ESMO 2023: LBA13
Novartis is eagerly advancing its radiotherapy drug, Pluvicto, with aspirations of its potential in earlier prostate cancer treatment. However, recent trial data has presented a mixed outcome, raising questions about its regulatory pathway.
In an impressive display, Pluvicto demonstrated a remarkable 57% reduction in the risk of disease progression or death compared to an androgen receptor inhibitor in patients with PSMA-positive, metastatic castration-resistant prostate cancer who had not previously undergone taxane-based chemotherapy. Such a substantial improvement in progression-free survival is typically cause for celebration in the field of oncology.
Nonetheless, this positive result was accompanied by a concerning revelation regarding patients’ life expectancy. In stark contrast to the remarkable progress in tumor control, the use of Pluvicto was associated with a 16% increased risk of death, as reported by investigators during the phase 3 PSMAfore trial, which was presented at the European Society for Medical Oncology 2023 Congress.
This discrepancy in overall survival results can be attributed to the fact that 84% of patients in the control group, whose disease had progressed, subsequently received Pluvicto. To address this issue, an adjustment for crossover treatments was made, revealing a 20% reduction in the risk of death associated with Pluvicto when compared to the control group. However, it’s important to acknowledge that this analysis essentially compared pre-taxane Pluvicto with the radiotherapy itself when used later. This trial was not originally designed to evaluate this sequencing scenario, making the adjusted analysis a somewhat artificial calculation, despite it being the pre-specified method for overall survival in the PSMAfore trial.
It’s crucial to emphasize that Pluvicto has already gained FDA approval as a later-line, post-taxane therapy. Hence, the crossover-adjusted analysis does not accurately reflect real-world clinical practice.
The most recent overall survival data comes from the second interim analysis of the PSMAfore trial. The trial had initially achieved its primary endpoint in the first interim analysis after a median follow-up of 7.3 months. However, the FDA requested a more mature overall survival analysis before considering an approval application.
A negative trend in overall survival would be a significant concern for the FDA. Even though the data do not conclusively suggest that Pluvicto is causing harm, any possibility of a potential negative impact on patient survival is something the FDA is typically cautious about.
The reasons behind the lack of translation of Pluvicto’s considerable tumor progression benefit into prolonged overall survival remain somewhat mysterious. Factors directly assessing Pluvicto’s benefits, including tumor shrinkage, quality of life, and safety, have all demonstrated favorable outcomes.
Notably, adverse events of grade 3 or higher were less frequent in the Pluvicto arm, occurring in 34% of patients versus 44% in the control group. Dry mouth was the most common side effect in the Pluvicto group, affecting more than half of the patients, but with only 1% reporting grade 3 or higher cases. Rates of high-grade anemia were similar in both arms, at around 6%. Adverse effects led to discontinuation in 5.7% of patients in the Pluvicto arm and 5.2% in the control group.
Despite the ongoing debate regarding Pluvicto’s sequencing, it’s argued that compelling patients to receive a second androgen pathway inhibitor, shown to be inferior based on this data, does not align with the best clinical practice. The antiandrogen drugs used in the PSMAfore trial were Johnson & Johnson’s Zytiga and Pfizer and Astellas’ Xtandi.
Novartis is set to provide further insight into its regulatory strategy in the upcoming third-quarter earnings report, slated for release on Tuesday.
Novartis has projected that Pluvicto holds the potential for more than $2 billion in peak sales, a number that could significantly expand if it gains entry into the taxane-naïve setting. The therapy has experienced rapid growth in the post-taxane segment, resulting in a supply shortage earlier this year. Pluvicto accrued sales of $451 million in the first half of 2023, consistently surpassing analyst expectations.
While the drug showed a remarkable 57% reduction in disease progression risk in certain patients, it also raised concerns due to a 16% increased risk of death. The discrepancy in overall survival results can be attributed to treatment crossover in the control group. An adjusted analysis demonstrated a 20% reduction in death risk but is somewhat artificial since it compared pre-taxane Pluvicto with later use. Pluvicto already holds FDA approval as a later-line therapy, so the adjusted analysis may not reflect real-world practice. Further analysis and discussions with regulatory authorities are needed to clarify the drug’s role and safety in prostate cancer treatment.
To enhance its manufacturing capabilities, Novartis recently secured FDA approval for a radioligand therapy production facility in Millburn, New Jersey. Additionally, the company anticipates the opening of another facility in Indianapolis in the coming months, pending FDA approval. These endeavors reflect Novartis’s commitment to meeting the growing demand for its innovative radiotherapy.