjusted analysis is more of an artificial calculation that doesn’t reflect real-world practice, despite it being the prespecified method for overall survival in PSMAfore.
The current overall survival data actually came from the second interim analysis of PSMAfore. The trial hit its primary endpoint at the first interim analysis after a median follow-up of 7.3 months. At that time, Pluvicto showed a 59% reduction in the risk of progression or death compared with control. But Novartis didn’t file for an approval because the FDA wanted to see a more mature overall survival analysis.
Having a negative trend in overall survival would be a big red flag with the FDA. Even though the readout doesn’t mean Pluvicto necessarily caused more harm, the possibility of a potential detriment to patient survival is something that the FDA doesn’t usually tolerate.
Why Pluvicto’s large tumor progression benefit didn’t translate into prolonged overall survival is a bit of a mystery. As Legos noted, all factors related to directly assessing the benefit of Pluvicto are favorable, including tumor shrinkage, quality of life and safety.
Grade 3 or above adverse events were seen in 34% of patients in the Pluvicto arm versus 44% in control. Dry mouth occurred in more than half of the patients in the Pluvicto arm, but only 1% were grade 3 or above. The rates of high-grade anemia were also similar between the two arms at around 6%. Side effects led to discontinuation in 5.7% and 5.2% of patients in the two trial arms, respectively.
Although the Pluvicto sequencing question remains open, Legos argued that “to require patients to receive a second androgen pathway inhibitor that we know is inferior based on these data does not make a lot of sense.” The antiandrogen drugs used in PSMAfore were Johnson & Johnson’s Zytiga and Pfizer and Astellas’ Xtandi.
In a Monday note to clients, analysts at Leerink Partners said that the PSMAfore data have proven that Pluvicto is better than the switching antiandrogen strategy, and that it can move the Novartis drug to the pre-chemo setting.
But echoing Christopher Sweeney from the University of Adelaide, who was invited by ESMO to discuss the PSMAfore data, the Leerink team suggested that it was less clear whether Pluvicto can displace the chemotherapy docetaxel or a PARP inhibitor in patients with BRCA-mutated tumors. During his presentation at ESMO, Sweeney called switching antiandrogen therapy a “weak control” that’s easy to beat.
Still, the Leerink analysts aruged that “even with this caveat, Pluvicto is poised to be the new standard in pre-chemo mCRPC.”
Novartis will share its regulatory plan from here during the company’s third-quarter earnings report on Tuesday.
Novartis has estimated Pluvicto could generate more than $2 billion in peak sales. And being able to move into the taxane-naïve setting would triple the number of patients that Pluvicto could target, according to the company.
The radiotherapy has enjoyed fast growth in the post-taxane setting, having triggered a shortage for a few months earlier this year. Pluvicto brought in $451 million sales in the first half of 2023 after repeatedly beating analysts’ expectations.
To increase supply, Novartis recently won FDA go-ahead for a radioligand therapy manufacturing facility in Millburn, New Jersey. It also expects another facility in Indianapolis to open in the coming months, pending FDA approval.
Editor's Note: The story has been updated with additional comments from a Leerink note to clients and from Christopher Sweeney.