Introduction
Radiopharmaceutical therapy (RPT)—encompassing radioligand therapy (RLT), targeted alpha therapy (TAT), and peptide receptor radionuclide therapy (PRRT)—has matured from a niche modality into a cornerstone of precision oncology between 2020 and July 2026. By combining molecular targeting with the cytotoxic effects of ionizing radiation, these agents enable a "see-and-treat" theranostic strategy: a companion diagnostic imaging agent identifies eligible patients, and the therapeutic counterpart delivers localized irradiation to tumour cells expressing the target biomarker. As of mid-2026, two agents carry global regulatory approval, over 400 clinical trials are registered on ClinicalTrials.gov, and industry M&A activity has surpassed $10 billion since 2023. This review synthesizes the clinical, regulatory, commercial, and manufacturing developments shaping the field for medical professionals. 159
Approved Products and Pivotal Clinical Evidence
Lutathera® ([¹⁷⁷Lu]Lu-DOTA-TATE), targeting somatostatin receptor type 2 (SSTR2), was approved by the FDA in January 2018 and by the EMA in September 2017, establishing it as the foundation of PRRT. The pivotal Phase III NETTER-1 trial demonstrated a median progression-free survival (PFS) of 28.4 months versus 8.4 months with high-dose octreotide (hazard ratio [HR] 0.21; p<0.001) in SSTR-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs), with an objective response rate (ORR) of 18% versus 3%. In April 2024, the FDA expanded the indication to paediatric patients aged ≥12 years with advanced SSTR-positive G1–G2 GEP-NETs based on the Phase 2 NETTER-P trial. 159
Pluvicto® (lutetium Lu-177 vipivotide tetraxetan; formerly ¹⁷⁷Lu-PSMA-617), targeting prostate-specific membrane antigen (PSMA), received FDA approval on 23 March 2022 and EMA authorisation on 9 December 2022 for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) following prior androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy. The Phase III VISION trial (n=831) demonstrated median overall survival (OS) of 15.3 versus 11.3 months with best standard of care (BSoC) alone (HR 0.62; p<0.001), median radiographic progression-free survival (rPFS) of 8.7 versus 3.4 months (HR 0.40; p<0.001), and ORR of 30% versus 2%. On 28 March 2025, the FDA expanded the indication to include PSMA-positive mCRPC patients treated with one ARPI deemed appropriate to delay chemotherapy, based on the Phase III PSMAfore trial (rPFS 9.3 vs. 5.6 months; HR 0.41; p<0.0001). In November 2025, China's National Medical Products Administration (NMPA) approved Pluvicto for dual mCRPC indications, marking the first PSMA-targeting RLT licensed in China. 12316
The diagnostic theranostic partner, Locametz® (gallium Ga-68 gozetotide), was approved concurrently with Pluvicto in March 2022 and enables PSMA-positive lesion identification by positron emission tomography (PET) imaging, functioning as the eligibility gating tool in both approvals. PSMA is expressed in >80% of prostate cancers, providing a broadly actionable phenotypic biomarker. 9
Table 1. Key Approved and Late-Stage Oncology Radiopharmaceutical Assets (2020–July 2026)
| Asset | Target | Radionuclide | Indication | Regulatory Status (US / EU / China) | Primary Efficacy | Key Safety Signal |
|---|---|---|---|---|---|---|
| Pluvicto® (¹⁷⁷Lu-PSMA-617) | PSMA | ¹⁷⁷Lu (β−) | PSMA+ mCRPC | FDA 03/2022 (expanded 03/2025); EMA 12/2022; NMPA 11/2025 | OS 15.3 vs 11.3 mo; rPFS 8.7 vs 3.4 mo | Xerostomia 39%, anaemia G3–4 13%, thrombocytopenia G3–4 8% |
| Lutathera® (¹⁷⁷Lu-DOTATATE) | SSTR2 | ¹⁷⁷Lu (β−) | GEP-NET (G1–G2); paediatric expansion 2024 | FDA/EMA approved; NMPA 11/2025 | mPFS 28.4 vs 8.4 mo (HR 0.21; p<0.001); ORR 18% vs 3% | Lymphopenia G3–4 44%, renal toxicity, MDS ~2.7% |
| ²²⁵Ac-PSMA-617 | PSMA | ²²⁵Ac (α) | PSMA+ mCRPC (post-¹⁷⁷Lu; investigational) | Compassionate use / investigational | PSA decline ≥50% in 65%; OS 7.7 mo | Xerostomia 100% any grade; 23% discontinuation |
| RYZ101 (²²⁵Ac-DOTATATE) | SSTR2 | ²²⁵Ac (α) | GEP-NET refractory to ¹⁷⁷Lu | Phase III (ACTION-1; pending results) | Phase 1b: confirmed ORR 29%, no DLT at 120 kBq/kg | No dose-limiting toxicity at evaluated dose |
| ¹⁷⁷Lu-rhPSMA-10.1 | PSMA | ¹⁷⁷Lu (β−) | Prostate cancer | Phase II | Under evaluation | Under evaluation |
| ²²⁵Ac-Pelgifatamab (BAY-3546828) | PSMA | ²²⁵Ac (α) | Prostate cancer | Phase I | Under evaluation | Under evaluation |
| 3BP-227 (¹⁷⁷Lu-3BP-227) | NTR1 | ¹⁷⁷Lu (β−) | Colorectal cancer | Phase II | Under evaluation | Under evaluation |
| Satoreotide tetraxetan (¹⁷⁷Lu/²²⁵Ac/¹⁶¹Tb aliases) | SSTR | Multiple | Breast cancer | Phase II | Under evaluation | Under evaluation |
Safety Considerations and Dosimetry
Across approved agents, the dominant toxicity patterns are myelosuppression (anaemia, thrombocytopenia, lymphopenia), xerostomia (dry mouth), fatigue, and nausea. In VISION, grade 3–4 anaemia occurred in 13% of patients receiving Pluvicto, thrombocytopenia in 8%, and treatment discontinuation due to adverse reactions in 12%. Dosimetry data from VISION revealed highest radiation-absorbed doses in lacrimal glands (92 Gy), salivary glands (28 Gy), kidneys (19 Gy), and urinary bladder wall (14 Gy) across six cycles, directly explaining the patterns of xerostomia and the requirement for serial renal function monitoring. 222
Alpha-emitter TAT with ²²⁵Ac-PSMA-617 carries a substantially higher xerostomia burden: all patients experience at least grade 1–2 dry mouth, with 23% discontinuing therapy due to intolerable xerostomia or haematological toxicity. Renal toxicity is a standing concern in SSTR-directed PRRT, particularly with ⁹⁰Y-labelled peptides; mandatory amino acid renal protection infusion is required for Lutathera. Rare but serious long-term effects include myelodysplastic syndrome (MDS) and acute leukaemia, reported at approximately 2.7% and 0.5% incidence, respectively, in Lutathera studies. 596
Table 2. Major Clinical Trial Readouts (2020–July 2026)
| Trial | Phase | N | Population | Primary Endpoint | Key Efficacy Result | Status |
|---|---|---|---|---|---|---|
| VISION | III | 831 | PSMA+ mCRPC post-ARPI/taxane | OS; rPFS | OS 15.3 vs 11.3 mo (HR 0.62); rPFS 8.7 vs 3.4 mo (HR 0.40); ORR 30% vs 2% | Completed; basis for FDA/EMA/NMPA approval |
| PSMAfore | III | 468 | PSMA+ mCRPC post-1 ARPI, chemo-deferral | rPFS | rPFS 9.3 vs 5.6 mo (HR 0.41; p<0.0001); mOS 24.5 vs 23.1 mo (NS) | Completed; basis for March 2025 US label expansion |
| TheraP | II | 200 | mCRPC post-docetaxel | PSA response ≥50% | 66% vs 37% vs cabazitaxel; biochemical PFS HR 0.69 | Completed; supports earlier PSMA RLT use |
| NETTER-1 | III | 231 | SSTR+ GEP-NET, progressive midgut | PFS | mPFS 28.4 vs 8.4 mo (HR 0.21; p<0.001); ORR 18% vs 3% | Completed; foundational PRRT registration trial |
| NETTER-2 | III | — | G2–G3 GEP-NET, first-line | PFS | Significantly prolonged mPFS vs SSA monotherapy | Completed; extends PRRT to higher-grade, earlier-line |
| COMPETE | III | — | SSTR+ G1–G2 GEP-NET, progressive | PFS vs everolimus | mPFS 29.3 vs 14.1 mo (p=0.022; ¹⁷⁷Lu-DOTATOC) | Results presented ENETS 2025 |
| ACTION-1 (RYZ101) | III | — | SSTR2+ GEP-NET post-¹⁷⁷Lu | TBD | Phase 1b: ORR 29%, no DLT | Ongoing |
Emerging Targets and Pipeline Diversification
While PSMA and SSTR remain dominant (accounting for ~65% of registered RLT trials), the pipeline is diversifying. Fibroblast activation protein (FAP)-targeted theranostics have gained particular momentum, especially in China: in early April 2025, Chengdu Nureite received NMPA acceptance for both a therapeutic (¹⁷⁷Lu-NRT6020) and a companion diagnostic (⁶⁸Ga-NRT6020) in the same clinical trial application, following December 2024 FDA Investigational New Drug (IND) clearance. Other active targets in development include GRPR (gastrin-releasing peptide receptor), CAIX (carbonic anhydrase IX), CXCR4, DLL3 (delta-like ligand 3) in small cell lung cancer, HER2, nectin-4, FRα (folate receptor alpha), and GPC3 (glypican-3) in hepatocellular carcinoma. However, pivotal efficacy and safety trial data for FAP, HER2, and DLL3 radiopharmaceuticals were not available in the retrieved materials; these should be regarded as emerging rather than validated platforms. 151714
Industry Deal Activity and Manufacturing Investment
The period 2023–2024 witnessed unprecedented M&A consolidation, with major pharmaceutical companies acquiring radiopharmaceutical platforms:
Table 3. Notable Transactions and Partnerships (2020–July 2026)
| Acquirer / Partner | Target / Asset | Date | Value | Strategic Focus |
|---|---|---|---|---|
| Eli Lilly | Point BioPharma | October 2023 | $1.4 billion | ¹⁷⁷Lu assets and pipeline |
| Bristol Myers Squibb | RayzeBio | December 2023 | $4.1 billion | ²²⁵Ac-based TAT (RYZ101) |
| AstraZeneca | Fusion Pharmaceuticals | March 2024 | $2.4 billion | ²²⁵Ac-based radiotherapies |
| Novartis | Mariana Oncology | May 2024 | $1 billion | ²²⁵Ac-based platforms |
| Sanofi | RadioMedix / Orano Med | September 2024 | $356 million upfront | Lead-212 (AlphaMedix) for NETs |
| Novartis | PeptiDream (licensing expansion) | April 2024 | Up to $2.71 billion | Peptide-based RLT discovery |
| Eli Lilly & Aktis Oncology | Alpha miniproteins (nectin-4 etc.) | May 2024 | $60M upfront + $1.1B potential | TAT in solid tumours |
| Eli Lilly & Radionetics | GPCR small molecule RLT | July 2024 | $140M + buyout option | Novel targeting modalities |
| ITM Isotopen & Endocyte (Novartis) | ¹⁷⁷Lu supply | 2018; expanded 2020 | Undisclosed | ¹⁷⁷Lu supply security through 2035 |
| ITM Isotope Technologies Munich & ILL | n.c.a. ¹⁷⁷Lu production | June 2025 | Undisclosed | Priority reactor irradiation access |
Three strategic themes dominate: (1) consolidation of alpha-particle platforms (²²⁵Ac) by large pharma; (2) expansion of lutetium-177 pipelines; and (3) investment in novel isotopes (lead-212, polonium-210) and targeting modalities. Manufacturing capacity has scaled substantially: Novartis has expanded facilities across Millburn NJ, Zaragoza, Ivrea, Indianapolis, and is developing a third US site in Carlsbad CA. AstraZeneca invested in Nucleus RadioPharma's Series A to establish multiple US manufacturing facilities including one near Mayo Clinic. 1314
Regulatory and Guideline Landscape
Patient selection via molecular imaging is integral to RLT. PSMA PET (Locametz) gates eligibility for Pluvicto; SSTR PET (⁶⁸Ga-DOTATATE/DOTATOC or ⁶⁴Cu-DOTATATE) is required before PRRT, with dual ¹⁸F-FDG PET recommended to exclude discordant SSTR-negative/FDG-positive lesions that may disqualify patients. The EMA issued updated radiopharmaceutical manufacturing guidance effective October 2025, addressing active substance characterization, stability, radiochemical purity, and specific activity requirements. The FDA issued the guidance "Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development" (Docket FDA-2025-D-1757) to support personalised dosing strategies during clinical development. Joint EANM/IAEA/SNMMI practical guidance published in June 2026 establishes standardised PRRT patient selection, dosimetry, and toxicity monitoring frameworks. 618197
In China, regulatory momentum accelerated markedly in 2025: Xiantong Pharma received NMPA acceptance for a Class 3 [¹⁷⁷Lu]Lu-oxodotreotide injection; Maideno Medical received a Class 1 clinical trial application acceptance; and Hexin Pharma advanced HX02, a dual-target radiopharmaceutical. China's prostate cancer burden—with 54% of patients presenting at metastatic stage and a 36.6% five-year survival rate in the castration-resistant stage—underscores the clinical urgency of these approvals. 317
Market Outlook: Drivers and Barriers
Table 4. Market Outlook — Drivers and Barriers (2026–2030)
| Drivers | Barriers |
|---|---|
| Proven OS and PFS benefits in mCRPC and GEP-NET | Limited ²²⁵Ac supply; geopolitical risk (Russia-Ukraine) affecting one supplier |
| Pluvicto March 2025 label expansion tripling eligible mCRPC population | Specialized nuclear medicine infrastructure required; limited qualified centres |
| NETTER-2 and COMPETE extending PRRT to earlier-line and higher-grade NETs | High treatment costs; reimbursement variability across US payers and HTA systems |
| Entry of Eli Lilly, BMS, AstraZeneca, Sanofi validating long-term viability | Short radioactive half-lives necessitate just-in-time manufacturing and rapid distribution |
| Emerging targets (FAP, HER2, DLL3) expanding addressable populations | PSMA-negative or neuroendocrine-variant prostate cancers limiting patient selection |
| Theranostic integration improving patient selection and outcomes | Immature long-term safety data for combination and alpha-emitter approaches |
| China NMPA acceleration and domestic manufacturing investment | Regulatory complexity for novel modalities; manufacturing process changes require bridging studies |
| ITM–ILL ¹⁷⁷Lu supply agreement securing priority reactor access through 2025+ | Xerostomia and myelosuppression constraining tolerability, particularly in TAT |
The global radiopharmaceutical therapy market is entering a "commercialization realization period." Analysts position radiopharmaceutical-drug conjugates (RDCs) to follow the growth trajectory of antibody-drug conjugates (ADCs), with added resistance-resistance advantages due to physical radiation-induced cytotoxicity. The competitive landscape now involves all major oncology pharma players, reducing single-company dependency and accelerating clinical development across multiple tumour types. 21
Conclusion
From 2020 to July 2026, oncology radiopharmaceuticals have transitioned from investigational agents to an established precision oncology pillar. VISION and NETTER-1 provide the clinical bedrock for PSMA and SSTR targeting; PSMAfore expands the eligible mCRPC population substantially; and NETTER-2/COMPETE confirm PRRT utility in earlier lines. Alpha-emitter platforms (²²⁵Ac-PSMA, RYZ101) demonstrate proof-of-concept in salvage settings, though xerostomia and haematologic toxicity require careful patient selection. Manufacturing partnerships—notably the ITM–ILL ¹⁷⁷Lu supply agreement and Novartis's multi-site production network—are addressing isotope supply bottlenecks. Industry consolidation exceeding $10 billion signals durable commercial confidence. Key unresolved challenges include ²²⁵Ac supply, reimbursement access, qualified treatment centre availability, and the generation of mature efficacy data for emerging targets such as FAP, HER2, and DLL3—areas where no pivotal readouts were available in the retrieved materials as of July 2026. 13141520