NEW YORK – Novartis' targeted radiopharmaceutical Pluvicto (lutetium vipivotide tetraxetan) more than doubled the median progression-free survival for patients with metastatic castration-resistant prostate cancer who hadn't received chemo before, according to much-anticipated data presented during the European Society for Medical Oncology Congress on Monday.
Oliver Sartor, the director of radiopharmaceutical trials at the Mayo Clinic, presented results from the Phase III PSMAfore clinical trial in which 468 patients with mCRPC who had previously received treatment with an androgen receptor pathway inhibitor (ARPI), but not chemo, were randomized to receive either Pluvicto or a second ARPI, such as Janssen's Zytiga (abiraterone) or Erleada (apalutamide), Pfizer and Astellas' Xtandi (enzalutamide), or Bayer's Nubeqa (darolutamide). All patients had to have at least one prostate-specific membrane antigen (PSMA)-expressing cancer lesion, as determined by Novartis' diagnostic radioligand Locametz (68Ga-PSMA-11).
An important aspect of the trial design, which Sartor emphasized repeatedly throughout his presentation, was that it permitted crossover. If patients experienced disease progression after the second ARPI, they could go on to receive Pluvicto — and 84.2 percent of patients whose cancers progressed on the anti-androgen arm did exactly that.
"I've actually never seen a Phase III trial with this degree of crossover," Sartor said.
Because PSMAfore investigators knew that this crossover effect would inevitably impact overall survival estimates for the control group, they shifted focus to progression-free survival instead, even though overall survival is the gold standard for randomized trial endpoints. The investigators did look at overall survival, despite the confounding setup, as a secondary endpoint and performed a statistical analysis to adjust for the crossover.
The study showed a clear progression-free survival benefit with Pluvicto. After a median follow-up of 15.9 months, patients treated with Pluvicto lived for a median of 12.02 months without their cancers progressing, while patients treated with a second ARPI lived for a median of 5.59 months without their cancers progressing.
"There is no doubt about it," Sartor said. "This is unequivocally a positive trial by the progression-free survival criteria. More than doubling [median progression-free survival], I think, is quite nice."
The overall response rate for patients on Pluvicto was 50.7 percent versus 14.9 percent for patients in the control arm. For patients who did respond to their respective treatments, the median duration of response was 13.63 months for patients in the Pluvicto arm versus 10.05 months in the ARPI arm. The complete response rates were 21.1 percent versus 2.7 percent, respectively.
Significant declines in prostate-specific antigen (PSA) expression levels — which many oncologists routinely use to track patients' cancer progression or monitor treatment response — were more frequent in the Pluvicto group than in the control group. PSA declines of 50 percent or more were seen in 57.6 percent of patients on Pluvicto versus 20.4 percent of patients on ARPIs.
Even though Sartor reported median overall survival outcomes in his presentation, he again underscored that this endpoint is not that informative for gauging Pluvicto benefit due to crossover. Patients lived for a median of 19.25 months when they received Pluvicto. Meanwhile, most of those who received ARPI therapy went on to receive Pluvicto after their cancers progressed. This likely accounts for why patients in the control arm had a very similar, and ultimately slightly improved, median overall survival of 19.71 months.
In terms of side effects, 33.9 percent of patients on Pluvicto experienced a grade 3 or 4 adverse event, whereas the same was true for 43.1 percent of patients on hormone therapy. Serious adverse events affected 20.3 percent and 28.0 percent of patients, respectively. Patients on Pluvicto reported better quality-of-life outcomes than those on their second hormone therapy.
"This is a remarkable adverse event profile," Sartor said.
In a discussion of the PSMAfore data following Sartor's presentation, Christopher Sweeney, a medical oncologist at the University of Adelaide in Australia, agreed that the trial clearly showed that patients benefit on Pluvicto and applauded the researchers, but he also noted several limitations in the study.
For one, he questioned the choice to compare Pluvicto to a second course of hormone therapy. "To be very frank, hormone switch as the control arm is a weak control because it is not life-prolonging," he said. Even though patients in the control arm could get Pluvicto after progressing on hormone therapy, the fact that some 15 percent of patients did not cross over to the Pluvicto arm suggested to Sweeney that they had a clinical decline that prevented them from doing so.
"This weak hormonal therapy switch treatment may have meant they missed getting a treatment option in the future," he said.
In Sweeney's view, the trial also doesn't paint a clear picture about which patients are most likely to benefit based on the degree of PSMA expression seen with a PSMA PET scan. It would also be nice to know, he said, whether patients can stop Pluvicto once the gallium-labeled imaging scan isn't showing PSMA-expressing tumors anymore.
"What we do know from exploratory post hoc analyses of [prior Pluvicto trials is that] patients who had a higher PSMA PET uptake … derived the most benefit," he said. Indeed, in prior trials, including the Phase III VISION trial that led to Pluvicto's regulatory approvals in the US and Europe in chemotherapy-refractory patients, those with tumors that showed a mean PSMA standard uptake value (SUV) of 10 or greater when they received the gallium-labeled Locametz were most likely to benefit.
"This hasn't been reported with PSMAfore, but I hope it will be," Sweeney said, adding that truly personalizing therapy becomes all the more pressing in earlier treatment lines. "We need to define the best first-line mCRPC option for each individual patient."
Looking ahead, Sweeney said choosing the best treatment for patients with mCRPC is going to require thoughtful, highly personalized considerations. "Remember that old-fashioned thing called our brains and our clinical training? We can use that to make clinical decisions for our patients," he said.
To put the PSMAfore data into context, Sweeney attempted to outline a simplified map of what he sees as the "principles" for treating men with metastatic prostate cancer. For one, he said, all patients with hormone-sensitive cancer should receive the most effective hormone therapy available to them. Based on patients' disease characteristics and their clinical fitness, he said, oncologists could add chemotherapy or prostate radiation. At this point, Sweeney said, patients should ideally receive germline genetic screening and genetic counseling.
As the next "principle," Sweeney said patients should receive PSMA PET scans and have their tumors profiled for actionable biomarkers like BRCA1/2 and other DNA damage repair gene mutations, which can inform eligibility for PARP inhibitors. Then, based on the somatic and germline testing data and patients' suitability for chemotherapy, oncologists "should develop individual treatment plans with the greatest chance of benefit as first-line therapy for each patient."
All of these personalization steps and strategies assume an "ideal setting," in which patients can access the best therapies for their cancers. "We've got to do the best we can," Sweeney said.
However, the reality over the past year has been that many patients haven't been able to access Pluvicto because Novartis lacked manufacturing capacity to meet demand. Novartis has since said it's solved its supply issues, but it remains to be seen whether the drugmaker could ensure enough Pluvicto for a patient population that, with an earlier-stage approval, could triple in size. It also remains to be seen whether regulators will approve a therapy based on a trial in which patients in the control arm fared slightly better in terms of overall survival.
Novartis said last year that it is already talking with health authorities about expanding Pluvicto's approval based on PSMAfore data, and on Tuesday morning, the firm said it was planning to file for approval in treatment-naïve mCRPC during 2024, once it has additional data on both the crossover-adjusted and unadjusted overall survival outcomes.
The Swiss drugmaker has also been evaluating Pluvicto as a treatment for hormone-sensitive prostate cancer in the PSMAddition study and has plans to start a trial evaluating the radiopharmaceutical in patients with oligometastatic prostate cancers that have metastasized to the bones.