BioNTech and partner DualityBio are accelerating the development of their B7-H3 antibody-drug conjugate into a phase 3 trial for metastatic castration-resistant prostate cancer (mCRPC). With encouraging phase 1/2 data, the partners are leveraging a lean clinical strategy, aiming to achieve success with a trial roughly half the size of the competing program from Merck & Co. and Daiichi Sankyo.
BioNTech’s new phase 3 for BNT324, also known as DB-1311, is slated to start next month with a goal to enroll 736 mCRPC patients, according to ClinicalTrials.gov. By comparison, Merck’s ongoing IDeate-Prostate01 trial for ifinatamab deruxtecan (I-DXd) is recruiting up to 1,440 patients. Both studies are pitting the respective B7-H3 ADC against docetaxel and prednisone.
“We’re confident that we’re going to have sufficient statistical power,” Duality’s chief medical officer, Hua Mu, M.D., Ph.D., told Fierce Biotech when referring to the trial’s dual primary endpoints of radiographic progression-free survival (rPFS) and OS, as well as key secondary endpoints.
BioNTech and Duality’s confidence of a more efficient trial is rooted in updated phase 1/2 data presented at the ASCO Genitourinary Cancers Symposium.
Promising early-phase results
Among 129 evaluable patients with mCRPC who had tried a median four prior lines of therapy, BNT324 achieved a median rPFS length of 11.3 months and a median OS of 22.5 months.
Notably, in 45 patients who had failed on Novartis’ radioligand therapy Pluvicto, the median rPFS also landed at 11.3 months and median OS was not reached in this subpopulation.
Historical data from past clinical trials suggest that median rPFS typically range between five months to eight months for people with heavily pretreated mCRPC, Mu said. For reference, Janux Therapeutics recently reported rPFS of 7.3 months among 108 patients who received various doses of the company’s PSMAxCD3 T-cell engager JANX007. Johnson & Johnson’s KLK2 bispecific pasritamig recorded an rPFS of 7.9 months among 33 patients, and Amgen’s STEAP1-targeted xaluritamig had 7.8 months among 47 patients.
While BNT324’s rPFS data look impressive, its results on another common prostate cancer measurement—the proportion of patients who have had at least a 50% reduction in PSA levels from baseline—are weak compared with PSMA-directed bispecifics.
In 121 patients evaluable for PSA response, the PSA50 rate was only 33.9% for BNT324, or 27.3% for those previously treated with Pluvicto. In contrast, PSMA bispecifics have posted PSA50 rates of above 80%.
PSA response is a clinically relevant endpoint to measure early responses, but it does not reflect longer-term efficacy and is not an approvable endpoint by the FDA, Mu said.
PSMA has a strong correlation with PSA levels. Therefore, a PSMA-targeting agent can have a dramatic effect on lowering PSA; but whether that can translate into rPFS and OS benefit remains to be seen, Mu added.
Safety is also critical to the BioNTech/Duality drug’s profile and the companies’ confidence in the drug’s eventual success, Mu stressed.
Tolerability issues can lead to dose reductions or even treatment termination, which will impact long-term efficacy data, Mu explained. And that’s also an important factor to take into consideration when calculating the sample size of a pivotal trial, he said.
“I keep emphasizing the importance of greater toxicity profile, and that’s particularly relevant for prostate cancer, because prostate cancer patients in general tend to live longer, so you have to give a treatment longer to those patients,” Mu said. “Tolerability is key, particularly if you want to improve those long-term efficacy endpoints.”
In 110 patients who received BNT324 at a dose of 6 mg/kg given once every three weeks, grade 3 or above treatment-related adverse events (TRAEs) were reported in 22 (20%) patients, a rate that Mu described as “outstanding for an ADC drug.” These include only one grade 4 TRAE—of platelet count decrease—and no grade 5 event. Neutrophil count decrease (8.2%) and anemia (7.4%) were the most common high-grade TRAEs.
Adjudicated interstitial lung disease (ILD), an adverse event of interest for ADCs, only occurred in one patient (0.9%) at grade 2. ILD is a known problem for Daiichi’s DXd platform, which includes I-DXd. The FDA recently put a brief hold on a phase 3 trial of I-DXd in small cell lung cancer (SCLC) after an unexpectedly high number of ILD-related deaths.
A quarter of patients in Duality’s phase 1/2 efficacy dataset got a higher 9 mg/kg dose. But the company later decided to focus enrollment on the 6 mg/kg dose after it showed comparable efficacy but better tolerability than the higher dose, Mu explained.
Although Mu wouldn’t spell out the exact dosing regimen to be used in the upcoming phase 3, the 6 mg/kg is likely the choice based on the presented data and company messaging.
The phase 3 will include chemo-naïve patients, and it will allow enrollment for patients who have tried Pluvicto. Mu declined to provide other detailed trial design information, such as whether the study is powered to run subgroup analysis in Pluvicto-naïve and Pluvicto-experienced populations, only saying that Duality and BioNTech are aligned with the FDA on the protocol.
Sizing up competition
B7-H3 has lately become a hot target in oncology, as molecules against it demonstrated broad activity across various tumor types. BNT324 is one of two ADCs that BioNTech obtained by paying Duality $170 million upfront in 2023. Shortly after that, Merck picked up I-DXd as part of a larger ADC collaboration with Daiichi that was worth $4 billion upfront. That same year, GSK got its B7-H3 ADC from Hansoh Pharma.
Roche joined the game this year by licensing MediLink Therapeutics’ candidate. That followed a China-only deal last year between Qilu Pharmaceutical and Chinese compatriot Minghui Pharmaceutical.
But as all these programs have initially focused on SCLC, BioNTech and Duality have decided to move to prostate cancer for BNT324’s first registrational trial. While BNT324 has also generated promising data in SCLC, prostate cancer is a relatively emerging indication for the class with a big unmet medical need as it’s a major tumor type in the U.S., Europe and China, Mu explained.
BNT324 is the second B7-H3 drug to enter pivotal tests in prostate cancer, and Mu is hopeful that with an efficient trial design backed by promising early data, “there’s a possibility we may catch up or surpass” I-DXd.
Both BNT324 and I-DXd use TOPO1 payloads, but Duality believes its payload is more potent, Mu said. While I-DXd was designed to have a drug-antibody ratio (DAR) of four on average to maintain a favorable safety profile, BNT324 uses a higher DAR of six, enhancing its antitumor potency.
The antibody parts bind to different B7-H3 isoforms. B7-H3 has two isoforms, 4Ig and 2Ig, with the latter expressed more commonly in normal tissues. So, Duality designed its molecule with increased specificity to the 4Ig form.
A B7-H3 ADC could also have several advantages over PSMA-targeting drugs, Mu suggested.
For one thing, a PSMA-directed drug like Pluvicto may need to select patients based on the biomarker. By comparison, B7-H3 is highly expressed across mCRPC.
In addition, continued anti-PSMA treatment may lead to PSMA expression downregulation while PSMA-negative cells survive and expand, causing resistance, Mu explained. A B7-H3 agent won’t have that problem.
BNT324’s favorable safety profile has inspired BioNTech and Duality to explore the drug in combinations. BioNTech is testing the B7-H3 ADC alongside its Bristol Myers Squibb-partnered PD-L1xVEGF bispecific pumitamig in early-stage trials across multiple tumor types. And Mu hypothesized that B7-H3 ADC might be combinable with a PSMA bispecific.
As part of their 2023 deal, Duality has the right to exercise a co-development, profit/loss-sharing option for BNT-324 for the U.S. market. Mu wouldn’t say whether the partners are pursuing that path but said: “Our goal is to become an integrated biopharma. We’re very interested in the co-development, co-commercialization [structure], as we communicated before. We’re actively working on that.”
BioNTech is preparing an FDA filing for the other candidate in the partnership, HER2-targeted trastuzumab pamirtecan, in second-line HER2-positive endometrial cancer this year following phase 2 data.