NEW YORK – It has only been one week since the US Food and Drug Administration approved Novartis' targeted radioligand therapy Pluvicto (177Lu-PSMA-617 or lutetium Lu 177 vipivotide tetraxetan), but oncologists, drugmakers, and nuclear medicine experts are already predicting that the treatment will have sweeping implications for prostate cancer treatment and the theranostics space at large.
Before Pluvicto, other targeted radioligands on the market were for rarer cancers, such as Novartis' Lutathera (lutetium Lu 177 dotatate) for gastroenteropancreatic neuroendocrine tumors. But now, Pluvicto's approval for certain prostate cancer patients, who have one of the most common tumor types, has signaled to the field that applying the precision medicine framework to radiation therapy is feasible, effective for patients, and likely quite lucrative.
The FDA specifically approved Pluvicto — an injectable therapy comprising a molecule that targets the prostate-specific membrane antigen (PSMA) and a linked dose of the radioactive beta-emitting isotope lutetium-177 — for progressive metastatic castration-resistant prostate cancer patients after prior treatment with androgen receptor pathway inhibitors and taxane-based chemotherapy. Simultaneously, the agency also approved Novartis' Locametz (gallium Ga 68 gozetotide) as an imaging agent for identifying mCRPC patients with PSMA-positive lesions who are eligible to receive Pluvicto.
Patients' tumors must express PSMA to be eligible for the radiopharmaceutical, and oncologists must determine this using a PSMA-11 PET imaging agent that fundamentally works the same way as the therapy: via a PSMA-targeting molecule linked to a radioactive element, but one that emits enough radiation to glow on a PET scan but not enough to deliver a cell-killing therapeutic effect. The FDA-approved label for Pluvicto notes that treatment-eligible patients must be identified using Locametz or another FDA-approved PSMA-11 (gallium Ga 68 gozetotide) imaging agent.
Novartis' success in bringing a targeted radioligand with a companion imaging agent to market for prostate cancer has energized the competitive landscape, spurring other drugmakers to launch or advance their own products for common cancers. The way the FDA chose to approve Pluvicto — in combination with a specific type of PET imaging agent to identify treatment-eligible patients — has implications for the future development of this space, too.
The FDA's Pluvicto approval was highly anticipated among oncologists following the strong benefit seen with the treatment compared to best available standard therapy in the pivotal Phase III VISION trial. However, many wondered how regulators might specify eligibility criteria for the therapy.
In VISION, investigators used Novartis' Locametz and Telix Pharmaceuticals' Illuccix (TLX591-CDx) to determine PSMA positivity before treating patients with Pluvicto. However, there are other ways to identify the 80 percent of prostate cancer patients with PSMA-expressing lesions, which have not been approved for use specifically alongside Pluvicto, that oncologists could theoretically use to identify eligible patients. Lantheus Holdings markets a fluorine-18 (F18) PSMA PET imaging product called Pylarify, for instance, which was approved last year.
"It's not like there is only one PSMA molecule that we can radiolabel," said Cameron Foster, director of theranostics at the University of California, Davis. "There are several, and there will be new ones down the line."
Clinicians have been parsing the words in Pluvicto's label carefully, trying to figure out the FDA's meaning. The label states: "Select patients for treatment using Locametz or an approved PSMA-11 imaging agent based on PSMA expression in tumors." While the label doesn't name the radioisotope in Locametz — gallium-68 — the agency seems to emphasize the need for this particular radioisotope by mentioning "PSMA-11." Only PSMA-11 imaging agents are gallium-68 labeled, pointed out Hossein Jadvar, a professor of radiology at University of Southern California Keck School of Medicine.
"That is the very first question I asked my colleagues. … 'Why did [FDA] say PSMA-11?'" Jadvar said, explaining that if one were to follow the precise labeling language about the imaging agent, doctors could currently use gallium-68-labeled products. By that rationale, other PSMA PET imaging methods, such as Lantheus' Pylarify, which uses F18 instead of gallium-68, seem to fall outside of the labeling language describing appropriate imaging products.
The specificity around what imaging agent can be used is critical because it controls who can access the drug. "Linking Pluvicto to a specific PSMA agent is, in my opinion, a bit troublesome, because there are other PSMA imaging agents," UC Davis' Foster said. "For something that should be championed in a way that we're increasing access, this seems unfortunately restrictive."
The labeling language matters particularly for cancer centers that are getting their ducks in a row, by setting up necessary infrastructure, logistics, billing codes, and the like, so they can offer Pluvicto to patients. Foster noted, for example, that the label will likely influence which imaging agent UC Davis uses to screen patients for PSMA eligibility, which could impact patient access.
The labeling language "made me change the way that I was going to push for which imaging agent we would have preference for at our institution," he said. "Originally, we were probably going to be going with the F18 tracer … but now, unless an FDA amendment comes out, we're going to be using the gallium-68."
This means that UC Davis will also have to deal with the hurdles surrounding gallium-68 procurement. Making the gallium-68 imaging agent requires gallium generators. "And those are not in easy supply," Foster said, explaining that because gallium has a shorter half-life than F18, centers need to make it on site using a generator, which costs somewhere close to six figures and has to be replaced periodically since it runs down over time.
Because F18 has a longer half-life, it's easier to generate at a remote location and ship longer distances, Foster explained. "Access to F18 … that's much more widespread across the country."
Given these considerations, other centers might ignore the FDA label and continue screening patients with F18 PSMA PET imaging, according to USC's Jadvar. Of course, this would mean off-label use, which comes with its own set of logistical and potentially costly barriers.
"We are likely going to be doing the screening with Pylarify," USC's Jadvar said. "Because I don't think we're going to buy a gallium-68 generator when there's a PSMA agent we can just order and they bring it to us as a unit dose."
The FDA approved Lantheus' F18 imaging agent Pylarify last year for staging and determining recurrence in PSMA-positive prostate cancer patients, as opposed to screening for Pluvicto. Since then, many centers like USC have put in place the infrastructure for administering it.
Although using Pylarify or another non-gallium-68 imaging agent would be off-label, Jadvar noted that the literature already shows that most PSMA PET imaging approaches can equivalently identify PSMA-positive prostate cancer lesions. A head-to-head comparison of gallium 68-based PSMA imaging and F18-based PSMA imaging published in 2020 in the Journal of Nuclear Medicine, for instance, found "almost perfect concordance between the two tracers" in their ability to identify PSMA-avid lesions.
Meanwhile, Pluvicto's label could very well expand to include other imaging approaches. Just this week, Lantheus and Novartis inked a deal to use Pylarify as a selection tool for future Pluvicto trials, presumably with the goal of increasing the range of imaging agents that can be used to identify eligible patients.
"We look forward to collaborating to further explore how PSMA PET imaging agents like Pylarify may aid in increasing accessibility to PSMA-targeted therapeutics," Lantheus CEO Mary Anne Heino said in a statement.
In the meantime, "people are just going to order Pylarify anyway," Jadvar predicted.
But other oncologists like Foster may stick to the labeling language and use Locametz, much to Novartis' benefit. Lantheus recently estimated that, with Pluvicto on the market, PSMA PET imaging will increase by roughly 30,000 de novo scans per year, yielding a $1.1 billion market opportunity. The wholesale acquisition cost for the maximum dose of Locametz is $5,600, while Pluvicto's maximum list price is $255,000.
Novartis plans to expand Pluvicto and its companion imaging agent into even larger indications and has Phase III trials underway for prostate cancer patients who are hormone-sensitive as well as those not previously treated with taxane-based chemotherapy. In a call last month to discuss Novartis' fourth quarter 2021 and full-year financial earnings, Susanne Schaffert, head of Novartis' oncology business unit, said that these additional indications could potentially quadruple the eligible patient population for Pluvicto.
Competition on Novartis' heels
The Pluvicto approval may have been the first PSMA-targeted radiopharmaceutical to enter the prostate cancer space, but it's unlikely to be the last.
Earlier this month, Bracco Imaging spun out a new subsidiary, Blue Earth Therapeutics, devoted to developing radiopharmaceuticals. It is planning to develop agents for PSMA-positive prostate cancer that are structured slightly differently than Pluvicto, using an F18-enabled binding domain in a "radiohybrid" approach instead of one designed for gallium or lutetium. The therapies are still in early stages, and the companion imaging agent developed by sister company Blue Earth Diagnostics is not yet FDA-approved, but the firm sees a competitive advantage given the easier-to-access F18.
Telix Pharmaceuticals, the firm that markets the other FDA-approved PSMA-11 gallium-68 imaging product Illuccix, is already moving beyond prostate cancer, eyeing unmet need in clear-cell kidney cancer and triple-negative breast cancer with a radiopharmaceutical program that targets CA9 as opposed to PSMA.
Beyond new spinouts and specialized nuclear medicine firms, big pharma players are also stepping into the space. Bayer, which has marketed a radiopharmaceutical for prostate cancer called Xofigo (radium 223 dichloride) since 2013, is eager to maintain the market for its drug in the face of new competition.
Xofigo isn't technically a targeted radiopharmaceutical — it comprises radium-223 without a linked binding molecule — but it does behave in a similar way since radium-223 is absorbed uniquely by bone. Accordingly, the therapy does target cancer lesions in the bone, where prostate cancer tumors are known to metastasize. Importantly, though, patients receiving Xofigo cannot have visceral metastases — that is, lesions in vital organs like the liver, lung, and central nervous system — making the pool of eligible patients smaller.
Bayer VP and Head of US Oncology Medical Affairs Iain Webb suggested that Xofigo and Pluvicto might be effective when used sequentially. In the VISION trial, some patients had received Xofigo before their cancer recurred and they got Pluvicto in the study, though Webb acknowledge that the benefit of sequential administration of these drugs would need to be better characterized in a separate trial.
Despite Bayer's view that Xofigo still fits into the advanced prostate cancer treatment landscape, the therapy's sales have been on a downward trajectory in recent years. In 2020, amid the COVID-19 pandemic, annual sales of Xofigo declined 13.5 percent year over year from €303 million ($338 million) to €262 million. Drug sales did not recover in 2021, dropping an additional half a percent to €261 million ($291 million). However, the company recently acquired two firms, Noria Therapeutics and subsidiary PSMA Therapeutics, to advance targeted radiopharmaceutical programs that would bolster its presence in this space and allow it to compete more aggressively with players like Novartis.
Several targeted radiopharmaceuticals in Bayer's pipeline are in early-phase trials and differ from Pluvicto in that they use different radioactive elements such as actinium and thorium-227 instead of lutetium. When they decay, these elements give off alpha, rather than beta, particles, Webb explained, which means they have a shorter wavelength and thus stay more localized inside the body.
Bayer is focusing on this distinction as an advantage and calling the development program its "targeted alpha therapy," or TαT, platform.
While any efficacy advantage of these therapies will have to be proven in clinical trials, logistically, alpha emitters may have an upper hand on beta emitters in that they're easier to handle, Webb said. With alpha emitters, patients don't have to be secluded from family members. Pluvicto's label, in contrast, cautions patients to limit contact with household members, children, and pregnant women and limit sexual activity.
Bayer is particularly optimistic about its targeted thorium-227 compounds (TTC), which it is developing for multiple tumor types, focusing on targets such as mesothelin and HER2, as well as PSMA in mCRPC.
Like Novartis did in the VISION trial, Webb expects to confirm that mCRPC patients have PSMA-positive lesions using a specific imaging agent in the registrational trials of its radiopharmaceuticals. "Knowing what we know today, the most likely scenario is that we will be using some form of PSMA PET imaging to define patient eligibility for our targeted alpha therapy," Webb said. While it's not clear which imaging agent Bayer will use, the company will select one with patient accessibility in mind.
Despite the myriad considerations with these new treatments in terms of the companion imaging agents, cost, and access, patients and their oncologists, including UC Davis' Foster, are largely heralding the advent of targeted radionuclides for prostate cancer. "This is great for patients," Foster said. "The take-home message in the industry is that we are thrilled that this got approved, even with the imaging agents. … We can deal with that."
And ultimately, with more products and data, he hopes that nuclear medicine will stop being a last-ditch option for patients and move into earlier lines. "Having more of these agents like Lutathera, Xofigo, and now Pluvicto, we'll really start to push to our medical oncology partners to get patients on these agents sooner," he said. "And maybe these patients will never get to late-stage treatment because we can cure them. That's always the dream."