Cabometyx, Tecentriq stave off prostate cancer progression as Exelixis joins Novartis on FDA's wait list

Another prostate cancer trial has hit its main goal, and yet the drug developer can’t immediately file for an FDA approval.

The latest trial win comes from a combination of Exelixis’ Cabometyx and Roche’s Tecentriq used in patients with metastatic castration-resistant prostate cancer (mCRPC). The combo reduced the risk of progression or death by 35% compared with a change of novel hormonal therapy among patients who had progressed on a prior anti-androgen drug, according to data presented at the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium.

The progression-free survival analysis, performed in the first 400 patients randomized to the phase 3 CONTACT-02 trial, showed that patients who got the combo went a median 6.3 months without disease progression, versus 4.2 months for control. The phase 3 CONTACT-02 trial has therefore hit one of its dual primary endpoints. But, as Exelixis has previously announced, the company is not applying for an FDA go-ahead just yet.

That’s because the FDA is asking for more mature data on the Cabometyx-Tecentriq regimen’s performance in extending patients’ lives, Exelixis’ newly minted chief medical officer, Amy Peterson, M.D., said during the company’s third-quarter earnings call in November and confirmed to Fierce Pharma in an interview about the detailed CONTACT-02 data.

Peterson said she couldn’t speak about what the FDA is specifically looking for, but said the company expects a final overall survival analysis this year.

“It is a therapy that we feel compelled to bring to patients as quickly as possible with the right amount of data,” Peterson said. “We’ll see what the FDA has to say with regard to specific requests.”

PD-1/L1 immuno-oncology therapies boast a wide range of approvals in multiple tumor types, but prostate cancer remains a relatively white space. And having a Tecentriq-containing regimen could fill that blank, Peterson argued.

“This will really resonate with patients who are wondering, why can’t I have an I-O therapy? Why can’t you give me with my prostate cancer an I-O therapy?” Peterson added. “And if this combination were to be approved, they would now have access to that.”

Exelixis’ situation draws a comparison to what Novartis is experiencing with Pluvicto. In the phase 3 PSMAfore trial, the Novartis radioligand therapy significantly cut the risk of disease progression or death by 57% compared with a change of androgen receptor inhibitor in certain patients with mCRPC. But the Swiss pharma is also delaying an FDA filing, pending longer follow-up of overall survival.

Despite their shared regulatory speed bump and comparator arm, the two trials are very different and can’t be compared side by side, Peterson and the CONTACT-02 trial’s lead investigator, Neeraj Agarwal, M.D., from the University of Utah, explained in separate interviews.

First of all, the Novartis trial is only for patients with PSMA-positive tumors, while the Exelixis study doesn’t have that restriction. But patients must have measurable disease to be eligible for CONTACT-02, while PSMAfore didn’t require that.

Besides, a relatively small number of patients enrolled in PSMAfore had visceral disease, whereas all of CONTACT-02 patients had visceral metastasis, which according to Agarwal is growing in prevalence among mCRPC patients. What’s more, liver metastasis, a negative prognostic factor, was observed in a quarter of CONTACT-02 patients, while PSMAfore had 4%. Plus, about 20% of patients in the Exelixis trial had previously received the chemotherapy docetaxel in the metastatic castration-sensitive stage of disease while the Novartis study didn’t allow prior exposure to chemo.

Agarwal pointed to how long patients stayed alive in the two trials’ control arms to show that CONTACT-02 enrolled a sicker population. In the CONTACT-02 study, patients in the control arm lived a median 14.6 months, whereas the median overall survival was around 20 months in PSMAfore’s control group, Agarwal noted.

At an interim analysis where the overall survival readout was 45% mature, Pluvicto showed a preliminary negative trend indicating an increased risk of death. Novartis has contributed the results to a high crossover rate, as 84% of patients in the control arm actually went on to receive Pluvicto following disease progression.

Exelixis’ situation is a bit better. At the current interim analysis of CONTACT-02 with 49% data maturity, overall survival is trending in favor of Cabometyx and Tecentriq. At a median follow-up of 12 months for all enrolled patients, the combo is currently linked to a 21% reduction in the risk of death as the median overall survival was 16.7 months for the combo and 14.6 months for a second novel hormonal therapy.

Agarwal acknowledged that the survival advantage of the combo is getting narrower as the trial progresses. But given that all patients will eventually die, Agarwal emphasized “a nice suppression” of the death risk based on the immature data.

Both progression-free survival and overall survival were so far positive for the combo across some patient subgroups with high-risk factors, including those with liver metastasis, bone metastasis and prior docetaxel use.

Calling the current overall survival data “very promising,” Agarwal said he remains hopeful that the trial might eventually hit statistical significance on that endpoint. Either way, the trial is already successful thanks to its dual primary endpoint design.

“I think we have a very good scope of this combination being applied in the community because it is so widely available and so easily administered,” Agarwal said, referring to the fact that radioligand therapies such as Pluvicto must be given at designated treatment centers.

Cabometyx comes with myriads of side effects thanks to its mechanism of action against multiple targets. Those toxicities may sound overwhelming, but they are mostly manageable, Agarwal said. In CONTACT-02, about 13% of patients discontinued any component of the combo regimen because of treatment-related adverse events, versus 2% in the control arm.

As a potential filing for CONTACT-02 got postponed, Exelixis at the beginning of the year launched a business restructuring to reduce its workforce by 13%, or about 175 employees. The overhaul allows Exelixis to focus its resources on developing some early-stage clinical candidates and to “move quickly into the right registrational studies” upon positive signals, Peterson said.

Exelixis’ and Novartis’ delays reflect a broader push at the FDA’s oncology department with an emphasis on overall survival data. Also in mCRPC, the FDA in June 2023 cleared Pfizer’s PARP inhibitor Talzenna, used in combination with Xtandi, only for treating mCRPC that has homologous recombination repair (HRR) gene mutations. Agarwal is also the lead investigator of the phase 3 TALAPRO-2 trial, which actually tested the Talzenna-Xtandi pairing in a wider patient population.

That Pfizer study is on track to report the final overall survival analysis this year, including for non-HRR patients, Agarwal said. Pfizer has said it plans to file for an approval in the all-comers population if the final data come in its favor.