Will the Coming Radiopharmaceutical Wave Reach More Patients With Cancer?

Rising interest in solutions that target cancer therapies directly has fueled growth in radiopharmaceuticals, a sector witnessing new studies, banner trial results, and, most recently, an FDA approval that promises to greatly expand who can receive treatment.

Radiopharmaceuticals pinpoint delivery of radionuclides to targeted lesions to diagnose and treat multiple diseases. In cancer care, radioligand therapy (RLT) combines a radioisotope with a ligand, which binds the agent to markers on specific cancer cells. RLTs have gained notice as the need grows for treatments in refractory tumor types that do not respond to existing therapies.¹

The sector has seen billions in merger and acquisition activity in recent years; a September 2024 analysis by Insight Partners estimated the value of the global radiopharmaceuticals sector, including cancer treatments, would grow from $9.07 billion in 2023 to $26.51 billion by 2031.²

The FDA’s March 28, 2025, approval of an added indication for lutetium Lu 177 vipivotide tetraxetan (Pluvicto; Novartis Pharmaceuticals Corporation) in metastatic castration-resistant prostate cancer (mCRPC) could triple the number of patients eligible for the therapy, company officials said in a statement. The new indication allows treatment for prostate-specific membrane antigen (PSMA)–positive disease following androgen receptor pathway inhibitor (ARPI) therapy in patients for whom it is “considered appropriate to delay chemotherapy,” Novartis officials said.³ This follows the March 2022 approval for patients with PSMA-positive mCRPC treated with ARPI therapy and taxane-based chemotherapy.⁴

Michael J. Morris, MD | Image credit: MSKCC

Use of the RLT earlier on during treatment could be a game-changer, Michael J. Morris, MD, prostate cancer section head, genitourinary oncology, Memorial Sloan Kettering Cancer Center, said in the statement. “The earlier indication…could really change our treatment paradigms for patients with mCRPC,” said Morris, who led the key study driving the approval. “It offers a targeted therapy that better delays disease progression compared [with] a second ARPI.”³

Novartis leaders aren’t the only ones backing the idea that more patients could benefit from earlier treatment with radiopharmaceuticals. An official from Bayer, whose radium Ra 223 dichloride (Xofigo) was approved in 2013 to treat patients with CRPC and symptomatic bone metastases,⁵ told Evidence-Based Oncology (EBO) in a February interview that groundbreaking new data for Ra 223 have generated renewed interest in the therapy, and more patients should benefit.

Jorge Ortiz, MD | Image credit: LinkedIn

Jorge Ortiz, MD, global medical affairs head for Xofigo at Bayer Oncology, referenced PEACE-3 (NCT02194842),⁶ an investigator-initiated trial presented at the European Society for Medical Oncology (ESMO) in Barcelona, Spain, in October 2024. PEACE-3 data showed that adding Ra 233 to enzalutamide improved radiographic progression-free survival (rPFS) in untreated mCRPC and could offer a new first-line option.^6,7

“It’s about making sure the right patient gets treated with radium at the right time,” Ortiz said. “That right time is first-line mCRPC, and that’s where we saw the benefit.”

Enthusiasm for radiopharmaceuticals is spreading among clinicians despite recognized management challenges. RLTs have a limited treatment window due to their short half-life, so orders must be handled with great care, Naga Vara Kishore Pillarsetty, PhD, a radiochemist at Memorial Sloan Kettering Cancer Center, said in a February interview with EBO’s sister publication, Pharmacy Times®.⁸ (The half-life for Ra 223 is 11.4 days; it is 6.7 days for Lu 177). Pillarsetty noted that the very first “targeted therapy” was radioiodine (iodine 131), following studies by Saul Hertz, MD, in the 1940s whose data showed the effectiveness of iodine 131 in treating hyperthyroidism, leading to its use in thyroid cancer.^8,9

Naga Vara Kishore Pillarsetty, PhD | Image credit: MSKCC

Safety has always been a concern. Using a ligand to get the radioactive molecule to its precise target has significantly helped prevent organ damage, according to a January 2025 review article in Signal Transduction and Targeted Therapy.¹ 2019 FDA guidance outlined steps for industry to promote safety in developing RLTs in oncology.¹⁰ Posttreatment protocols vary; although patients receiving iodine 131 are advised to avoid small children for several days, Ra 223 is expelled in the urine and feces, so the Oncology Nursing Society advises routine good hygiene as sufficient.¹¹

Ortiz and Pillarsetty agreed that more must be done to educate doctors and patients about radiopharmaceuticals—and dispel myths as well.
It’s “absolutely true” that a patient may balk at hearing the word radium associated with their cancer treatment, Ortiz said. “We can all do a better job—pharma, clinicians, and patient advocacy groups—because it’s not only a very safe treatment in terms of the side effect profile,” he said, “but the delivery is easy.”

For patients treated with Ra 223, “it’s a 1-minute injection, and they then can go home,” Ortiz said.

To that end, leaders from the American Oncology Network (AON), which includes many small oncology practices, will discuss the use of radiopharmaceuticals at the community level on April 28, 2025, during the Community Oncology Alliance annual conference, in Lake Buena Vista, Florida.¹² Presenters Guy Messer, AS-NMT, BS-HCMGT, MBA, and Autumn Jones, BS-NMT, shared key points of their upcoming talk with EBO:

• Clinical trials are underway in multiple Indications, including prostate, breast, lung, colorectal, bladder, liver, glioblastoma, pancreatic, ovarian, lymphomas and osteosarcoma
• Most Medicare Administrative Contractors (MACs), reimburse radiopharmaceutical therapies at 95% Average Wholesale Price (AWP)
• AON is working to introduce radiopharmaceuticals into practices regardless of whether they currently provide positron emission tomography (PET) or radiation services.

PEACE-3 Results Spur Interest

Ra 223 was approved based on findings in the ALSYMPCA trial (NCT00699751), which evaluated 921 patients and demonstrated a 30% overall survival (OS) benefit with Ra 223 compared with placebo among patients who had previously received, were not eligible for, or had declined chemotherapy. Median OS was 14.9 months for the Ra 223 group and 11.3 months for the placebo group (HR, 0.70; 95% CI, 0.58-0.83; P < .001).¹³

ERA-223 (NCT02043678), a combination study whose findings were published in 2019, proved to be a setback, Ortiz said. That study paired Ra 223 with abiraterone acetate, a therapy typically given in the first line in patients with mCRPC who are progressing on androgen deprivation therapy. The combination did not improve symptomatic skeletal event-free survival in the population covered by the FDA approval, and study authors reported an increase in fractures.¹⁴

However, a pair of investigator-initiated studies were still in progress: one was PEACE-3 (NCT02194842), which paired Ra 223 with enzalutamide, the other standard first-line treatment. Following the results for ERA-223, investigators changed the protocol to require bone-protecting agents.

Results presented by Silke Gillessen, MD, head of the Department of Medical Oncology, Università della Svizzera Italiana, and medical and scientific director, Oncology Institute of Southern Switzerland, showed this new combination was associated with a 31% improvement in rPFS—19.4 months vs 16.4 months in the enzalutamide only arm (HR 0.69; 95% CI, 0.54-0.87; P = .0009). At 24 months, 45% of patients in the Ra 223 arm were free of radiographic progression compared with 36% in the monotherapy arm.⁶

“The primary end point, rPFS, was met, but the most surprising and exciting piece was the overall survival data,” Ortiz said. Early results show the combination demonstrated a 31% reduction in risk of death compared with the monotherapy arm, with median OS rising from 35 months to 42.3 months. A final OS analysis will be forthcoming, the study authors reported.^6,7

Mechanisms of Action: A-Emitters vs B-Emitters

The radiopharmaceutical sector is evolving from its historic focus on diagnostics, according to the Signal review article.¹ Zhang et al write, “Therapeutic isotopes with higher linear energy transfer and longer half-lives have been introduced…in recent years, as the major demand for radiopharmaceutical discovery has shifted from diagnostic imaging to targeted therapy.”

Among radionuclides, the authors outline differences between the α-emitters, of which Ra 223 is the only FDA-approved therapy, and ß-emitters, which include Lu 177, iodine 131, and several agents used in PET and single photon emission computed tomography (SPECT) imaging. (The authors also discuss smaller categories, such as Auger electron emitters.)

“The natural characteristics of α-particles (such as their short range and high energy) can cause irreversible damage to the DNA of cancer cells,” the authors write, making this group of agents an active research area with several therapies in development.¹

β-emitters, note the authors, “are cytotoxic against relatively large cancer deposits due to their emission of high-energy electrons in the medium tissue range.” Although these are more commonly used in practice, the authors cite some limitations: “ß-emitters have relatively low energy and poor tissue penetration, resulting in lower treatment efficacy for larger and malignant tumors.” ¹

In the interview, Ortiz emphasized Ra 223’s benefits as an α-emitting therapy. Bone metastases, which the therapy is designed to treat, affect 90% of patients with prostate cancer, he said. The α therapy “goes to places where there’s bone turnover, and those are bone metastases,” offering better survival than earlier ß-emitter bone therapies.

The α therapies, he said, “are unique because they have very high linear energy transfer—meaning the load of energy that is transferred is really high, so that it creates a double DNA strand break, and these cells generally are not able to recover from that.” Ortiz emphasized that these therapies “travel a very short distance, so they act where they are supposed to act, without affecting other cells.”

He noted that radium mimics the bone’s calcium in traveling to it. When bone metastases appear, they kill off existing bone, which tries to recover by creating new bone. Because the radium follows where the calcium is being pulled to kill the cancer, Ortiz said, it behaves as a targeted therapy.

Observers note the PEACE-3 trial could represent a change of fortune for Ra 223 following ERA-223. Writing for UroToday, Zachary Klaassen, MD, MSc; and Rashid Sayyid, MD, MSc, said the results demonstrate the importance of using bone-protecting agents with the combination. “These results potentially elevate 6 cycles of radium 223 into the first-line mCRPC disease space in combination with enzalutamide, with the caveat that patients being considered for this combination must have no evidence of visceral metastases and have asymptomatic/mildly symptomatic bone metastases,” unlike ALSYMPCA, where patients had symptomatic bone metastases.⁷

Activity in the Marketplace

A look at recent transactions involving radiopharmaceuticals highlights their growing importance:

Bayer. In May 2023, Bayer announced a strategic partnership with Bicycle Therapeutics, which is developing several α-emitter candidates, including therapies in prostate cancer. The potential value of this deal is $1.7 billion.¹⁵
Novartis. Along with lutetium Lu 177 vipivotide tetraxetan, Novartis already owns lutetium Lu 177 dotatate (Lutathera), approved to treat somatostatin receptor-positive (SSTR) gastroenteropancreatic neuroendocrine tumors (GEP-NETs).¹⁶ Zhang et al cite therapies targeting SSTR as one of the most promising research areas, and multiple transactions involve drugs for this target.¹

In May 2024, Novartis acquired Mariana Oncology, which is developing therapies involving actinium-225, an α-emitter. These include MC-339, which is now being studied in small cell lung cancer (SCLC).¹⁷ If Mariana achieves several milestones, the deal’s total value could rise to $1.75 billion.

Bristol Myers Squibb. Another actinium-225 therapy in development is RYZ101, or 225Ac-DOTATATE, an SSTR-targeting therapy developed by RayzeBio, which Bristol Myers Squibb acquired in February 2024 for $4.1 billion.^18,19 ClinicalTrials.gov includes several studies evaluating RYZ101: a phase 1/2 trial in patients with ER-positive, HER2-negative unresectable or metastatic breast cancer expressing SSTRs (TRACY-1; NCT06590857); a phase 1 trial for extensive-stage SCLC (NCT05595460); and a phase 3 trial for GEP-NETS (ACTION-1; NCT05477576).^20-22

Eli Lilly and Company. Previously an investor in Mariana Oncology, Eli Lilly acquired POINT Biopharma Global Inc for $1.4 billion in December 2023; its statement highlighted Lu 177 PNT2002, a PSMA-targeted radioligand therapy for mCRPC, and Lu 177 octreotate PNT2003, an SSTR-targeted radioligand therapy to treat GEP-NETs.23 POINT Biopharma is also developing a candidate to target FAP-α, another area the Zhang article highlights.^1,23

AstraZeneca. The global pharmaceutical company, which has made its mark in antibody-drug conjugates in recent years, acquired Fusion Pharmaceuticals Inc in March 2024 for $2 billion. A statement described interest in developing “next-generation radioconjugates,” including those targeting PSMA in prostate cancer.²⁴

Lantheus Holdings, Inc. In January 2025, Lantheus acquired Evergreen Theragnostics, Inc for $1 billion, betting on the combination of its diagnostics and a generic version of Lutathera now under development.²⁵

Overcoming Patient Resistance

MSKCC’s Pillarsetty said Novartis’ approvals for Lu 177-dotatate for neuroendocrine tumors and Lu 177 vipivotide tetraxetan for PSMA-positive prostate cancer set in motion the latest wave of interest in radiopharmaceuticals but work remains to eliminate the concerns persisting around these therapies. Over the years, he said, pharmaceutical companies have not done the best job communicating the benefits.

“The biggest stigma is that for patients,…this is usually something that’s harmful, but that’s not the case,” Pillarsetty said in the interview. Millions have been treated with radioiodine, he noted, and the risk of secondary cancers down the road is no worse than that from treatment with chemotherapy. “This is something [that] patients have to be reminded [about] all the time.”⁸

Ortiz, who spoke with EBO during the American Society of Clinical Oncology Genitourinary Cancers (ASCO GU) Symposium, agreed that patient and payer education would be critical to moving radiopharmaceuticals to the front of the treatment queue. At ASCO GU, Bayer presented a review of 48 real-world studies involving 15,000 patients treated with Ra 223 after adopting androgen pathway inhibitors. The authors concluded that patients who have at least 5 cycles of the therapy live longer than those who do not, yet Ra 223 is often given after other treatments, “which may limit its full effectiveness.”²⁶

“The findings highlight the survival benefits of early-use Ra 223 with completion of 5 [or more] cycles, a favorable safety profile, and low rates of fracture when guideline-recommended [bone-protecting agents] are used,” the authors wrote. Also at ASCO GU, findings from the Netherlands showed that retreatment with Ra 223 is safe in mCRPC.²⁷

Ortiz said more results involving Ra 223 are imminent, including a dosing study combining Ra 223 with the PARP inhibitor olaparib (NCT03317392). As Zhang et al explained, because the PARP pathway helps control the DNA repair pathway, PARP inhibitors may help radiopharmaceuticals block attempts to repair DNA damage.^1,28

Education is key as radiopharmaceuticals enter this new phase, Ortiz said. “We need to make a significantly better effort at communicating this to clinicians––especially in the community––to patients, and patient advocates because otherwise, lack of knowledge is probably going to be one of our highest challenges,” he said. Based on the results presented at ESMO, “the evidence is there.”

References
1. Zhang S, Wang X, Gao X, et al. Radiopharmaceuticals and their applications in medicine. Signal Transduct Target Ther. 2025;10:(1):1. doi:10.1038/s41392-024-02041-6
2. Radiopharmaceuticals market size to reach $26.51 billion by 2031. News release. Insight Partners. September 12, 2024. Accessed March 29, 2025. https://bit.ly/41UzIFH
3. FDA approves radioligand therapy Pluvicto for earlier use before chemotherapy in PSMA-positive metastatic castration-resistant prostate cancer. News release. Novartis. March 28, 2025. Accessed March 28, 2025. https://bit.ly/3E0xRG3
4. Fallah J, Agrawal S, Gittleman H, et al. FDA approval summary: lutetium Lu 177 vipivotide tetraxetan for patients with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2023;29(9):1651-1657. doi:10.1158/1078-0432.CCR-22-2875
5. Kluetz PG, Pierce W, Maher VE, et al. Radium Ra 223 dichloride injection: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res. 2014;20(1):9-14. doi:10.1158/1078-0432.CCR-13-2665
6. Gillessen S, Choudhury A, Saad F, et al. A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): first results of EORTC-GUCG 1333/PEACE-3. Ann Oncol. 2024;35 (suppl 2):S1254. doi:10.1016/annonc/annonc1623
7. Klaassen Z, Sayyid R. ESMO 2024 quick take insights: a focus on PEACE-3. UroToday. October 2024. Accessed March 29, 2025. https://www.urotoday.com/video-lectures/european-society-for-medical-oncology-esmo-2024-quick-takes/articles/155691-esmo-2024-quick-take-insights-a-focus-on-peace-3.html
8. Advancing cancer care: the role of radiopharmaceuticals in precision medicine. Pharmacy Times. February 3, 2025. Accessed March 29, 2025. https://www.pharmacytimes.com/view/advancing-cancer-care-the-role-of-radiopharmaceuticals-in-precision-medicine
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10. Oncology therapeutic radiopharmaceuticals: nonclinical studies and labeling recommendations; draft guidance for industry; availability. FDA. Accessed March 29, 2025. https://www.regulations.gov/docket/FDA-2018-D-1772
11. Safety is key in the use of radiopharmaceuticals. ONS Voice. April 13, 2019. Accessed March 29, 2025. https://www.ons.org/publications-research/voice/conferences/04-2019/safety-key-use-radiopharmaceuticals
12. 2025 Community Oncology Conference agenda. Community Oncology Alliance. Accessed March 28, 2025. https://coaconference.com/agenda/
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14. Smith M, Parker C, Saad F. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):408-419. doi:10.1016/S1470-2045(18)30860-X
15. Bayer and Bicycle Therapeutics enter strategic collaboration for development of novel targeted radionuclide therapies in oncology. News release. Bayer. May 10, 2023. Accessed March 29, 2025. https://www.bayer.com/media/en-us/bayer-and-bicycle-therapeutics-enter-strategic-collaboration-for-development-of-novel-targeted-radionuclide-therapies-in-oncology/
16. FDA approves lutetium Lu 177 dotatate for pediatric patients 12 years and older with GEP-NETS. FDA. April 23, 2024. Accessed March 29, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-dotatate-pediatric-patients-12-years-and-older-gep-nets
17. Novartis enters agreement to acquire Mariana Oncology, strengthening radioligand therapy pipeline. News release. Novartis. May 2, 2024. Accessed March 29, 2025. https://www.novartis.com/news/media-releases/novartis-enters-agreement-acquire-mariana-oncology-strengthening-radioligand-therapy-pipeline
18. Bristol Myers Squibb completes acquisition of RayzeBio, adding differentiated actinium-based radiopharmaceutical platform. News release. Bristol Myers Squibb. February 26, 2024. Accessed March 29, 2025. https://bit.ly/3EcE3uC
19. Han G, Hwang E, Lin F, et al. RYZ101 (Ac-225 DOTATATE) opportunity beyond gastroenteropancreatic neuroendocrine tumors: preclinical efficacy in small-cell lung cancer. Mol Cancer Ther. 2023;22(12):1434-1443. doi:10.1158/1535-7163.MCT-23-0029
20. Trial of 225Ac-DOTATATE (RYZ101) in subjects with ER+, HER2-negative unresectable or metastatic breast cancer expressing SSTRs (TRACY-1). ClinicalTrials.gov. Updated March 25, 2025. Accessed https://www.clinicaltrials.gov/study/NCT06590857
21. Study of RYZ101 in combination with SoC in subjects with SSTR+ ES-SCLC. ClinicalTrials.gov. Updated March 25, 2025. Accessed March 29, 2025. https://clinicaltrials.gov/study/NCT05595460
22. Study of RYZ101 compared with SOC in pts w inoperable SSTR+ well-differentiated GEP-NET that has progressed following 177Lu-SSA therapy (ACTION-1). ClinicalTrials.gov. Updated March 25, 2025. Accessed March 29, 2025. https://clinicaltrials.gov/study/NCT05477576
23. Lilly completes acquisition of POINT Biopharma. News release. Eli Lilly and Company. December 27, 2023. Accessed March 29, 2025. https://investor.lilly.com/news-releases/news-release-details/lilly-completes-acquisition-point-biopharma
24. AstraZeneca to acquire Fusion to accelerate the development of next-generation radioconjugates to treat cancer. News release. AstraZeneca. March 19, 2024. Accessed March 29, 2025. https://www.astrazeneca.com/media-centre/press-releases/2024/astrazeneca-to-acquire-fusion.html
25. Stempniak M. Lantheus to acquire radiopharma firm Evergreen Theragnostics for up to $1B. Radiology Business. January 29, 2025. Accessed March 29, 2025. https://radiologybusiness.com/topics/healthcare-management/mergers-and-acquisitions/lantheus-acquire-radiopharma-firm-evergreen-theragnostics-1b
26. Lunan M, Raval AD. Phan NTN, Korn MJ, Quintero V, McKay RR. Effectiveness and safety of radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC): a systematic literature review of 48 real-world studies. J Clin Oncol. 2025;43 (suppl 5):81. doi:10.1200/JCO.2025.43.5_suppl.81
27. van der Doelen MJ, van Riel JHHM, Donswijk ML, et al. Re-treatment of metastatic castration-resistant prostate cancer patients with radium-223 therapy in daily practice. J Clin Oncol. 2025;43(suppl 5):183. doi:10.1200/JCO.2025.43.5_suppl.183
28. Testing the safety of different doses of olaparib given radium-223 for men with advanced prostate cancer with bone metastasis. ClinicalTrials.gov. Updated April 1, 2025. Accessed April 1, 2025. https://clinicaltrials.gov/study/NCT03317392