Novartis gets a PSMAfore green flag at last

It’s been a long road, but Novartis has finally managed to convince the FDA to approve its radiopharmaceutical Pluvicto in an early prostate cancer setting, despite its PSMAfore study not showing a benefit on the key secondary endpoint of overall survival.

The company will now hope to accelerate sales of a therapy that made $1.4bn last year. Novartis reckons the PSMAfore indication will triple the number of patients eligible for Pluvicto, and has estimated that, eventually, annual product revenues could top $5bn.

The PSMA-targeting therapy was previously approved for metastatic castrate-resistant prostate cancer patients after androgen receptor pathway inhibitors (ARPI) and taxane-based chemo. The latest FDA nod is in a post-ARPI but pre-chemo population.

Novartis had originally hoped to file for approval in 2023, based on PSMAfore. The study enrolled patients who had progressed on one second-generation androgen receptor pathway inhibitor, such as Zytiga or Xtandi, and were randomised to receive either Pluvicto or a different androgen-receptor-targeting therapy.

At ESMO 2023 it became apparent that, although the study had produced a convincing result on its primary endpoint of progression-free survival, overall survival had been confounded by a high number of patients crossing over from control to Pluvicto.

This left Novartis waiting on updated overall survival numbers before it could file.

Now the final OS results are in, and they have improved – slightly. Unadjusted for crossover, the hazard ratio was 0.91, still not statistically significant. But on an adjusted basis, the hazard ratio was 0.59.

Evolving PSMAfore OS data

Source: company releases & ESMO 2023.

This was clearly enough for the FDA; the agency must also not have been troubled about questions around the control arm, with some noting that a patient would be unlikely to respond to one antiandrogen therapy when they've already failed on a similarly acting drug.

Novartis hopes to go even earlier with Pluvicto, with ongoing phase 3 trials in hormone-sensitive and localised oligometastatic prostate cancer. Results from the PSMAddition study in the former are due in the second quarter.

But the company is also looking beyond Pluvicto, which uses the beta-emitting radioisotope lutetium-177; Novartis has a couple of PSMA-targeting projects based around the alpha emitter actinium-225, which is said to be more potent and precise. Its first-generation actinium-based asset, Ac-PSMA-617, is already in phase 3.

However, the latest Pluvicto approval raises questions about the design of a recently begun pivotal trial of Ac-PSMA-617, called AcTFirst. That study is set to compare Ac-PSMA-617 versus against investigator’s choice of ARPI switch or chemo, rather than Pluvicto.

Competitors in the actinium space include AstraZeneca, through its $2bn purchase of Fusion, and Bristol Myers Squibb, via the $4bn purchase of RayzeBio.