Insights from PSMAfore: impact on health-related quality of life

Prostate cancer is one of the most common malignancies among men worldwide and remains a major cause of mortality, especially in advanced disease (1). It is biologically and clinically heterogeneous, with diverse histopathological subtypes and tissue biomarkers that can help inform prognosis and guide treatment stratification (2,3). Advances in molecular profiling have identified key genomic alterations that influence tumor growth, progression, and therapeutic resistance (4-6), supporting the development of more personalized treatment approaches. Diagnostic tools have also improved, with the integration of multiparametric imaging, targeted biopsy techniques, and more precise pathology assessment, which have strengthened the detection of clinically relevant tumors and improved risk classification (7,8).

Over the past decades, systemic therapy has significantly improved outcomes in patients with advanced, metastatic prostate cancer. However, despite advances in diagnosis and biological understanding, treatment is still challenging, as prognosis generally worsens once prostate cancer progresses, becoming castration-resistant [metastatic castration-resistant prostate cancer (mCRPC)] and androgen deprivation therapies lose effectiveness (9,10). Additionally, many patients continue to experience substantial morbidity from cancer-related pain, skeletal complications and functional decline, worsening health-related quality of life (HRQOL) (11-13).

A range of emerging innovative therapeutic strategies, including poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, radioligand therapies (RLTs) and bone-targeted therapies, have broadened the therapeutic landscape for managing mCRPC. The rationale to expand available treatment options comes from two key challenges in current practice: the sequential use of androgen receptor pathway inhibitors (ARPIs) may provide limited benefit due to cross-resistance, which leads to rapid progression (14,15), and taxane chemotherapy, although effective, is often unsuitable for many patients due to toxicity (16,17).

RLT, on the other hand, offers an effective and symptom-tolerable alternative. The VISION trial set the stage for prostate-specific membrane antigen (PSMA)-directed RLT with Lutetium-177-PSMA-617 (¹⁷⁷Lu-PSMA-617 or ¹⁷⁷Lu-vipivotide tetraxetan) plus standard of care (no active chemotherapy, immunotherapy, radioisotopes, or experimental drugs) as a therapeutic option for extensively pretreated mCRPC, confirming improvements in radiological progression-free survival (PFS) and overall survival (OS), in addition to delaying time-to-worsening HRQOL and to first symptomatic skeletal event (SSE) when compared to standard of care alone (18,19). Some plausible molecular evidence supporting these findings is based on selectively delivering cytotoxic radiation to PSMA-expressing tumor cells, thereby reducing tumor burden and alleviating symptoms regarding pain relief, likely through targeted destruction of metastatic lesions and consequent reduction in osteoblastic activity and bone microenvironment disruption. Moreover, the specificity of PSMA-targeting lowers off-target radiation exposure, which may limit systemic toxicity and preserve patients’ functional status and overall well-being (20,21).

Satapathy et al. (2022) (22) showed higher prostate-specific antigen (PSA) response rates, fewer severe adverse events, and better HRQOL outcomes in 40 chemotherapy-naïve mCRPC patients treated with ¹⁷⁷Lu-PSMA-617 compared to docetaxel. Likewise, the TheraP trial, conducted in 200 mCRPC patients post-docetaxel, reported that ¹⁷⁷Lu-PSMA-617 RLT promoted higher PSA response rates, fewer severe adverse events and improved patient-reported outcomes compared with cabazitaxel (23).

These prior studies demonstrating RLT benefits in patients previously treated with both ARPIs and taxanes raised an important question as to whether RLT should be considered earlier in the treatment course of mCRPC, encouraging ¹⁷⁷Lu-PSMA-617 RLT as a first-line treatment. The ENZA-p trial conducted in 162 mCRPC patients demonstrated longer PSA PFS, OS and pain improvement in 19 (61%) of 31 patients, when ¹⁷⁷Lu-PSMA-617 was combined with enzalutamide versus enzalutamide alone (24). Notably, this combination strategy not only enhanced clinical benefit but also preserved a favorable safety profile, with only minimal additional toxicity relative to enzalutamide alone, which supports the suitability of ¹⁷⁷Lu-PSMA-617 as an effective and safe first-line treatment.

Subsequently, the phase 3 PSMAfore trial randomly assigned 468 taxane-naïve mCRPC patients eligible for an ARPI switch to receive either ¹⁷⁷Lu-PSMA-617 or an ARPI change and impressively demonstrated that ¹⁷⁷Lu-PSMA-617 not only delayed disease progression but also provided important benefits beyond survival (25) as seen on the subsequent publication from this trial by Fizazi et al. (2025) (26), who undertook complementary analyses of the PSMAfore trial, focusing on time to worsening of HRQOL, pain progression, and time to first SSE, offering relevant information for clinical practice given that mCRPC patients often experience HRQOL decline, increase in pain, and skeletal complications (26).

To better understand patient-reported outcomes in this setting, the PSMAfore trial assessed HRQOL worsening using established minimum clinically important difference (MCID) thresholds for the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EuroQoL 5-Dimension 5-Level (EQ-5D-5L) questionnaires (27,28). Using these validated thresholds, ¹⁷⁷Lu-PSMA-617 significantly delayed HRQOL deterioration across all evaluated measures, suggesting that the treatment not only supports disease management but also prolongs the time before patients experience HRQOL declines substantial enough to influence clinical decisions (26). While MCIDs help clarify when a change becomes meaningful from the patient’s perspective, their use does not eliminate individual variability, reinforcing the need to integrate these metrics with clinical judgment and patient preferences.

Among the 468 patients studied (234 per arm), ¹⁷⁷Lu-PSMA-617 treatment delayed decline in all assessed HRQOL and pain outcomes compared to ARPI change: FACT-P (7.46 vs. 4.27 months, respectively), EQ-5D-5L (6.28 vs. 3.88 months, respectively), and Brief Pain Inventory-Short Form (BPI-SF) (5.03 vs. 3.65 months, respectively), time to first SSEs (not estimable versus 17.97 months, respectively), occurrence of SSEs (13% vs. 29%, respectively), need for palliative bone pain radiotherapy (7% vs. 18%, respectively), and occurrence of pathological bone fractures (2% vs. 6%, respectively). Therefore, ¹⁷⁷Lu-PSMA-617 RLT offered superior disease control and preservation of HRQOL, which are key factors in assessing clinical benefit and deciding the most appropriate therapeutic route (26).

When evaluating therapeutic options for mCRPC, ¹⁷⁷Lu-PSMA-617 demonstrated substantial advantages over the ARPI arm, both in terms of clinical efficacy and overall disease management. The observed delay of nearly 3 to 4 months in time to worsening HRQOL and pain outcomes represents a meaningful gain for patients, offering not only extended disease control but also improved quality of life during treatment.

Integrating these findings into treatment sequencing, HRQOL with ¹⁷⁷Lu-PSMA-617 remaining stable, supports this therapy’s early use in taxane-naïve mCRPC patients (25,26). By preserving functional well-being while providing effective disease control, ¹⁷⁷Lu-PSMA-617 therapy could be prioritized immediately after progression on a single ARPI, especially in patients with symptomatic bone metastases or a higher risk of chemotherapy-related toxicity, allowing an effective treatment strategy while maintaining patients’ quality of life.

Moreover, event curves clearly indicated that patients treated with ¹⁷⁷Lu-PSMA-617 experienced far fewer complications compared with those receiving ARPI. The reduction in SSEs, pathological bone fractures, tumor-related orthopedic surgeries, and the need for radiotherapy to relieve bone pain highlights the RLT’s capacity to mitigate the physical and emotional burden of an advanced disease.

The observed clinical benefits could, in theory, reduce downstream healthcare expenditures. However, whether these translate into meaningful economic value is uncertain, given the considerable direct costs of RLT and the lack of robust pharmacoeconomic data.

The favorable safety profile of ¹⁷⁷Lu-PSMA-617 RLT represents a clear clinical advantage over ARPIs. In the Fizazi et al. study, patients in the ¹⁷⁷Lu-PSMA-617 arm experienced fewer high-grade treatment-emergent adverse events and a reduced need for dose modifications, reflecting a safer toxicity profile. These benefits are especially relevant when compared with conventional chemotherapy, which is frequently associated with severe toxicities such as myelosuppression, fatigue, and gastrointestinal complications, which frequently require dose reductions, hospitalizations, or even treatment discontinuation. By minimizing these adverse events, ¹⁷⁷Lu-PSMA-617 therapy not only preserves patients’ quality of life but also reduces the clinical and economic burden on healthcare systems (26).

Regarding the representativeness of the trial, the efficacy of ¹⁷⁷Lu-PSMA-617 not being assessed in patients for whom taxane-based chemotherapy would be the next-line therapy limits its applicability. This limitation becomes more evident when considering the CARD trial, which showed that switching between abiraterone and enzalutamide provides minimal benefit due to cross-resistance, whereas cabazitaxel significantly improved PFS and OS (29). These findings indicate that an ARPI switch is a weak comparator. Consequently, the use of the same control arm in PSMAfore limits the strength of its conclusions regarding ¹⁷⁷Lu-PSMA-617. Overall, these data highlight the need for trials directly comparing ¹⁷⁷Lu-PSMA-617 with chemotherapy after progression on first-line ARPI to more firmly define its role in the current treatment landscape.

Moreover, because the study population was predominantly composed of white males, taxane-naive, and restricted to PSMA-positive patients, the results cannot be generalized to a broader mCRPC population. Finally, the high crossover rate (57%) from the ARPI arm to ¹⁷⁷Lu-PSMA-617, which, while ethically justified, confounded the OS analysis and may have underestimated the true benefit of the RLT (26), thus indirectly showing the clear benefit of RLT in comparison with ARPIs. This crossover diluted the observed survival difference, making it harder to interpret the actual advantage of the therapy. To address this in future trials, strategies such as pre-specified delayed-treatment cohorts and alternative randomization schemes could organize and balance treatment groups more precisely beginning from the randomization phase, ensuring that, if crossover occurs, it reduces the proportion of patients in the control group who will cross over quickly and improving the similarly between the clinical subgroups; besides, advanced statistical correction methods allows that the impact of the crossover to be mathematically adjusted, thus producing a more accurate analysis of the treatment effect.

From an economic perspective, the cost limitations highlighted suggest the need for optimized patient selection and stratified cost-effectiveness approaches. By reducing downstream healthcare utilization, including skeletal-related events, hospitalizations, and supportive care needs, when paired with appropriate patient selection, its superior clinical efficacy can translate into a more favorable long-term economic profile compared with lower-cost but less effective alternatives. These strategies could improve real-world feasibility and ensure equitable access.

The potential financial impact of introducing ¹⁷⁷Lu-PSMA-617 earlier in the treatment sequence is substantial. Primary use may improve patients’ quality of life, delay SSEs, and reduce the need for additional medical care (26). However, the initial cost of RLT is high. Currently, robust pharmacoeconomic data for early line use in taxane-naïve mCRPC are limited (30,31). Therefore, studies evaluating both the economic impact and value for healthcare systems are needed to understand whether the clinical benefits are worth the expense in real-world settings.

As the study is ongoing, the final OS analysis will be critical to fully assess the survival impact. Even so, meaningful improvements in quality of life have been observed as the RLT treatment delayed worsening of HRQOL, pain, and time to first SSE compared with an ARPI switch (16).

¹⁷⁷Lu-PSMA-617 is emerging as a promising therapeutic option for taxane-naive patients whose disease has progressed after one ARPI and who are eligible for ARPI change. Taken together, current evidence supports the promise of introducing PSMA-targeted RLT earlier in the treatment sequence. Available findings also point to the possibility of positioning ¹⁷⁷Lu-PSMA-617 before taxane chemotherapy in selected patients, although definitive OS analyses and broader real-world validation and cost-effectiveness studies would be essential to define its role in clinical practice.

As RLT advances in the therapeutic pathway, upcoming trials should incorporate HRQOL measures as key endpoints, ensuring that treatment benefits are evaluated not only in terms of survival or disease control but also in how patients feel and perform during therapy. Over time, these findings may influence future updates of clinical guidelines, including those from the European Association of Urology (EAU) and European Association of Nuclear Medicine (EANM), particularly regarding the integration of PSMA-targeted RLT at an earlier stage.

Finally, the wider adoption of PSMA-based RLT would require careful consideration of service capacity, as nuclear medicine departments may face challenges in accommodating an increase in the number of eligible patients, potentially affecting treatment accessibility during the transition period.

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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.