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In Small Prostate Cancer Trial, UCSF Researchers Present a Case for Pluvicto-Keytruda Combo

Prostate Cancer treatment

NEW YORK – Researchers at the University of California, San Francisco have shown in a study published in Lancet Oncology this week that a single dose of Novartis' radiopharmaceutical Pluvicto (lutetium vipivotide tetraxetan) followed by Merck's checkpoint inhibitor Keytruda (pembrolizumab) benefits certain metastatic castration-resistant prostate cancer patients.

In the efficacy-evaluable population of 25 mCRPC patients in the Phase I trial, 56 percent responded to a dose of Pluvicto followed by maintenance Keytruda after a median follow-up of 16.5 months. Five percent of patients had a complete response to the treatment combination, 47 percent had a partial response, and 28 percent had stable disease. Among 43 patients included in the safety analysis, just two had grade 3 or higher treatment-related adverse events.  

The Phase I results come just a week after the European Society for Medical Oncology Congress, where Novartis presented much-anticipated results from the Phase III PSMAfore trial, in which mCRPC patients who'd previously received an androgen receptor pathway inhibitor (ARPI), but not chemotherapy, lived longer without their cancers progressing with Pluvicto than with a second ARPI.

According to Rahul Aggarwal, the co-leader of the genitourinary oncology program at UCSF and the lead author of the Lancet Oncology study, the patient population in the Phase I trial — mCRPC patients who'd received prior ARPIs and had prostate-specific membrane antigen (PSMA)-positive cancers, as assessed by diagnostic radioactive tracers — was similar to the population enrolled in PSMAfore. This raises questions as to why the UCSF team wanted to add an immune checkpoint inhibitor to Pluvicto when the latter could be beneficial on its own.

Aggarwal offered several rationales. For one, his trial treated patients with just one round of Pluvicto before beginning maintenance Keytruda. In PSMAfore, patients received six cycles of Pluvicto, in line with the regimen specified for third-line mCRPC treatment in the agent's US Food and Drug Administration-approved label.

"You're really sparing the bone marrow from potential toxicity and decreasing blood counts that might make it more challenging to give patients subsequent therapies like chemotherapy and other radiopharmaceuticals," he said. "Giving six doses of Pluvicto may not be the right approach for every patient."

Aggarwal hesitated to directly compare the small, single-arm Phase I UCSF trial to Novartis' large, randomized PSMAfore trial. Beyond differences in size and design, the trials also involved somewhat different patient populations in that those in the UCSF trial had to have at least three PSMA-positive lesions according to a gallium-labeled PSMA PET imaging scan, while Novartis' PSMAfore trial required patients have one PSMA-positive lesion in scans.

Even after accounting for all the caveats of cross-trial comparisons, there are still reasons to believe the toxicities with Pluvicto-Keytruda are indeed lower than six cycles of Pluvicto. Researchers presented data during ESMO showing that 33.9 percent of patients on Pluvicto experienced a grade 3 or 4 adverse event.

Of course, immunotherapy agents like Keytruda bring their own set of adverse events. But in the UCSF trial, Aggarwal said these immunotherapy-associated toxicities were few and far between and mostly reversible. "In terms of durability and being able to maintain on therapy and being eligible for subsequent therapies, I would think of Keytruda in a very different category than I would a radioligand therapy that's going to potentially have a more durable impact on the bone marrow reserve," he said.

In addition to the potentially improved safety profile with the radiopharmaceutical-immunotherapy combination, Aggarwal said there are reasons to suspect the drugs complement each other from an efficacy standpoint.

Even though immune checkpoint inhibitors have not historically demonstrated much benefit in prostate cancer patients, prior studies have shown that "priming" the immune system with a treatment like radiation can help.

"You can see upregulation of some of the effector cells that achieve an immune response against the cancer," Aggarwal explained. "There's pretty good laboratory data and rationale for combining radiation with immunotherapy." When radiation induces anti-tumor immunity, these data show that immune effector cells can be recruited to the metastases sites to attack the cancerous lesions.

Trials combining external beam radiation with immunotherapy agents like Keytruda haven't been that successful, but Aggarwal said a more targeted, tumor-specific approach like a radioligand could be more effective.

"You're getting more direct tumor cell kill, and in the process of antigen release and other mechanisms, that might be a better way to stimulate that immune response against cancer," Aggarwal said. "That's the concept we wanted to test that's novel in the study."

Importantly, because the trial wasn't randomized, Aggarwal acknowledged that it wasn't possible to separate the effect of Pluvicto from Keytrdua. But there were signs that the two medications may be working synergistically. "We did see differences in the circulating immune microenvironment in responders versus non-responders, and that tells us that there may be something happening immunologically that can distinguish the group of patients that's most likely to benefit," he said. "And it suggests that Keytruda is contributing" benefit.

The durability of responses among patients in the small trial further support the notion that "there's something to the combination," Aggarwal said. "Given that we're only giving a single priming dose of Pluvicto, to see the durability of responses that we did suggests that Keytruda is contributing." The patients in the UCSF trial weren't genomically selected, either, he noted, whereas in other immunotherapy prostate cancer studies, Keytruda's benefit is typically limited to patients with prostate cancers with high tumor-mutational burden or microsatellite instability.

Beyond potential efficacy or safety advantages of the Pluvicto-Keytruda combo, giving patients one Pluvicto infusion may put less pressure on already strained manufacturing processes for radiopharmaceuticals. "[Radiopharmaceutical therapy] is hard with scheduling," Aggarwal said. "Even at my institution where we have a pretty high capacity … it's not easy, not only from a supply standpoint but also from a logistics standpoint given the radiation safety and precautions patients have to take."

Indeed, administering radiopharmaceuticals requires specialized personnel and facilities that not every patient can access. "This is not a trivial type of treatment," he said. "Compared to pulling infusion medicines [like Keytruda] off the shelf, this is certainly more involved."

Looking ahead, Aggarwal said he and his team are gearing up for a Phase II trial that is slated to begin enrolling patients before year end. The trial will evaluate the Pluvicto-Keytruda combination but with adaptive dosing for Pluvicto based on patients' prostate-specific antigen kinetics. Patients in the trial can receive more than one Pluvicto infusion if their PSA begins to rise, Aggarwal explained. "This adaptive dosing design will hopefully decrease dose intensity and lead to more durable response and progression-free survival compared to what we see with Pluvicto alone," he said.

Now that the progression-free survival data and response data are available from PSMAfore as well as VISION, the initial trial that led to Pluvicto's approval, Aggarwal said he and his team will have a better idea how the outcomes of their trial compare to Pluvicto monotherapy.

Ultimately, Aggarwal said he's hoping to test the combination in a randomized clinical trial, and that he and his team are in talks with potential company sponsors interested in the combination approach. "We'll see how the field develops here," he said. "It's an exciting time for sure."