Modern oncology is increasingly defined by precision medicine — treating disease based not just on its location, but on its unique molecular characteristics. Among the most promising advances in this space is the field of theranostics, a portmanteau of “therapy” and “diagnostics.” Theranostics uses a shared molecular target to first diagnose and then treat cancer, often by pairing radiopharmaceuticals for imaging with therapeutic counterparts.
Introduction: Theranostics and the Rise of Targeted Radioligand Therapy
Modern oncology is increasingly defined by precision medicine — treating disease based not just on its location, but on its unique molecular characteristics. Among the most promising advances in this space is the field of theranostics, a portmanteau of “therapy” and “diagnostics.” Theranostics uses a shared molecular target to first diagnose and then treat cancer, often by pairing radiopharmaceuticals for imaging with therapeutic counterparts.
This concept has revolutionized prostate cancer management, particularly in cases of metastatic castration-resistant prostate cancer (mCRPC). A key molecular target in this context is prostate-specific membrane antigen (PSMA) — a transmembrane glycoprotein overexpressed on the surface of most prostate cancer cells, especially in aggressive and metastatic disease.
Using PSMA-targeted PET imaging agents (e.g., Ga-68-PSMA-11 or F-18-DCFPyL), clinicians can detect and stage disease with high sensitivity. If lesions are shown to be PSMA-positive, the patient may be eligible for treatment with a therapeutic agent such as Pluvicto™ (lutetium Lu 177 vipivotide tetraxetan) — a PSMA-targeted radioligand therapy (RLT) that exemplifies the theranostic paradigm. Approved by the FDA, Health Canada, and other international agencies, Pluvicto is rapidly becoming a cornerstone in the treatment of advanced prostate cancer.
What Is Pluvicto?
Pluvicto is a radioligand therapy that combines two critical components:
Lutetium-177 (Lu-177): A beta-emitting radioisotope that delivers ionizing radiation.
Vipivotide tetraxetan: A PSMA-targeting ligand that directs the therapy to prostate cancer cells.
Once administered intravenously, Pluvicto circulates through the bloodstream, binds to PSMA-expressing tumor cells, and is internalized. The Lu-177 component then emits short-range beta particles, causing lethal double-stranded DNA breaks — effectively killing cancer cells while minimizing off-target toxicity.
This highly targeted mechanism distinguishes Pluvicto from systemic chemotherapy and underscores its role in theranostic treatment.
Regulatory Approvals and Indications
Pluvicto received:
FDA approval (March 2022) for use in adult patients with PSMA-positive mCRPC who had previously received at least one androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy.
Expanded FDA approval (March 2025) for patients with PSMA-positive mCRPC who have received prior ARPI therapy and are either appropriate to delay chemotherapy or have already received taxane-based chemotherapy.
It has also been approved by the European Medicines Agency and Health Canada.
Health Canada approved Pluvicto on August 25, 2022, as the first targeted radioligand therapy for treating PSMA-positive mCRPC in adults who had received at least one ARPI and taxane chemotherapy.
Following national approval, the pan-Canadian Pharmaceutical Alliance (pCPA) negotiated reimbursement terms with the manufacturer, leading to public funding agreements in several provinces. Ontario was the first to implement public access, with the first patient receiving treatment at London Health Sciences Centre in December 2024. Alberta and Nova Scotia subsequently announced public reimbursement as well.
In Canada, public access to medications like Pluvicto is determined at the provincial and territorial level. Each jurisdiction evaluates the clinical efficacy, cost-effectiveness, and healthcare impact before listing a drug in its public formulary. The pCPA plays a central role in price negotiations, but final coverage decisions are made independently by each province.
Mechanism of Action: The Theranostic Cycle in Action
Pluvicto complements PSMA PET imaging agents used in diagnosis. The theranostic workflow involves:
Diagnosis: PSMA PET/CT confirms PSMA expression in metastatic lesions.
Treatment: Pluvicto targets and delivers radiation to the same PSMA-positive lesions.
Monitoring: Therapeutic response is tracked via imaging and biomarkers (e.g., PSA levels).
Lu-177 delivers cytotoxic beta radiation over a short range (1–2 mm), inducing DNA damage and cancer cell death, while sparing surrounding healthy tissue.
Clinical Trial Evidence
VISION Trial (NEJM, 2021)
Design: Phase 3, randomized, open-label, multicenter
Population: 831 patients with PSMA-positive mCRPC post-ARPI and chemotherapy
Results:
Median overall survival: 15.3 vs. 11.3 months
Radiographic progression-free survival: 8.7 vs. 3.4 months
Objective response rate: 30% vs. 2%
PSMAfore Trial (2024)
Design: Phase 3, pre-chemotherapy
Results: rPFS: 9.5 months (Pluvicto) vs. 5.6 months (alternative ARPI)
TheraP Trial (2021)
Design: Phase 2, randomized controlled trial in Australia
Comparison: Pluvicto vs. cabazitaxel in mCRPC patients post-docetaxel
Results:
PSA ≥50% reduction: 66% (Pluvicto) vs. 37% (cabazitaxel)
Fewer grade 3–4 adverse events: 33% vs. 53%
Overall survival similar: 19.1 vs. 19.6 months
Administration and Monitoring
Dose: 7.4 GBq (200 mCi) IV every 6 weeks
Cycles: Up to 6, based on response and tolerance
Eligibility: Confirmed PSMA-positive disease on PET/CT
Monitoring: Hematology, renal and liver function, PSA, and imaging
Side Effects and Safety
Common Side Effects of Pluvicto
Fatigue: 43%
Dry mouth (xerostomia): 38%
Nausea: 35%
Anemia: 31%
Decreased appetite: 21%
Constipation: 18%
Thrombocytopenia: 13%
Neutropenia: 8–10%
Renal toxicity is rare but monitored due to urinary excretion. Long-term data are still being evaluated.
Limitation of Pluvicto Treatment in mCRPC
While promising, Pluvicto faces several implementation hurdles:
Access and Infrastructure: Requires nuclear medicine facilities and trained personnel
Tumor Heterogeneity: Not all lesions express PSMA uniformly
Resistance Mechanisms: Under ongoing investigation
Ongoing and future studies include:
PSMAddition: Pluvicto in metastatic hormone-sensitive disease
LuPARP: Pluvicto + olaparib (PARP inhibitor)
Checkpoint inhibitor combinations
Next-generation alpha therapies (e.g., Actinium-225)
Conclusion
Pluvicto represents a paradigm shift in prostate cancer management, embodying the full potential of theranostics — from precise diagnosis to targeted treatment. Its approval in multiple jurisdictions, including Canada, and integration into provincial healthcare systems, highlights its growing clinical significance.
As clinical evidence continues to support its efficacy and safety, and as infrastructure and funding improve, Pluvicto is set to become a mainstay in the treatment of advanced prostate cancer and a model for theranostic strategies in other cancers.
