FibroGen throws down the prostate cancer gauntlet

There has been much recent activity in prostate cancer, with various players emerging and, in some cases, attracting big pharma bucks. FibroGen was one of the companies to report early data, on its CD46-targeting ADC FG-3246, but investors weren’t convinced, sending the group’s stock down at the start of this month.

FibroGen has come out swinging, with its new chief medical officer, Deyaa Adib, telling ApexOnco that he isn’t troubled by comparisons against the likes of Ambrx’s ARX517 – now in the hands of Johnson & Johnson – and Janux’s JANX007.

He notes that FibroGen is rare among its peers in disclosing progression-free survival data, and throws down the gauntlet to the group’s rivals. “I’d challenge them to show us their Kaplan-Meier curve for progression-free survival. If they’d had a good PFS figure, they would have shown it.”

Meaningful endpoint

FibroGen reported median radiographic PFS of 8.7 months in its phase 1 trial of FG-3246, which enrolled late-line metastatic castration-resistant prostate cancer patients. The group also gave the percentage of evaluable patients achieving a response as well as PSA50, a 50% of greater decrease in the biomarker prostate-specific antigen.

Investors were likely disappointed by the fact that, on a cross-trial basis, the PSA50 rate with FG-3246 wasn’t all that impressive, with some pointing to the fact that on this measure Janux’s JANX007 looked like the project to beat.

Adib dismisses such concerns: “PSA is a signal of clinical activity, but it is not a proper surrogate endpoint, and the FDA will never approve a drug based on PSA. The only two clinically meaningful endpoints in prostate cancer are PFS and overall survival.” 

Adib compares FG-3246’s 8.7 months of mPFS favourably to the 6.4-month benefit seen with Novartis’s radiopharmaceutical Pluvicto in the PSMAfore trial. 

“And we’re not talking about five or six patients. We have a very respectable sample size in our phase 1,” he adds. The study did enrol a decent number of patients, 56, but not all of these were included in the various analyses.

Changing landscape

Adib also isn’t troubled by the threat posed by Pluvicto in the relapsed but pre-chemo setting that FibroGen is shooting for. 

Novartis is planning a Pluvicto filing here in the second half of 2024 based on updated overall survival data from PSMAfore, which showed a hazard ratio of under 1.0 in the intent-to-treat population unadjusted for crossover. An 84% crossover rate has made this trial’s overall survival result particularly hard to interpret. 

FibroGen’s Adib believes that Pluvicto, which contains the active substance lutetium, will be approved, but adds: “You won’t see significant clinical uptake because it’s very toxic.” He contends that Novartis is replacing lutetium with a potentially more precise radioactive payload, actinium; the Swiss company has two actinium-based projects in phase 1.

However, Novartis's first-quarter results presentation, released yesterday, makes it clear that Pluvicto and other lutetium-based assets are still a big focus for the Swiss group.

Differences

It’s hard to pick a winner from the current crop of early-stage prostate cancer challengers at this point, not least because of differences in how results have been reported. 

While PSA50 rates with Janux’s JNX007 are promising, a closer look at that group’s publicly disclosed data shows a lacklustre response rate. The phase 1 study of the PSMA-targeting agent has apparently enrolled all-comers, so it will be interesting to see how this project performs in a PSMA-selected population.

Ambrx also carried out an all-comers trial for its PSMA-directed ADC, but questions remain about its dataset, with the company focusing on different cohorts for its various endpoints. That is now J&J's concern.

Xencor has already been punished for disappointing results and a high rate of adverse events with vudalimab; meanwhile, toxicity could also hold back Amgen’s Steap1-targeting T-cell engager xaluritamig.

Things could become clearer as more data are reported, but for now FibroGen still thinks it’s in with a fighting chance – even if the markets don’t agree.

Cross-trial comparison of notable early-stage projects for relapsed mCRPC

Notes: *56% with 1st dose ≥0.1mg/ 83% with 1st step dose ≥0.2mg; **as per swimmers plot, Janux Mar 2024 presentation; ^Cohorts 6-8 only; ^^Cohorts 4-8; ^^^includes one death deemed treatment related. Source: company statements.