Introduction

There have been numerous controversies regarding the indications and utility of prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) scans, as well as the appropriate course of action following a positive result. Current debates surrounding the use of hormonal therapy or androgen deprivation therapy (ADT) for radical treatment include its role in patients treated with brachytherapy, its use in the unfavorable intermediate-risk group, and the optimal duration of therapy in various scenarios. Questions arise regarding the optimal choice of ADT, as many options are available, including gonadotropin-releasing hormone antagonists, anti-androgen monotherapy, and androgen receptor pathway inhibitors. Our expert team has focused on management controversies in this review and provides updates on these issues by searching PubMed, websites of large institutes, and Google. We aim to derive answers from the most recent updates within the past five years. The search term used was the specific controversy in question. We are pleased to present this work with the latest references to benefit prostate cancer patients, oncologists, and researchers, ensuring no commercial conflict of interest or bias against any industry products.

The three PSMA assays currently approved for use in PSMA PET imaging by the U.S. Food and Drug Administration include Gallium-68 PSMA-11, Flotufolastat F 18 (Posluma), and Piflufolastat F 18 (Pylarify) [1]. This review focuses on recent publications that critically address the following questions and controversies regarding the application of PSMA PET in prostate cancer: (1) A summary of the global situation, including information from American, Australian, Canadian, and European guidelines, as well as websites of major institutes [2–11]. (2) What are the indications and utility of PSMA PET? Is it cost-effective? (3) What are the radical or curative treatment options, and how do they compare with each other? (4) What are the optimal sequences for multi-modality treatment? (5) What supportive therapies are available? (6) How should the disease be monitored?

Rather than offering a standard systemic review of all major landmark studies, this article focuses on selected practical studies, highlighting controversies and emphasizing the need for caution. While we cannot include all available information regarding PSMA, it summarizes management controversies as assessed by our experienced expert team. Many of the aforementioned controversies are frequently debated during Multidisciplinary Disease Team Rounds at cancer centers worldwide. These controversies have been carefully organized within a single article for the convenience of busy physicians. We strive to provide a valuable resource for prostate cancer patients, specialists, and researchers.

Brief global overview of prostate cancer

Prostate cancer is less prevalent in Asian countries. However, it is the fourth most common cancer globally and the second most common cancer in men, after lung cancer [12]. The high incidence of prostate cancer in Western countries is likely linked to dietary factors, although genetic factors also play a significant role. There is a rising trend in prostate cancer cases among Asian men [12]. However, due to the relatively lower incidence, screening is generally not considered necessary in Asian countries, whereas its necessity remains a controversial topic in the Western world. Differences between American and European screening studies can be attributed to baseline screening practices in the United States, where individuals often undergo screening through their family doctors before participating in screening trials [13, 14]. We refer to this as “contamination”, where pre-screened individuals naturally derive less benefit from screening trials. In contrast, baseline screening is less common in Europe, resulting in lower prostate cancer mortality among those enrolling in screening trials. Unfortunately, in the United States, such contamination has led to a decrease in prostate-specific antigen (PSA) screening rates [13].

Prostate cancer disproportionately affects countries with a low social-demographic index (SDI), primarily due to inadequate preventive and treatment methods in these regions. The highest mortality rates are observed in African countries, where harmful mutations linked to disease aggressiveness are prevalent. It is suspected that global prostate cancer incidence continues to rise [15]. Unfortunately, in many developing countries, access to PSMA PET remains limited, and the results of related trials may not be applicable to these regions.

What are the indications and utility of PSMA PET?

The role of PSMA PET is best summarized in the updated statement from the 1.2025 version of the National Comprehensive Cancer Network (NCCN) in the United States [3]: “Because of the increased sensitivity and specificity of PSMA PET tracers for detecting micro-metastatic disease compared to conventional imaging, e.g., computerized tomography (CT)/bone scan at both initial staging and biochemical relapse, conventional imaging is not a necessary prerequisite to PSMA PET and that PSMA PET/CT or PSMA PET/MRI (magnetic resonance imaging) can serve as an equally effective, if not more effective frontline imaging tool.”. The Radiographic Assessments for Detection of Advanced Recurrence (RADAR) study also provides guidance on next generation imaging [16, 17].

The 2024 update of the European Association of Urology guidelines [10] recommends prioritizing PSMA PET imaging over conventional bone scans and CT for staging high-risk localized or locally advanced prostate cancer.

Sood et al. [18] reviewed a total of 148 studies—130 focused on PET and 18 on biomarkers—and concluded that PSMA PET use led to a management change in 20–30% of patients [19]. Similarly, tissue-based prognostic biomarkers, including Decipher, Prolaris, and Oncotype Dx, in the pretherapy primary prostate cancer setting resulted in management changes for up to 65% of patients. Notably, in the postsurgical primary prostate cancer setting, biomarker-guided adjuvant radiation therapy (RT) was associated with improved oncological control, demonstrated by a 22% reduction in 2-year biochemical failure (level 2b) [18].

The utility of PSMA PET in guiding RT has been highlighted in the American Society of Clinical Oncology guideline (2020) and the Advanced Prostate Cancer Consensus Conference (2024) [4, 14, 20]. PSMA PET can be used for initial staging and confirming local relapse in the prostate bed and pelvic lymph nodes. When the disease is extra-nodal or in cases of biochemical recurrence, PSMA PET seems to be more cost-effective than conventional imaging. Furthermore, the 2023 American Urological Association advanced prostate cancer guideline emphasized the preferential use of PSMA PET imaging over conventional imaging in cases of biochemical recurrence after local therapy failure, citing its superior sensitivity [4]. The use of whole-body MRI for staging is less well known [21]. The Australian Prostate-Specific Membrane Antigen PET-CT (ProPSMA) study in patients with high-risk prostate cancer prior to curative-intent surgery or radiotherapy found that the scan offers superior accuracy, more definitive results, and lower radiation exposure compared to conventional imaging [22]. ProPSMA study showed other important results. One that is often overlooked is the high kappa, which speaks to the reliability of the test: reporter agreement was high for both nodal (kappa 0.87, 95% CI 0.81–0.94) and distant metastatic disease (kappa 0.88, 95% CI 0.92–0.94). It also facilitates curative treatments while avoiding unnecessary and potentially harmful interventions [22]. A health economics assessment demonstrated its cost-effectiveness compared to standard imaging [23]. However, a joint European and United States study reported conflicting findings [24].

After PSMA PET staging, what are the local radical/curative treatment options?

For individuals with negative PSMA PET results and no distant metastases, surgery and/or radiotherapy remain the two primary treatment modalities, serving as the standard of care and commonly utilized options. Additionally, the combination of flutamide and finasteride can be used to manage both early and advanced prostate cancer while preserving potency [34]. Dutasteride alone has been shown to help delay biochemical failure in the Avodart After Radical Therapy for Prostate Cancer Study (ARTS) trial [35]. High-intensity focused ultrasound (HIFU) and cryotherapy are focal treatment alternatives that heavily rely on PSMA PET; however, these approaches lack the extensive track record of current standard-of-care treatments [36–45].

Best sequence(s) for multimodality treatment

Different sequences of the aforementioned therapies can be adjusted for therapeutic advantage, such as neoadjuvant enzalutamide [81]. According to preliminary trials and reviews [2], PSMA radioligand therapy may serve as an alternative systemic treatment. Further research into androgen resistance, including potential drugs or regimen modifications to delay its onset, will greatly benefit patients [82]. The RADICALS-HD trial (A Randomized Controlled Trial of ADT Duration with Postoperative Radiotherapy for Prostate Cancer) aimed to assess the efficacy of different ADT durations combined with postoperative radiotherapy. Patients with PSA levels below 5 ng/mL were eligible. The trial found that adding 24 months of adjuvant ADT to postoperative adjuvant radiotherapy significantly improved metastasis-free survival compared to 6 months (P = 0.029) [83]. However, when comparing 6 months of adjuvant ADT to no ADT, no significant benefit was observed [84]. Historically, the RTOG employed 2 months of neoadjuvant ADT alongside the initiation of radiotherapy, followed by concurrent and adjuvant ADT [85]. However, an analysis of two trials by Spratt et al. [86] concluded that adjuvant ADT is preferable to neoadjuvant ADT.

ADT has many side effects. Cardiac, peripheral vascular disease, thrombosis, and cerebrovascular toxicities, along with excess cardiovascular mortality, do not appear to increase mortality in randomized controlled trials. However, retrospective series have frequently documented these side effects [87]. The discrepancy arises because trial participants are typically younger, healthier, and have a better performance status. Additionally, these trials only account for fatal cardiac disease, whereas retrospective series include all cardiovascular and cerebrovascular events. It should be noted that even androgen receptor pathway inhibitors can exhibit cardiotoxicities when used in combination with ADT, as shown in a meta-analysis by El-Taji et al. [88]. This analysis evaluated risk ratios for all-grade and grade 3 or higher cardiovascular events (primary outcomes), as well as secondary outcomes such as hypertension, acute coronary syndrome, cardiac dysrhythmia, cardiovascular death, cerebrovascular events, and venous thromboembolism. Cardiac toxicities can, however, be mitigated as suggested by Crawford et al. [89]. Treatment should be tailored to each patient, considering factors like the necessity to shrink the prostate gland before radiotherapy to reduce the irradiation volume, baseline urinary symptoms, and existing comorbidities. A practical caution is to limit the duration of ADT as much as possible while still maintaining optimal outcomes as supported by literature. This is particularly relevant for patients with diabetes, cardiovascular or liver diseases, cognitive impairment, sexual dysfunction and osteoporosis. As a result, high-risk patients are now commonly treated with 18–24 months of ADT, whereas previously, 24–36 months were recommended [89].

The preservation of sexual function varies in importance among patients and requires an open dialogue between the doctor and patient. Older patients may prioritize overall survival rather than sexual function. Conversely, lonely widowers may lean toward more conservative or non-curative treatments due to limited family support and the challenges of managing treatment side effects alone.

What supportive therapies are available?

All patients should receive general health advice to manage treatment-related adverse effects, including those affecting sexual life, mood, diet, and bone health, along with guidance on exercise to enhance their quality of life, as recommended in RTOG 0126 [96, 97]. Hot flashes, a common adverse effect, can disrupt sleep and significantly impact quality of life, potentially leading to treatment discontinuation. Non-hormonal pharmacological treatments (e.g., antidepressants, antiepileptics, antihypertensives), physical and behavioral interventions (e.g., acupuncture, yoga/exercise, relaxation techniques, cognitive behavioral therapy), and natural health products (e.g., black cohosh, flax, vitamin E, ginseng) have all been studied for their effectiveness in managing hot flashes [98].

Supervised exercise has been shown to improve both quality of life and survival. For instance, Tai Chi, a Chinese martial art, has demonstrated benefits in alleviating fatigue, improving balance and preventing falls, as supported by the literature [99–103]. To prevent osteoporosis, patients should undergo monitoring with bone mineral densitometry [104]. Additionally, patients with a history of myocardial infarction or stroke may require a referral to a cardiologist for evaluation before starting hormonal therapy. The use of gonadotropin releasing hormone antagonists may be a better alternative for men with a prior history of myocardial infarction or stroke [79].

How to monitor disease?

For monitoring disease progression, both serum PSA and testosterone levels are currently utilized. In most Canadian centers, family doctors and nurses assist with follow-up for stable patients after two years, as blood tests are relatively simple to perform. Digital examinations are no longer necessary, making telehealth visits increasingly practical for rural patients [105]. The question of whether PSMA PET can be used more frequently while maintaining a sustainable healthcare budget remains unanswered and requires further research [106]. The NCCN has established a standardized monitoring protocol [3]. The PSA threshold for relapse or recurrence is defined by the Phoenix criteria after radiotherapy (nadir PSA + 2 ng/mL) [107] and a value of 0.2 ng/mL for post-prostatectomy patients [108]. However, with the advancement of ultrasensitive assays, these standard nadir values may evolve as more research becomes available [109, 110]. Additionally, circulating tumor cell detection as an early indicator of relapse is an emerging technology that holds significant promise for the future [111].

Conclusions

In summary, due to its increased sensitivity and specificity for detecting micro-metastatic disease compared to conventional imaging at both initial staging and biochemical relapse, conventional imaging is not a necessary prerequisite for PSMA PET. PSMA PET/CT or PSMA PET/MRI can serve as an equally effective, if not more effective, frontline imaging tool and can also be used for re-staging during recurrence. Contemporary curative and radical treatment options include surgery, RT (external beam radiotherapy with or without brachytherapy and the emerging neoadjuvant lutetium PSMA), hormonal therapy (gonadotropin-releasing hormone agonists/antagonists with or without androgen receptor pathway inhibitors), and systemic therapy (hormonal therapy, chemotherapy, immunotherapy, and miscellaneous inhibitors). Details of treatment sequences and alternatives have been summarized above.

To choose the best treatment, whether conservative or aggressive, start with a digital rectal exam and a thorough history that includes health, comorbidities, psychosocial factors (especially sexual function), and the baseline International Prostate Symptom Score (I-PSS). The physician then estimates the prognosis using tools such as the NCCN website and considers genomic biomarkers for risk assessment and treatment planning, while also accounting for drug interactions and prioritizing the preferences of the patient and caregiver. Several new agents introduced in the past decade, such as abiraterone, are associated with side effects like fatigue, hypertension, diabetes mellitus, and hepatotoxicity. For monitoring disease during and after treatment, both serum PSA and testosterone levels are essential.

Future research should focus on the sustainability and cost-effectiveness of routine PSMA PET for initial diagnosis, treatment monitoring, and follow-up. While the Australian ProPSMA study indicated that PSMA PET is cost-effective in Australia, research from the United States and Europe has yielded conflicting results. Further investigations into the cost-effectiveness of PSMA PET are necessary to maximize patient benefits while managing healthcare costs. A randomized study on the survival benefit of PSMA PET is unlikely to be feasible, as nonrandomized studies have already demonstrated improved survival following staging with PSMA PET instead of conventional imaging.