2ⁿᵈ Edition of the Cancer R&D World Conference 2026

Abstract

Background:
This update explores the growing role of prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) in the initial and salvage treatment of nodal and distant metastases in prostate cancer. PSMA PET has rapidly emerged as a preferred imaging modality, offering improved sensitivity and specificity over conventional imaging. However, treatment decisions following positive PSMA PET findings remain the subject of ongoing debate. Key areas of controversy include therapeutic strategy selection, timing of intervention, monitoring for disease progression, and the intensification of treatment approaches for metastatic castration-resistant prostate cancer (mCRPC).

Methods:
A review of current literature and clinical trials was conducted, focusing on management strategies for nodal and distant metastases identified on PSMA PET imaging. The analysis encompasses systemic therapies, local interventions, and evolving roles of radiotherapy and immunotherapy.

Results:
For nodal metastases, both metastasis-directed therapy (MDT) and systemic treatment options have been explored. Total androgen blockade—consisting of a gonadotropin-releasing hormone (GnRH) agonist or antagonist in combination with an anti-androgen—is currently recommended. GnRH antagonists—such as subcutaneous degarelix and oral relugolix—offer faster testosterone suppression, reduced risk of flare, and fewer cardiovascular complications compared to GnRH agonists. Intermittent androgen deprivation therapy (ADT) is generally discouraged in patients with nodal or distant metastases due to less favorable survival outcomes. Prostatectomy for oligometastatic cases remains investigational, with ongoing research evaluating its potential role in selected patients.

Upon progression to mCRPC, therapeutic intensification becomes essential. Options include radium-223 and lutetium-177 PSMA-targeted radioligand therapy—alongside stereotactic body radiotherapy (SBRT), chemotherapy, and immunotherapy. Notably, lutetium-177 PSMA therapy has received FDA approval for mCRPC patients who have progressed on androgen receptor pathway inhibitors (ARPIs), marking a significant advance in targeted systemic treatment.

Triplet therapy regimens and early radiopharmaceutical interventions are increasingly considered for younger, fit patients with good performance status. Additionally, pembrolizumab (an immune checkpoint inhibitor) and poly (ADP-ribose) polymerase (PARP) inhibitors have become standard-of-care treatments for mCRPC patients harboring germline or somatic BRCA1/2 or ATM mutations. However, questions remain regarding the prognostic versus predictive value of these tumor suppressor gene alterations, and how best to incorporate genetic findings into clinical decision-making.

PSMA PET has also altered restaging paradigms, enabling earlier detection of recurrence and improved lesion localization compared to conventional computed tomography and bone scans. This enhanced sensitivity may lead to earlier intervention, although the clinical benefit of treating lesions at ultra-low PSA levels remains under investigation.

Systemic treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy, androgen receptor pathway inhibitors, chemotherapy, and radiopharmaceuticals, all of which have associated toxicity. PSMA PET/CT–guided, metastasis-directed radiotherapy may offer durable disease control with low toxicity rates in patients with mCRPC who have a limited number of metastases. There are five prospective PSMA PET/CT studies (including HORRAD trial and arm H of the STAMPEDE study) for patients with mCRPC who had up to five sites of oligo-recurrent or oligo-progressive disease on PSMA PET/CT and subsequently received definitive-intent, metastasis-directed radiotherapy to all new or progressing sites with concurrent androgen deprivation therapy. PSMA PET/CT–guided, metastasis-directed radiotherapy appears to offer durable disease control with low toxicity rates for oligometastatic castration-resistant prostate cancer.

Conclusion:
The integration of PSMA PET into prostate cancer care has transformed diagnostic and therapeutic pathways for patients with nodal and distant metastases. While it offers powerful insights into disease burden, the optimal management of PSMA PET–detected lesions remains a complex and evolving field. Balancing systemic and local treatments, interpreting molecular findings, and personalizing therapy based on patient-specific factors are all vital considerations.