From Trial to Treatment: Targeted Radionuclide Therapy Comes of Age in mCRPC

From Trial to Treatment: Integrating Targeted Radionuclide Therapy Data Into Evidence-Based mCRPC Care - Integrating_Targeted_Radionuclide_Therapy_Data_Into_Evidence-Based_mCRPC_Care

A patient-advocate briefing on the evidence, the fine print, and what's still unsettled — IPCSG Newsletter

BLUF (Bottom Line Up Front): 

Two PSMA-targeted radioligand therapies are now FDA-approved for metastatic castration-resistant prostate cancer (mCRPC) — lutetium-177 vipivotide tetraxetan (Pluvicto), approved post-taxane in 2022 and expanded to pre-taxane use in March 2025 — alongside radium-223 (Xofigo), approved in 2013 for symptomatic bone-only disease. New Phase 3 data (PSMAddition) now show a benefit when Pluvicto is added even earlier, in hormone-sensitive disease, and Novartis has filed for that expanded use with decisions expected in the second half of 2026. Not every radioligand candidate is panning out, however: Lantheus disclosed in 2026 SEC filings that it will not file for approval of its competing agent, 177Lu-PNT2002, despite earlier positive progression-free survival data, because the overall-survival results were confounded by heavy trial crossover. Patent litigation among Novartis, Eli Lilly/POINT Biopharma, and Curium over lutetium-177 manufacturing and PSMA-ligand patents continues in parallel, and isotope-supply constraints remain a real-world bottleneck. For patients and caregivers, the practical message is unchanged from the underlying trial data: these are genuine survival-extending tools with a manageable but distinct side-effect profile (dry mouth, fatigue, anemia, kidney and marrow effects) that require real logistical planning around radiation-safety precautions at home.

Why This Matters Now

For more than a decade, "radionuclide therapy" in prostate cancer meant one drug: radium-223 (Xofigo), a bone-seeking alpha-emitter approved in 2013 for men with symptomatic, bone-only mCRPC. The 2022 approval of lutetium-177 vipivotide tetraxetan (Pluvicto) — a beta-emitting radioligand that binds directly to prostate-specific membrane antigen (PSMA) on tumor cells — opened a genuinely new chapter: a therapy that can be targeted using a PET scan first, then delivered systemically to wherever PSMA-avid disease has spread, not just bone. This piece walks through where the evidence stands as of mid-2026, based on a recent PRIME Education-accredited CME activity ("From Trial to Treatment: Integrating Targeted Radionuclide Therapy Data into Evidence-Based mCRPC Care," faculty Evan Y. Yu, MD, and Scott T. Tagawa, MD) together with subsequent trial updates, regulatory filings, and litigation not covered in that slide deck.

The Biomarker-Driven Landscape

Modern mCRPC treatment selection increasingly turns on two categories of biomarker: imaging-based (PSMA-PET positivity, or a positive bone scan with negative cross-sectional imaging) and molecular (BRCA1/2 and other homologous recombination repair mutations directing PARP inhibitors; mismatch-repair deficiency/MSI-High directing checkpoint inhibitors; HER2 3+ directing antibody-drug conjugates). Targeted radionuclide therapy sits in the imaging-biomarker arm: a man must first have a PSMA-PET scan (using an FDA-approved tracer — Ga-68 PSMA-11, F-18 piflufolastat, or F-18 flotufolastat) showing tumor uptake above liver background, with no PSMA-negative lesions of concerning size, before he is considered a candidate for PSMA-targeted radioligand therapy.

Current NCCN Treatment Framework (Version 2.2026)

Disease State	Radionuclide-Related Options
Pre-ARPI (hormone-sensitive, bone metastases)	Radium-223 + enzalutamide (useful in certain circumstances)
Post-ARPI / Pre-docetaxel	Lutetium-177 vipivotide tetraxetan for PSMA-positive metastases (preferred, Category 1); radium-223 for symptomatic bone-predominant disease
Post-ARPI / Post-docetaxel	Lutetium-177 vipivotide tetraxetan for PSMA-positive metastases (Category 1)

Source: NCCN Clinical Practice Guidelines in Oncology – Prostate Cancer, Version 2.2026.

The Pivotal and Emerging Trials

VISION — the original approval (post-taxane)

VISION randomized 831 men with progressive PSMA-positive mCRPC who had already received an ARPI and a taxane to lutetium-177 vipivotide tetraxetan plus standard care versus standard care alone. Median radiographic progression-free survival was 8.7 months versus 3.4 months, and median overall survival was 15.3 versus 11.3 months, supporting the original March 2022 FDA approval. The most frequent side effects were fatigue, dry mouth, nausea, and anemia.

PSMAfore — moving earlier, pre-chemotherapy

PSMAfore tested the same drug in taxane-naïve men whose disease had progressed on an ARPI, comparing it against simply switching to a different ARPI. Radiographic progression-free survival more than doubled (11.6 vs. 5.6 months), though the overall-survival difference was not statistically significant at the reported analysis — a result Novartis has attributed to the roughly 60% of control-arm patients who crossed over to receive lutetium-177 vipivotide tetraxetan after progression. This trial supported the FDA's March 28, 2025 label expansion, allowing use before chemotherapy in appropriate patients.

UPDATE PSMAddition — now moving into hormone-sensitive disease

PSMAddition is testing lutetium-177 vipivotide tetraxetan added to standard hormonal therapy (ADT plus an ARPI) in men with newly diagnosed or minimally treated, PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC) — a much earlier disease state than any prior radioligand trial. The primary analysis, presented at the 2026 ASCO Annual Meeting, showed a 28% reduction in the risk of radiographic progression or death (HR 0.72; 95% CI 0.58–0.90), consistent across disease-volume and de novo/recurrent subgroups. A subsequent interim analysis presented at the 2026 AUA Annual Meeting reported a 58% reduction in risk of PSA progression (HR 0.42; 95% CI 0.30–0.59) with deeper PSA responses sustained through 48 weeks. Novartis has filed supplemental applications in the United States, China, and Japan, with decisions expected in the second half of 2026; if approved, this would be the first PSMA-targeted radioligand therapy authorized in hormone-sensitive disease, well before castration resistance develops.

UPDATE AcTION — the next isotope, actinium-225

Alongside the PSMAddition data, Novartis presented early Phase 1 results from the AcTION trial of 225Ac-PSMA-617, an alpha-emitting radioligand, in men with PSMA-positive mCRPC. Early findings showed PSA declines and radiographic responses with a manageable safety profile, supporting continued development of an alpha-emitter option — potentially useful for patients whose disease does not respond adequately to beta-emitting lutetium-177.

DEVELOPING SPLASH / 177Lu-PNT2002 — a competing agent that will not reach the market

This is the most significant update not reflected in the CME slide deck. The Phase 3 SPLASH trial tested 177Lu-PNT2002 (Lu-PSMA-I&T), developed by POINT Biopharma and licensed by Lantheus, against a change of ARPI in men who progressed after one prior ARPI. The initial radiographic progression-free survival readout (9.5 vs. 6.0 months; HR 0.71) was positive and was featured favorably at the 2024 ESMO Congress and in the CME activity reviewed here. However, in its fiscal-year 2026 Form 10-Q filed with the SEC, Lantheus disclosed that the trial's overall-survival analysis, now at 100% of pre-specified events, remains confounded by an "overwhelming" rate of crossover from the control arm to the experimental drug — and that the company does not currently plan to pursue a New Drug Application or further invest in this asset. Eli Lilly acquired POINT Biopharma in 2024 for roughly $1.4 billion, in significant part for this same molecule; as of this writing there is no public indication that Lilly intends to independently pursue approval either. Patients and caregivers should be aware that headline trial results presented at conferences do not always translate into a marketed drug, and that overall-survival confounding by crossover — the same issue affecting PSMAfore's OS analysis — is becoming a recurring theme across this drug class as trials allow control-arm patients to receive the experimental radioligand after progression.

Radium-223 — the original agent, still relevant

ALSYMPCA, the trial supporting radium-223's 2013 approval, enrolled men with symptomatic, bone-only mCRPC and showed a median overall-survival benefit (14.9 vs. 11.3 months) and a longer time to first symptomatic skeletal event. More recently, PEACE-3 tested radium-223 combined with enzalutamide in men with asymptomatic or mildly symptomatic CRPC and bone metastases, using bone-protective agents (zoledronic acid or denosumab) in both arms — a safeguard added after earlier radium-223 combination trials raised fracture-risk concerns. PEACE-3 showed improved radiographic progression-free survival (19.4 vs. 16.4 months; HR 0.69) and a positive interim overall-survival trend (42.3 vs. 35 months; HR 0.69), with hypertension as the most common higher-grade side effect in the combination arm.

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Intellectual Property Fights Behind the Scenes

Novartis has been aggressively defending its radioligand-therapy patent estate as competitors have moved into the same chemical space:

• Novartis and Purdue Research Foundation v. Eli Lilly (and POINT Biopharma affiliates), filed in the Southern District of Indiana in June 2024, alleges that 177Lu-PNT2002 infringes U.S. Patent No. 10,624,970, covering PSMA-targeting conjugates. Defendants argued the case should be paused or dismissed because PNT2002 was, in their view, far from a realistic commercial launch; a magistrate judge granted a stay pending resolution of the motion to dismiss. Lantheus's 2026 disclosure that it will not file for approval of PNT2002 may render much of this dispute moot.
• Novartis v. POINT Biopharma / Lantheus over PNT2003, a proposed generic version of Novartis's neuroendocrine tumor radioligand Lutathera, centers on whether Lantheus's New Drug Application (which could carry 180 days of generic market exclusivity if approved) infringes Novartis patents covering stable radionuclide formulations.
• Novartis v. Curium, filed in Delaware in October 2024 (after an earlier Missouri filing was withdrawn), similarly challenges a proposed generic lutetium Lu-177 solution on formulation-patent grounds.

None of this litigation currently affects patient access to Pluvicto or Xofigo, which remain approved and on the market; it primarily concerns whether and when lower-cost or competing radioligand products can enter the U.S. market.

The Supply Chain Problem Nobody Puts on a Slide

Radioligand therapies cannot simply be stockpiled: lutetium-177 has a half-life of about 6.6 days, so production, quality control, and shipping all have to be tightly choreographed around each patient's infusion date. After Pluvicto's 2022 launch, demand outstripped supply from Novartis's original Ivrea, Italy manufacturing site, and the FDA placed the drug on its drug-shortage list in early 2023; additional manufacturing capacity came online later that year to ease the bottleneck. Industry reporting in 2026 continues to describe the broader isotope supply chain — irradiation capacity, enriched targets, and specialized production workforce — as under sustained pressure as more radioligand therapies move toward approval and use earlier in the disease course. Patients scheduling radioligand therapy should expect their care team to coordinate dosing windows carefully and should ask in advance about contingency plans if a scheduled dose is delayed.

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Living With Radionuclide Therapy: Managing Side Effects at Home

Because these are radioactive drugs, the day-to-day precautions differ meaningfully between the two approved agents — a distinction that matters enormously for caregivers and spouses.

Precaution	Lutetium-177 vipivotide tetraxetan (Pluvicto)	Radium-223 (Xofigo)
Close contact with household members	Limit contact under 3 feet for 2 days; 7 days around children or pregnant women	No restrictions on personal or physical contact
Sexual activity	Avoid for 7 days	Not specifically restricted beyond general hygiene
Sleeping arrangements	Separate bedroom: 3 days from household contacts, 7 days from children, 15 days from pregnant women	No specific restriction
Bathroom use	Sit to urinate for 3 days, double-flush, use a separate toilet if possible	Use a toilet when possible; flush several times after each use for 1 week after last dose
Lab monitoring	Kidney function and CBCs before and during treatment; encourage frequent urination and hydration	CBCs before initiation and before every dose; monitor hydration and urine output

Xerostomia (Dry Mouth) — Unique to PSMA-Targeted Therapy

Because salivary glands also express PSMA, they take up the radioligand and can be damaged in the process — dry mouth affected 39–58% of patients across the pivotal Pluvicto trials, making it the most common side effect after fatigue. Recommended management follows a step-up approach:

• Mild: increased hydration, good oral hygiene, artificial saliva sprays or gels, saline or baking-soda rinses, over-the-counter dry-mouth products (e.g., Biotene, ACT Dry Mouth, BioXtra), oral-adhering disks, humidifier use, and avoiding known triggers such as antihistamines and salty foods.
• Moderate to severe: prescription sialagogues (pilocarpine or cevimeline), acupuncture-like transcutaneous electrical nerve stimulation (ALTENS), interventional sialendoscopy, or, in consultation with the treating team, adjusting the radioligand dosing schedule.

Illustrative Case Patterns From the CME Activity

The educational activity walked through three hypothetical patient scenarios that reflect common real-world decision points:

1. Rising PSA on ADT + ARPI, asymptomatic, PSMA-PET-avid bone and nodal disease, no visceral metastases — faculty favored lutetium-177 vipivotide tetraxetan over docetaxel, citing the pre-taxane approval and favorable tolerability.
2. Symptomatic, bone-only disease after ADT alone, PSMA uptake below liver background (i.e., not a PSMA-PET candidate) — faculty favored radium-223 with enzalutamide, since this patient had not yet received an ARPI and the disease was confined to bone.
3. New hepatic and osseous metastases with rising PSA and opioid-requiring pain after ADT + abiraterone — faculty favored docetaxel, reflecting that visceral (liver) metastases are a disease-state factor that currently favors chemotherapy over radioligand therapy, since existing radioligand trials selected for bone/node-predominant, PSMA-avid disease.

Faculty discussion emphasized that treatment selection should weigh prior therapy exposure and resistance, biomarker status, disease burden and location (especially visceral vs. bone/node disease), patient age and comorbidities, prior toxicities, mode of administration, clinical-trial availability, cost/insurance access, and patient preference — not biomarker status alone.

What This Means for Patients and Caregivers

• PSMA-PET imaging is now a gatekeeper test for radioligand therapy eligibility — ask specifically whether your scan showed PSMA-positive disease everywhere your cancer is known to be, and whether any spots were PSMA-negative.
• Sequencing matters: whether you've had a taxane, and whether your ARPI has already been tried, changes which options apply to you under current guidelines.
• Not every "positive" trial becomes an approved drug — the PNT2002/SPLASH story is a useful reminder to ask your oncologist about the current regulatory status of any radioligand therapy you read about, rather than assuming conference-presented data equals market access.
• Radiation-safety precautions at home are real and differ by drug; ask your nuclear medicine team for the specific written instructions for your agent, and make sure a spouse or caregiver hears them directly, as Terri and I have found firsthand.
• Dry mouth is common enough with PSMA-targeted therapy that it's worth raising early, before it affects eating, speaking, or quality of life, rather than waiting for it to become severe.

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Glossary

ADT: Androgen deprivation therapy
ARPI: Androgen receptor pathway inhibitor
CRPC/mCRPC: (Metastatic) castration-resistant prostate cancer
mHSPC: Metastatic hormone-sensitive prostate cancer
rPFS: Radiographic progression-free survival
OS: Overall survival
PSMA: Prostate-specific membrane antigen
PET: Positron emission tomography
RLT: Radioligand therapy
HRRm: Homologous recombination repair mutation
NDA/sNDA: (Supplemental) New Drug Application

About this briefing: This article draws on a jointly accredited continuing-education activity, "From Trial to Treatment: Integrating Targeted Radionuclide Therapy Data into Evidence-Based mCRPC Care" (PRIME® Education, LLC, 2025–2026), with faculty Evan Y. Yu, MD, and Scott T. Tagawa, MD. That activity discloses that both faculty report consulting and/or research-support relationships with numerous companies active in this space, including Novartis, Bayer, Lantheus, Janssen, Merck, and others; the activity itself was supported by an educational grant from Novartis, which markets Pluvicto. Readers should weigh that funding source when considering how trial results are framed, and should not treat this summary, or the underlying CME activity, as a substitute for individualized medical advice. Facts drawn from sources published after that CME activity (regulatory filings, subsequent trial readouts, and litigation) are noted with an "UPDATE" tag above and cited separately below.

Sources

1. PRIME® Education, LLC. From Trial to Treatment: Integrating Targeted Radionuclide Therapy Data into Evidence-Based mCRPC Care (CME/CE slide deck). 2025–2026. Faculty: Evan Y. Yu, MD; Scott T. Tagawa, MD. https://media.primeinc.org/upload/programs/24WB258/Integrating_Targeted_Radionuclide_Therapy_Data_Into_Evidence-Based_mCRPC_Care_Slides.pdf
2. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer (VISION). N Engl J Med. 2021;385(12):1091-1103. https://www.nejm.org/doi/full/10.1056/NEJMoa2107322
3. Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore). Lancet. 2024;404(10459):1227-1239.
4. U.S. Food and Drug Administration. FDA expands Pluvicto's metastatic castration-resistant prostate cancer indication. March 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication
5. Novartis. Novartis Pluvicto™ demonstrates statistically significant and clinically meaningful rPFS benefit in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition topline). June 2, 2025. https://www.novartis.com/news/media-releases/novartis-pluvictotm-demonstrates-statistically-significant-and-clinically-meaningful-rpfs-benefit-patients-psma-positive-metastatic-hormone-sensitive-prostate-cancer
6. Novartis. Pluvicto® demonstrated consistent efficacy across key patient subgroups in metastatic hormone-sensitive prostate cancer (PSMAddition, ASCO 2026 subgroup data; AcTION Phase 1 225Ac-PSMA-617 data). May 31, 2026. https://www.novartis.com/us-en/news/media-releases/pluvicto-demonstrated-consistent-efficacy-across-key-patient-subgroups-metastatic-hormone-sensitive-prostate-cancer
7. Novartis. New PSMAddition data show 58% lower risk of PSA progression with Pluvicto® in metastatic hormone-sensitive prostate cancer (AUA 2026). May 17, 2026. https://www.novartis.com/news/media-releases/new-psmaddition-data-show-58-lower-risk-psa-progression-pluvicto-metastatic-hormone-sensitive-prostate-cancer
8. Lantheus Holdings, Inc. Form 10-Q, Q1 FY2026 (SPLASH/PNT2002 overall-survival readout and decision not to pursue an NDA). Filed with the U.S. Securities and Exchange Commission. https://www.sec.gov/Archives/edgar/data/0001521036/000119312526210373/lnth-20260331.htm
9. Lantheus Holdings, Inc. and POINT Biopharma Global Inc. Lantheus and POINT Biopharma Announce Positive Topline Results from Pivotal SPLASH Trial in Metastatic Castration-Resistant Prostate Cancer. December 18, 2023. https://lantheusholdings.gcs-web.com/news-releases/news-release-details/lantheus-and-point-biopharma-announce-positive-topline-results
10. Fierce Pharma. In defense of radioligand therapies, Novartis fired off patent lawsuits against Lilly and other rivals. November 4, 2024. https://www.fiercepharma.com/pharma/novartis-sues-lilly-others-over-radioligand-therapies-pluvicto-lutathera
11. Institute for Intellectual Property Law (iniplaw.org). Novartis Battles Competitors Over Patent Disputes in Radiopharmaceuticals (Novartis v. Lilly/POINT re U.S. Patent 10,624,970; Novartis v. POINT/Lantheus re PNT2003; Novartis v. Curium re Lutetium Lu-177 generic). November 12, 2024. https://www.iniplaw.org/novartis-battles-competitors-over-patent-disputes-in-radiopharmaceuticals/
12. Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer (ALSYMPCA). N Engl J Med. 2013;369(3):213-223.
13. Tombal B, Loriot Y, Saad F, et al. Radium-223 and enzalutamide in metastatic castration-resistant prostate cancer (PEACE-3). Ann Oncol. 2025;36(9):1058-1067.
14. Sartor O, et al. Phase 3 SPLASH trial of 177Lu-PNT2002 (Lu-PSMA-I&T) versus alternate androgen receptor pathway inhibitor in mCRPC. Ann Oncol. 2024;35(Suppl 7):S1254-S1255. Abstract LBA65.
15. Science & Medicine Group. Radiopharmaceutical Supply Chain Under Pressure: Can Infrastructure Keep Up with Demand? May 15, 2026. https://www.scienceandmedicinegroup.com/resource/radiopharmaceutical-supply-chain-under-pressure-can-infrastructure-keep-up-with-demand/
16. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 2.2026. www.nccn.org (registration required for full guideline access).
17. Al-Khanaty A, Chen D, Walbaum J, et al. Guideline of guidelines: lutetium-177 PSMA radioligand therapy in advanced prostate cancer. BJU Int. 2026 Apr 14 [Epub ahead of print]. https://www.urotoday.com/recent-abstracts/urologic-oncology/prostate-cancer/168236-guideline-of-guidelines-lutetium-177-psma-radioligand-therapy-in-advanced-prostate-cancer.html
18. Pepin A, et al. Xerostomia management strategies after PSMA-targeted radioligand therapy. Pract Radiat Oncol. 2025;15(1):14-18.
19. American Cancer Society. Cancer Facts & Figures 2025. Accessed via PRIME Education CME slide deck, October 13, 2025.

This newsletter is prepared for patient and caregiver education by the Informed Prostate Cancer Support Group (IPCSG) and is not a substitute for individualized advice from your own oncology team. Always confirm current regulatory status, dosing, and eligibility criteria with your treating physician before making treatment decisions.