Novartis' $10 Billion Radiopharmaceutical Pluvicto Expands into Second-Line mCRPC Treatment with FDA Approval

Recently, Novartis announced that its重磅 nuclear medicine product Pluvicto (lutetium Lu 177 vipivotide tetraxetan) has been approved by the U.S. FDA for patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have previously received androgen receptor pathway inhibitor (ARPI) treatment and are considered suitable for delaying chemotherapy.

As the first nuclear medicine targeting PSMA, Pluvicto can precisely radiate prostate cancer and has the potential to replace whole-body radiotherapy. Financial reports show,In 2024, Pluvicto achieved sales of $1.392 billion, becoming the first "blockbuster drug" in the global nuclear medicine field.

The approval of this new indication advances Pluvicto treatment to the frontline for patients with early-stage disease progression who have not undergone chemotherapy, expanding the eligible patient population by threefold.

The expansion of Pluvicto's application scope this time is essentially based on clinical applications and related data, advancing the drug treatment lines, indirectly affirming the regulatory and clinical recognition of Pluvicto's efficacy.

Dr. Michael Morris, Chief of the Genitourinary Oncology Prostate Cancer Section at Memorial Sloan Kettering Cancer Center and the lead investigator of the U.S. study, stated: The early indication of Pluvicto may revolutionize the treatment paradigm for mCRPC. Compared to second-line ARPI, it provides a more effective targeted therapy to delay disease progression. This approval is a significant milestone, opening up better treatment options for mCRPC patients who have progressed on first-line ARPI and have not received chemotherapy.

Compared with the FDA's first approval in 2022 and the ongoing application for market entry in China, Pluvicto’s initial indication targets mCRPC patients who have received androgen receptor inhibitors and taxane chemotherapy.This new indication has been expanded to include patients with mCRPC who have not received chemotherapy, allowing Pluvicto to be used after one androgen receptor pathway inhibitor (ARPI) and before chemotherapy, enabling more patients to benefit from this innovative therapy earlier in the course of their disease (after first-line treatment progression).

This approval is based on the positive results of the Phase III PSMAfore study. The study is a multicenter, randomized, open-label clinical trial (n=469) that evaluated the efficacy and safety of switching PSMA-positive mCRPC patients from ARPI treatment to Pluvicto treatment.

The study results showed significant efficacy of Pluvicto when used early before chemotherapy: compared with the control group,Pluvicto® doubled the median radiographic progression-free survival (rPFS) from 5.6 months to 11.6 months, reducing the risk of disease progression by 59%. Meanwhile, the overall response rate in the Pluvicto® group reached 30%, offering patients more positive treatment outcomes.

At the same time, the study results indicate that Pluvict demonstrated consistent and favorable safety in line with previous trials. The most frequently reported adverse events across all levels were mainly grade 1-2, including dry mouth (61%), fatigue (53%), nausea (32%), and constipation (22%).

From a clinical perspective, more than 35,000 men die from prostate cancer each year, making it one of the most prevalent malignant tumors among men in Europe and America, with its incidence continuing to rise. In China, the incidence of prostate cancer is also showing a continuous upward trend. According to the "2018 Chinese Expert Consensus on Diagnosis and Treatment of Metastatic Prostate Cancer," there were 60,300 new cases of prostate cancer in China in 2015, with about 26,600 deaths, andMost patients with prostate cancer have already developed metastases at the time of initial diagnosis.

Currently, hormone therapy ARPI and chemotherapy are the basic treatments for mCRPC.Due to side effects, many patients and their healthcare providers prefer to avoid or delay chemotherapy, and multi-national treatment guidelines recommend avoiding the use of multiple ARPIs.

Prostate cancer, once patients enter the stage of positive metastatic castration-resistant prostate cancer (mCRPC), generally has a poor prognosis. The main goals are to prolong patient survival and improve quality of life. Novartis' press release specifically pointed out,Approximately half of the patients do not live long enough to receive a second treatment for mCRPC, highlighting the necessity of using effective and tolerable therapies early on.This approval not only provides a new early treatment option, but alsoPluvicto will not impair a patient’s ability to receive subsequent chemotherapy.

Pluvicto is a radioligand therapy that ensures precise destruction of cancer cells expressing PSMA while maximizing the protection of normal tissues such as the bladder through the accurate binding mechanism of the 177Lu isotope with the PSMA ligand. Beta rays release 0.5MeV energy within a 7mm range. Compared with traditional systemic radiotherapy, radioligands offer the advantages of precise tumor targeting, powerful killing, and limited damage to surrounding tissues.

In 2024, Novartis, the "leader" in the global nuclear medicine field, achieved nuclear medicine product revenue surpassing the US$2 billion mark for the first time.Among them, Pluvicto's sales revenue increased by 42% year-on-year to $1.392 billion, making it the first "blockbuster" drug in the global nuclear medicine field to surpass $1 billion in annual sales; Lutathera's sales revenue reached $724 million.

Notably, both of Novartis' key nuclear medicine products achieved rapid commercial scaling after their market launch.Pluvicto was first approved for marketing in 2022 and became the world's top nuclear medicine within just three years of its launch. Lutathera, which was approved in 2018, entered Novartis' top 20 revenue-generating brands for the first time seven years after its launch, and Novartis expects it to become the next billion-dollar nuclear medicine.

The two "epoch-making" products that propelled Novartis to the top of the nuclear medicine field were both acquired through early acquisitions.——Originating from the "nuclear medicine empire" strategy of Novartis CEO Vas Narasimhan, in 2017, Novartis acquired Advanced Accelerator Applications for $3.9 billion, obtaining Lutathera. In 2018, Lutathera was launched in the United States. In the same year, Novartis spent another $2.1 billion to acquire Endocyte, securing Pluvicto, which was already in Phase III clinical trials.

However, a sharp eye for product selection alone is not enough to build a "nuclear medicine empire."The key lies in its rapidly constructed "production-transportation-application" industrial chain and "diagnosis-treatment" product ecosystem loop in the later stage.

In terms of product closed-loop ecosystem, Novartis has built an integrated "diagnosis-treatment" system — that is, the same targeting ligand and linker can be combined with radionuclides for either therapeutic or diagnostic imaging purposes. Each therapeutic drug can have a corresponding diagnostic agent. After being diagnosed with a disease, patients can use the corresponding medication for treatment, saving time and improving efficiency while avoiding ineffective medication.Novartis' 68Ga-PSMA-11, Lutathera, and Pluvicto (177Lu) all target PSMA, and are respectively used for PET imaging and treatment of gastroenteropancreatic neuroendocrine tumors and prostate cancer.

In December 2020, Novartis' 68Ga-PSMA-11 received FDA approval, becoming the first drug for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA)-positive lesions. Administered intravenously, it indicates PSMA-positive prostate lesions present in body tissues through PET imaging.

In the industrial chain, Novartis accelerates the radiopharmaceuticals "last mile" by laying out isotope factories, modular production systems, and efficient transportation networks.From the beginning, the acquisition of Advanced Accelerator Applications (AAA) by Novartis not only brought a radiopharmaceutical technology platform to nuclear medicine developers but also served as a producer of Lutetium-177 (177Lu), addressing the early supply of radionuclides.

Restricted by the half-life of radioactive isotopes, the activity of nuclear medicine will decrease within a specific time period, thus requiring timely delivery and administration to patients.Due to the limited time window for administration, these drugs are typically produced in single-dose forms, taking into account transportation distance and drug delivery cycles. Not only are mature and complete upstream and downstream industries and nuclear pharmacy support required, but also the presence of medical institutions with the qualification for clinical use of radiopharmaceuticals within a certain range.

As early as 2018, when Lutathera was launched in the U.S., Novartis faced challenges related to the difficulty of radiopharmaceutical transportation and clinical application. Lutathera's sales initially grew very rapidly, generating $167 million in revenue in its first year after approval and increasing to $441 million in the second year, but then plateaued. One reason is that the qualifications of medical institutions and limitations in production and transportation cycles restricted the widespread adoption of Lutathera. If medical institutions capable of providing treatment reach patient capacity saturation, Lutathera’s sales will hit a bottleneck.

Looking at Pluvicto, for example, for patients in the United States, before the new factory is approved in 2024, Pluvicto needs to be shipped from the Italian factory and undergo inspections by customs, the FDA, and others. However, the half-life of Lu-177 is 6.647 days, and the shelf life of Pluvicto is only 5 days. Any weather impact or inspection delays could result in the drug becoming ineffective.

To address the imminent capacity issues, Novartis has accelerated the layout of radionuclide factories in nearly six years, and currently operates four RLT production bases globally.Successfully integrated the upstream, midstream, and downstream industrial chain supply ecosystem from the preparation of radionuclide raw materials to final clinical application, meticulously creating a precise radionuclide control, strict radiation protection, and highly efficient logistics transportation system, thereby ensuring that patients within medical institutions can receive treatment promptly within the drug's validity period calculated in "hours."

After seven years of efforts in the global supply chain, Novartis is ushering in a rapid growth phase for Lutathera and Pluvicto in 2024 and 2025. Meanwhile, the Chinese market may become the next breakout point.

In November 2024, Novartis' Pluvicto marketing application submitted to the CDE was accepted and has been included in the priority review, with the indication specified for mCRPC patients who have received androgen receptor inhibitors and taxane chemotherapy.On February 9, 2025, the clinical trial application for Lutathera and 68Ga-PSMA-11 was accepted by the Center for Drug Evaluation of the China National Medical Products Administration.

Production base in China has also started operation.In July last year, Novartis' first radiopharmaceuticals production base in China officially broke ground in Haiyan, Zhejiang, with a total investment of 600 million RMB. It is expected to begin production by the end of 2026.This is also the first foreign investment project in China's nuclear medicine field, as well as a signal that imported original radioligand therapies are gradually entering the Chinese market.

Moreover, for Novartis, which is "not short of money," it is worth noting whether the operation model of nuclear pharmacies in China will choose "cooperation and sharing" or "going it alone."

Due to the impact of half-life, medium- and short-term radionuclide drugs need to rely on the network of radiopharmacies/drug centers for production and delivery. China's radiopharmacy resources are mainly concentrated in two companies: China Isotope & Radiation Corporation and Dongcheng Pharmaceutical. For emerging nuclear medicine companies, building their own radiopharmacies faces significant time and financial pressures, with a construction cycle of at least three years and an investment of over 40 million yuan for a single radiopharmacy. Therefore, emerging nuclear medicine companies will first focus on building competitive advantages in single-category products, then collaborate with the radiopharmacy resources of companies like China Isotope & Radiation Corporation and Dongcheng Pharmaceutical.

In contrast, according to data from the UNM College of Pharmacy's official website, there are approximately 600 radiopharmacies globally, with over 400 located in the United States. According to Cardinal Health's official website, a representative company of U.S. nuclear pharmacies, it operates more than 130 nuclear pharmacies and over 30 cyclotrons, possessing the supply chain capability to provide delivery services within three hours to more than 95% of medical institutions across the U.S.

At the 2025 JPM Conference, Novartis clearly demonstrated its firm commitment to the radiopharmaceuticals sector, revealing plans to further increase investment over the next three years to enhance the RLT technology platform. Novartis is continuously researching an extensive portfolio of RLT products, exploring new isotopes, ligands, and combination therapies, including 177Lu-NeoB and 225Ac-PSMA-617, aiming to expand beyond gastrointestinal pancreatic neuroendocrine tumors and prostate cancer into breast cancer, colon cancer, lung cancer, and pancreatic cancer.

Novartis stated that the marketing applications for Pluvicto have been accepted in China (for use after taxane chemotherapy) and Japan (for use before/after taxane chemotherapy). Results from the PSMAddition study in metastatic hormone-sensitive prostate cancer (mHSPC) are expected to be announced in the second half of 2025, with the Phase III clinical trial of Ac-PSMA-617 set to commence in 2025.

In May 2024, Novartis acquired the radiopharmaceutical company Mariana Oncology for $1.75 billion.In the latest earnings report interpretation, Novartis predicted that radiopharmaceuticals would become its "industry worth over 20 billion US dollars", new M&A and BD might be on the way.