The scale of the current moment is captured by Czernin’s assessment that nuclear medicine is in the middle of a renaissance measurable in both scientific output and financial sustainability. That claim is not mere enthusiasm. Over the past decade, radioligand therapies targeting prostate-specific membrane antigen in prostate cancer and somatostatin receptors in neuroendocrine tumors have delivered survival benefits in pivotal trials, prompting regulatory approvals and triggering substantial industrial investment. The supplement reflects that shift across its entire breadth, covering radionuclide production and supply chains, personalized dosimetry, combination therapies, and the phase 3 trials expected to define the field’s next approved indications.

Yet the supplement is also candid about structural imbalances that could constrain growth. As Czernin observes, science is expanding faster than isotope production capacity, production capacity is expanding faster than dosimetric standardization, and clinical adoption is expanding faster than the trained workforce. In other words, each link in the theranostics chain is lagging behind the one before it, and the weakest links now sit in manufacturing, standardization, and manpower rather than in basic discovery. Industry, he notes, has recognized the opportunity and is funding it accordingly; the remaining burden falls on academic nuclear medicine to keep pace on evidence, personalization, and training.

One of the most technically consequential contributions examines the expanding therapeutic toolbox of emerging isotopes. Cindy Rodriguez, Grace K. Liles, Suzanne E. Lapi, and Jason S. Lewis break down which radionuclides can and cannot be produced at scale today. The distinction matters enormously at the bedside. Alpha-emitting isotopes such as actinium-225 deliver dense, double-strand DNA-breaking radiation over very short path lengths, making them attractive for precise tumor killing, but their global supply remains scarce and production routes are complex. Beta emitters such as lutetium-177 are easier to produce and already anchor approved therapies, while terbium-149, astatine-211, and lead-212 each present distinct chemistry, logistics, and dosimetry challenges that determine whether laboratory promise can ever reach routine clinical use.

Richard Zimmermann’s contribution on the supply chain sharpens that point with a provocative thesis: economics, not science, will decide which radionuclides make it to market. A radionuclide with elegant physics and favorable radiobiology is clinically irrelevant if reactor irradiation capacity, target material availability, generator networks, and reimbursement cannot sustain reliable delivery to hospitals. The supplement’s treatment of this conundrum underscores a reality often obscured by headline trial results: theranostics is as much an industrial logistics problem as a molecular one, and investors, manufacturers, and health systems must align before patients benefit at scale.

Clinical strategy is addressed through two complementary reviews. Yang Wang, Jane McKenzie, and Shahneen Sandhu survey radiopharmaceutical combination therapies in advanced prostate cancer, cataloging trials that pair radioligands with androgen receptor pathway inhibitors, chemotherapy, immunotherapy, and DNA damage response targeting in an effort to overcome monotherapy resistance. Meanwhile, Evan R. Abt, Caius G. Radu, Johannes Czernin, and Christine E. Mona dissect the biology of tumor resistance to radiopharmaceutical therapy itself, examining mechanisms such as heterogeneous target expression, impaired DNA repair pathways, and tumor microenvironmental factors that allow surviving clones to repopulate after treatment. Understanding these mechanisms is the prerequisite for rational combination design rather than empiric trial-and-error.

The phase 3 landscape receives its own detailed mapping from Wolfgang P. Fendler, Michael S. Hofman, David Kersting, Jeremie Calais, and Thomas A. Hope, who chart anticipated future indications across a remarkable slate of trials including PSMAcTION, STAMPEDE2, PSMA-DC, PSMAddition, NETTER-3, ACTION-1, and COMPOSE. These studies extend radioligand therapy into earlier disease stages, combine it with established systemic agents, and test novel targets and isotopes. Their results over the coming years will determine whether theranostics remains a late-line option for advanced disease or becomes embedded earlier in treatment algorithms for prostate cancer, neuroendocrine tumors, and potentially other malignancies.

Personalization is the field’s other great frontier. Richard L. Wahl and Yuni K. Dewaraja examine the evidence for dosimetry-driven personalization of radiopharmaceutical therapies, asking whether patient-specific absorbed dose calculations can and should replace the one-size-fits-all activity prescriptions that dominate current practice. Radiopharmaceutical therapy is unique among cancer treatments in that the therapeutic agent can be imaged directly as it distributes through the body, offering a built-in pharmacokinetic readout. Realizing that advantage requires standardized quantitative imaging, validated dose-response models, and clinical trial designs that test adaptive dosing, all of which remain works in progress despite growing enthusiasm.

Finally, the supplement confronts the human infrastructure problem. Martin Gotthardt, Hossein Jadvar, and David Mankoff argue for a dedicated nuclear oncology subspecialty with tailored training paths, contending that physicians must be fluent simultaneously in radionuclide therapy, molecular imaging, and systemic oncology. Boris Hadaschik and Oliver Sartor examine whether uro-oncologists have embraced nuclear medicine as a true partner in cancer therapy, a question of interdisciplinary trust that will shape referral patterns for years. Caner Civan, Wolfgang P. Fendler, Alina Küper, Lisa Bodei, Wolfgang A. Weber, Louise Emmett, and Ken Herrmann close the volume by taking stock of the field overall and looking ahead to emerging indications. Taken together, the supplement portrays a discipline at an inflection point: scientifically validated, commercially backed, and clinically expanding, but racing to build the isotope supply, dosimetric standards, and specialist workforce its own success now demands. The full supplement is available from The Journal of Nuclear Medicine, with publication support acknowledged from Novartis, Siemens, RayzeBio, and AstraZeneca.

Subject of Research: Current state and future directions of cancer theranostics, including radiopharmaceutical development, dosimetry, clinical trials, and workforce training

Article Title: What’s next for theranostics?

Article References: What’s next for theranostics?. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: theranostics, radiopharmaceuticals, nuclear medicine, radionuclide therapy, dosimetry, prostate cancer, neuroendocrine tumors, phase 3 trials, isotope production, tumor resistance, nuclear oncology, Journal of Nuclear Medicine

The original SURMOUNT-OSA program comprised two Phase 3, randomized, double-blind, placebo-controlled trials spanning 52 weeks. Study 1 enrolled 234 adults with moderate-to-severe sleep apnea, defined as an apnea-hypopnea index of at least 15 events per hour, and obesity, defined as a body mass index of at least 30 kilograms per square meter, who were not using PAP therapy. Study 2 enrolled 235 similar participants who were on PAP therapy, and asked them to withhold the device for roughly seven days before laboratory polysomnography so that their underlying disease severity could be measured. Participants received either the maximum tolerated dose of tirzepatide, 10 or 15 milligrams, or placebo. The primary results, published previously, showed clinically meaningful reductions in the apnea-hypopnea index, in sleep apnea-specific hypoxic burden, in body weight, and in systolic blood pressure, along with improvements in high-sensitivity C-reactive protein and patient-reported outcomes.

The new analyses asked a deceptively simple question: did the drug work equally well in everyone, or did its effectiveness depend on who the patient was at the start of the trial? The researchers stratified participants by baseline age, sex, apnea-hypopnea index severity, body mass index, and neck circumference, then estimated changes from baseline to week 52 using mixed models for repeated measures, adjusting for baseline values, geographic region, sex, and treatment. Because these exploratory analyses were descriptive rather than powered for formal statistical testing of heterogeneity, the authors caution that apparent differences between subgroups may reflect chance, residual confounding, differing baseline distributions, or regression to the mean. Still, the consistency of the direction of benefit across nearly every slice of the population is striking.

The headline finding is that tirzepatide outperformed placebo across all baseline subgroups. Participants on the drug experienced apnea-hypopnea index reductions ranging from roughly 20 to more than 50 events per hour depending on subgroup, compared with far smaller changes on placebo. When stratified by age, reductions ranged from 27.7 to 34.1 events per hour; by sex, from 19.8 to 32.6 events per hour; by baseline apnea-hypopnea index, from 12.1 to 52.2 events per hour; by body mass index, from 25.2 to 34.4 events per hour; and by neck circumference, from 23.9 to 30.8 events per hour. Sleep apnea-specific hypoxic burden, an emerging measure of the oxygen deprivation burden imposed by the disease, and systolic blood pressure also improved consistently, with blood pressure falling by roughly 6.7 to 10.2 millimeters of mercury across subgroups and studies—a magnitude that rivals or exceeds the modest reductions typically achieved with PAP therapy itself.

Some of the numerical patterns tracked physiology in intuitive ways. Men, who had higher baseline apnea-hypopnea indices than women in both trials, posted larger absolute reductions, from 30.6 events per hour in men versus 19.8 in women in Study 1, and 32.6 versus 24.8 in Study 2. Participants with the most severe disease at baseline, an apnea-hypopnea index of at least 70 events per hour, saw the largest absolute drops, at 43.3 events per hour in Study 1 and 52.2 events per hour in Study 2, although their relative improvement was smaller than in patients with milder disease. Younger participants on PAP therapy in Study 2 showed numerically greater reductions in the apnea-hypopnea index, hypoxic burden, and body weight than those aged 50 and older, hinting that obesity may play a stronger causal role in sleep apnea among younger patients, while age-related factors such as reduced lung function and weakened upper airway protective reflexes may dilute the benefit of weight loss in older adults.

Perhaps the most clinically resonant results concern categorical shifts in disease severity. Among tirzepatide-treated participants, 67.7 percent in Study 1 and 79.0 percent in Study 2 moved to a less severe apnea category by week 52, whereas most placebo participants, 64 to 70 percent, saw no clinically relevant change. Improvement crossed every baseline characteristic examined: by age, 62.4 to 77.8 percent of tirzepatide-treated participants improved depending on subgroup and study; by sex, 60.5 to 86.1 percent; and by body mass index, the proportion improving ranged from 57.0 to 80.5 percent. Even in the very severe subgroup with a baseline apnea-hypopnea index of at least 70 events per hour, where average starting values hovered around 86 to 91 events per hour, over half of tirzepatide-treated participants in both studies achieved reductions of at least 50 percent, and 31.8 to 64.6 percent improved in severity class.

The neck circumference findings add a physiologically interesting wrinkle. Neck circumference has been proposed as a better proxy than body mass index for the fat deposition around the upper airway that narrows breathing passages during sleep. Participants with larger necks, who tended to be younger, male, and heavier, showed numerically greater absolute reductions in apnea-hypopnea index and body weight than those with smaller necks, a pattern consistent across both studies. Meanwhile, weight reductions increased with higher baseline body mass index, particularly in Study 2, and apnea-hypopnea index improvements were broadly similar across body mass index categories, suggesting that patients with even the highest degrees of obesity stand to benefit. The authors note that these results contradict the assumption that heavier patients would need to lose more weight to achieve comparable airway improvement.

Underlying the results is a central scientific question: how much of tirzepatide’s effect on sleep apnea flows through weight loss, and how much is independent? A separate analysis of the SURMOUNT-OSA data found a linear association between the magnitude of weight reduction and improvements in the apnea-hypopnea index and hypoxic burden, pointing to weight loss as the dominant driver. But the authors caution that weight-independent effects cannot be excluded. Tirzepatide may influence several of the pathogenic pathways that produce sleep apnea, including insulin resistance and systemic inflammation, both of which have been identified as antecedent risk factors for the disorder and may affect airway muscle function and ventilatory control. Sex differences in these pathways, and evidence from other studies that women tend to lose more weight on incretin therapies than men, may help explain why weight changes by sex were inconsistent between the two trials even as apnea measures improved in both.

The authors are careful about the limitations. The 52-week duration of the trials leaves the long-term effects unknown, particularly since longer studies of tirzepatide have shown additional weight loss over time. Subgroup analyses were not powered for statistical significance, the models did not mutually adjust for all baseline characteristics, and factors such as socioeconomic status, prior apnea surgery, PAP adherence, and apnea endotypes were not captured. Discontinuation rates were also higher in the placebo arm, which may have inflated the apparent treatment difference. Still, the consistency of benefit across two independent trials, nearly five hundred participants, and every baseline characteristic examined represents an unusually robust signal for an exploratory analysis.

For clinicians and patients, the practical takeaway is considerable. Severity improvements on tirzepatide may open the door to alternative therapies such as oral appliances or positional therapy for patients shifted into milder disease categories, and the substantial blood pressure reductions may carry independent cardiovascular significance given the known links between sleep apnea, resistant hypertension, and cardiometabolic disease. Whether tirzepatide and PAP therapy together produce additive benefits, and whether the improvements endure over years, remain open questions that the authors say warrant further study. What is already clear is that the era of treating sleep apnea with machines alone is ending, and that a single medication can meaningfully reshape the disease across virtually the full spectrum of patients who have it.

Subject of Research: Effects of tirzepatide on obstructive sleep apnea severity and cardiometabolic measures across baseline patient subgroups in the SURMOUNT-OSA Phase 3 trials

Article Title: Association of tirzepatide with changes in OSA-related measures based on baseline characteristics – post hoc analyses of SURMOUNT-OSA

Article References: Falcon, B., Xie, C. C., Redline, S., Grunstein, R., Turnbull, C. D., Rapoport, D. M., Wang, H., Chakladar, S., Dimitriadis, G. K., Lau, E., Bednarik, J., Liao, B., & Malhotra, A. (2026). Association of tirzepatide with changes in OSA-related measures based on baseline characteristics – post hoc analyses of SURMOUNT-OSA. Journal of Clinical Sleep Medicine, 22(1), Article 155. https://doi.org/10.1007/s44470-026-00162-z

Image Credits: AI Generated

DOI: 10.1007/s44470-026-00162-z

Keywords: tirzepatide, obstructive sleep apnea, SURMOUNT-OSA, obesity, GLP-1 receptor agonist, apnea-hypopnea index, hypoxic burden, blood pressure, weight loss, sleep medicine, Phase 3 trials, post hoc analysis