Abstract
Background
Prostate cancer represents the third leading cause of cancer-related mortality in the male population. Androgen deprivation therapy efficacy has been significantly enhanced by the addition of docetaxel chemotherapy and androgen receptor pathway inhibitors (ARPI), such as abiraterone, enzalutamide, apalutamide, and darolutamide. These agents have demonstrated improvements in both overall survival (OS) and progression-free survival (PFS). Nevertheless, a subset of patients eventually progresses to metastatic castration-resistant prostate cancer (mCRPC). The prostate-specific antigen (PSA) nadir, defined as the lowest PSA level achieved during therapy, has emerged as an early surrogate marker of treatment response and favorable prognosis.
Objective
We conducted a meta-analysis to elucidate the prognostic value of the depth of PSA response in patients with metastatic metastatic hormone-sensitive prostate cancer (mHSPC) treated with ARPI or docetaxel.
Patients and Methods
This is a reconstructed individual patient data (IPD) meta-analysis, in which prospective and retrospective clinical trials concerning patients with mHSPC who received first-line therapy with an ARPI or docetaxel were included. Prospective or retrospective studies on mHSPC patients with available data on the lowest value of PSA reached were included. IPD from the Kaplan–Meier curves of enrolled studies were obtained with the software IPDfromKM. Primary endpoints of the analysis were overall survival (OS) and progression-free survival (PFS) in patients who reached a PSA nadir ≤ 0.2 versus PSA nadir > 0.2.
Results
A total of 8 reports from 8 studies were included, collecting data from 1638 patients for the OS analysis and 1104 for the PFS analysis. In terms of median PFS (mPFS), the PSA nadir ≤ 0.2 arm had an advantage: mPFS not reached (NR) versus 12.1 months HR 0.19 (95% CI 0.16–0.23, p < 0.0001). In terms of median OS (mOS) the PSA nadir ≤ 0.2 arm had an advantage compared with the PSA nadir > 0.2: mOS 92.8 months versus 34 months (HR 0.27, 95% CI 0.22–0.33, p < 0.0001).
Conclusions
This meta-analysis confirms the prognostic value of PSA nadir in patients with mHSPC treated with docetaxel or ARPIs. Achieving a PSA nadir ≤ 0.2 ng/mL was significantly associated with improved OS and PFS, highlighting its relevance as an early marker of treatment efficacy.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s11523-026-01234-z.
Key Points
| Achieving PSA nadir ≤ 0.2 ng/mL is strongly associated with improved survival in mHSPC. |
| PSA nadir may serve as an early and accessible prognostic biomarker. |
| High-volume and synchronous disease reduce the likelihood of a deep PSA response. |
Introduction
Prostate cancer is the most diagnosed malignancy among men in Western countries and represents the third leading cause of cancer-related mortality in the male population [1]. A significant proportion of patients either have metastatic disease at the time of diagnosis or develop it during the clinical course; in both cases, prognosis is significantly dismal.
The therapeutic landscape of metastatic hormone-sensitive prostate cancer (mHSPC) is rapidly evolving. Although androgen deprivation therapy (ADT) has long been the mainstay of therapy, its efficacy has been significantly enhanced by the addition of docetaxel chemotherapy [2, 3] and androgen receptor pathway inhibitors (ARPI), such as abiraterone [4], enzalutamide [5, 6], apalutamide [7] and darolutamide [8]. These agents have demonstrated substantial improvements in both overall survival (OS) and progression-free survival (PFS). More recently, the introduction of “triplet therapy,” which combines ADT + docetaxel and abiraterone or darolutamide, has further redefined the standard of care by providing meaningful clinical benefits without a notable increase in toxicity in patients with high-volume disease [9, 10].
However, therapeutic response in mHSPC remains heterogeneous. Indeed, a subset of patients fails to achieve an optimal response to these treatments and eventually progresses to metastatic castration-resistant prostate cancer (mCRPC), a condition associated with increased morbidity and mortality [11]. This variability highlights an unmet critical need for early, reliable, and accessible prognostic biomarkers that allow for the identification of patients most likely to benefit from intensified treatment strategies, thereby supporting a more individualized approach to therapy.
Among the most promising biomarkers, the prostate-specific antigen (PSA) nadir, defined as the lowest PSA level achieved during therapy, has emerged as an early surrogate marker of treatment response and favorable prognosis. Several studies have demonstrated that achieving a PSA nadir ≤ 0.2 ng/mL is associated with improved overall survival (OS) and delayed disease progression, regardless of the therapeutic regimen employed in mHSPC setting [12–18].
A recent post hoc OS analysis of CHAARTED trial reported 10-year OS outcomes and causes of death, stratified by baseline clinical characteristics (timing of metastatic disease and disease burden) and PSA nadir at 6 months, in patients with mHSPC treated with ADT with or without docetaxel. The findings revealed that a PSA nadir ≤ 0.2 ng/mL was significantly associated with prolonged median OS in both treatment arms and nearly 50% of such patients remaining alive at 8 years in univariable and multivariable analysis. These results further support the utility of PSA nadir as an on-treatment stratification tool and may warrant prospective investigation for eventual deescalation strategies in prospective studies [19].
In this context, we conduct a meta-analysis to elucidate the prognostic value of the depth of PSA response in patients with mHSPC treated with ARPI or docetaxel. The primary objectives were to quantify the association between a PSA nadir ≤ 0.2 ng/mL and both OS and PFS. Additionally, we aimed to assess whether PSA kinetics can effectively stratify outcomes across clinical subgroups defined by Gleason score, disease volume (low versus high), and the presence of synchronous versus metachronous metastases (synchronous means patients presenting with de novo metastatic disease, and metachronous to patients who developed metastases after prior therapy for localized prostate cancer). By addressing this unmet clinical need, this analysis aims to provide robust evidence supporting the use of PSA kinetics into therapeutic decision-making, thereby facilitating a more personalized management strategy for patients with mHSPC.
Methods
This is an individual patient data (IPD) meta-analysis, in which prospective and retrospective clinical trials concerning patients with mHSPC who received first-line therapy with an ARPI or docetaxel plus ADT were included. This analysis was not registered in meta-analysis databases.
Search Strategy, Inclusion/Exclusion Criteria, and Selection Processes
We searched EMBASE and MEDLINE databases with the keywords “metastatic” AND “hormone sensitive” AND “prostate cancer” AND “PSA nadir” The queue was:” ((((hormone sensitive) AND (PSA nadir)) AND (metastatic)) AND (prostate cancer))”. We also searched from abstract of main congresses (ASCO, ASCO GU, ESMO). We analyzed reports from January 2015 to September 2025. Search was performed in October 2025. We excluded studies on mCRPC and trials with no relevant data. The inclusion criteria in our research were: patients older than 18 years with diagnosis of mHSPC prostate adenocarcinoma, patients not eligible of curative surgery or radiotherapy, who have not received any therapy for their mHSPC at the moment of inclusion; with at least one measurable lesion for RECIST 1.1 criteria. Patients included must have received ADT plus ARPIs or chemotherapy (docetaxel) or the triplet (ADT + ARPI + docetaxel) as first-line treatment for mHSPC. We only included studies on absolute PSA nadir available (the lowest value of PSA reached) and excluded studies on PSA nadir at timepoint (for example, PSA nadir at 6 months from start of therapy). We excluded papers regarding patients who received ADT before the study, studies concerning patients with small cell prostate adenocarcinoma and neuroendocrine prostate cancer, patients with serious comorbidities (severe cardiovascular disease, patients with hepatic or renal failure, patients with ECOG PS score > 2), and patients with other neoplasms. We extracted data regarding number of enrolled patients, PSA nadir data, primary and secondary endpoints of the studies, and clinical features (Gleason score, CHAARTED high-volume disease, synchronous or metachronous disease).
Primary and Exploratory Endpoints
Clinical trials evaluating the prognostic effect of PSA nadir were included in this meta-analysis. We also collected data regarding Gleason score, disease volume according to CHAARTED criteria, and the appearance of synchronous or metachronous disease.
The primary endpoints of the analysis were OS (calculated from the date in which they started therapy to death from any cause) in patients who reached a PSA nadir ≤ 0.2 versus PSA nadir > 0.2 and PFS (calculated from the date in which they started therapy to progression according to enrolled trials) in patients who reached a PSA nadir ≤ 0.2 versus PSA nadir > 0.2.
Exploratory endpoint was the odds ratio (OR) for reaching a PSA nadir ≤ 0.2 according to clinical features such as: Gleason score, high volume versus low volume, and synchronous versus metachronous disease.
Statistical Analysis
With the software IPDfromKM (https://biostatistics.mdanderson.org/shinyapps/IPDfromKM/) we extracted IPD from the Kaplan–Meier (KM) curves of enrolled studies. This method, called “Shiny” allows for the analysis of the survival curves in a clinical trial to derive data from patients enrolled in the study. [20, 21] This can be useful to compare indirectly results among different clinical trials with similar population. Two authors (M.A.D.C., D.D.A.) independently performed the extraction. Summary statistics (median PFS, landmark analyses) were used to compare original and reconstructed data, and the most accurate extraction was selected for subsequent analyses.
In, we had IPD data, which permitted us to merge data from different trials in a comprehensive Kaplan–Meier curve.
Statistical analyses were made from R software v 4.4.1 using the data, table, survminer, ggplot2, meta, greed and survival packages.
Survival curves were estimated using the Kaplan–Meier product-limit method and were compared using the log-rank test. Hazard ratios (HRs) and relative 95% confidence intervals (95% CIs) were estimated with Cox regression analyses; PSA nadir was the only covariate (univariate). ORs and 95% CIs were estimated with a Mantel–Haenszel random effects model. This analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22].
For the secondary endpoints analysis, we collected Gleason score data (number of patients with Gleason > 8 versus Gleason < 8), high volume and low volume, and synchronous versus metachronous disease to analyze the odds ratio for these clinical features to reach a PSA nadir ≤ 0.2.
Furthermore, to account for potential study-level heterogeneity (e.g., variations in treatment regimens, study designs, and patient populations), a sensitivity analysis was performed using a Cox proportional hazards model stratified by the source study. This approach adjusts for baseline differences across the included trials to provide a more robust estimate of the pooled treatment effect. To assess the potential impact of pooling strategies, a sensitivity analysis was planned and conducted by excluding studies that evaluated a PSA nadir cutoff of ≤ 0.1 ng/mL (Matsubara et al. and Lam), wherein the corresponding > 0.1 ng/mL population could not be integrated into the > 0.2 ng/mL comparison arm; the last sensitivity analysis was performed excluding studies that used chemotherapy (docetaxel), rather than ARP (Wenzel et al. [12]).
Quality Assessment
To assess the risk of bias we used the Quality in Prognosis Studies (QUIPS) tool. Two authors (L.Z. and M.A.D.C.) independently evaluated each study across six domains (D1: study participation; D2: study attrition; D3: prognostic factor measurement; D4: outcome Measurement; D5: study confounding; D6: statistical analysis and reporting). Discrepancies were resolved by consensus.
Results
Included Studies
The systematic literature search identified 250 records: after exclusion of duplicate and nonrelevant reports, 8 reports from 8 studies were included [12–16, 18, 23, 24] (Fig. 1, Tables 1, 2).
Fig. 1.
PRISMA 2020 flow diagrams for systematic reviews that included searches of databases and registers.
Source: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71
Table 1.
Study design, patient number, and therapies of the included studies
| ID study and year | Prospective/retrospective study | Patients number | Therapy |
|---|---|---|---|
| Wenzel, 2024 [12] | Retrospective | 516 | ADT + ARPI/Docetaxel or triplets |
| Wenzel, 2024 [14] | Retrospective | 107 | ADT + Apalutamide |
| Gebrael, 2023 [16] | Retrospective | 205 | ADT + ARPI |
| Matsubara, 2020 [13] | Prospective | 597 | ADT + Abiraterone Acetate |
| Lam, 2024 [23] | Prospective | 574 | ADT + Abiraterone acetate |
| Wang, 2024 [15] | Retrospective | 102 | ADT + ARPI |
| Suzuki, 2024 [18] | Retrospective | 324 | ADT + Abiraterone acetate, Enzalutamide o Apalutamide |
| Saad, 2025 [24] | Post hoc analysis | 425 | ADT + Darolutamide |
Table 2.
Clinical characteristics of studies included in exploratory endpoint of odds ratio
| ID Study and year | PSA nadir cutoff | Patients with Gleason score < 8 | Patients with Gleason score ≥ 8 | High volume patients | Low volume patients | Synchronous metastatic patients | Total patients |
|---|---|---|---|---|---|---|---|
| Wenzel, 2024 [12] | ≤ 0.2 | 29 | 69 | 42 | 56 | 59 | 98 |
| > 0.2 | 38 | 102 | 95 | 45 | 119 | 140 | |
| Wenzel, 2024 [14] | ≤ 0.2 | 21 | 51 | 16 | 56 | 45 | 72 |
| > 0.2 | 10 | 25 | 24 | 11 | 29 | 35 | |
| Gebrael, 2023 [16] | ≤ 0.2 | 44 | 92 | 52 | 84 | 67 | 136 |
| > 0.2 | 17 | 52 | 46 | 23 | 49 | 69 | |
|
Saad, 2025 [24] |
<0.2 | 83 | 183 | 166 | 100 | 188 | 266 |
| ≥0.2 | 43 | 116 | 138 | 21 | 119 | 159 |
We collected data from 1638 patients for the OS analysis and 1104 for the PFS analysis. Data from all the trials were used for the OS analysis; only data from four trials [13, 15, 16, 24] were available for the PSA analysis. We performed a univariable analysis, collecting data from four studies [12, 14, 16, 24] (the ones that published data about these clinical features and their correlation with PSA nadir) to assess the secondary endpoint of OR considering well-known negative prognostic clinical features such as high Gleason score, high-volume disease, and synchronous metastases
Specific Consideration for the Included Studies
In the study from Matsubara et al. [13], OS and PFS data were calculated on patients who received abiraterone in mHSPC using PSA nadir cutoffs: PSA ≤ 0.1 versus PSA > 0.1; for our analysis we set the PSA cutoff at ≤ 0.2 versus > 0.2, so we collected only IPD from patients with PSA ≤ 0.1 from this study. The lower PSA of these patients could partially influence the pooled effect.
Wenzel et al. [12] published real-world data concerning OS from patients with mHSPC treated with docetaxel or ARPI, identifying different PSA nadir cutoffs (PSA < 0.2; 0.2 < PSA < 4; PSA > 4). We included the patients with PSA < 0.2 in the PSA ≤ 0.2 arm; patients with 0.2 < PSA < 4 and with PSA > 4 were included in the PSA >0.2 arm.
Lam [23] retrospectively published OS and PFS data on patients with mHSPC who received abiraterone or docetaxel with PSA nadir cutoffs PSA ≤ 0.1 versus PSA > 0.1. We collected only IPD from patients with PSA ≤ 0.1 and included in PSA ≤ 0.2 arm.
Wenzel et al. [14] published real-world data concerning OS from patients with mHSPC who received apalutamide; identifying different PSA nadir cutoffs (PSA < 0.2; 0.2 < PSA < 4; PSA > 4). We included the patients with PSA < 0.2 in the PSA ≤ 0.2 arm; patients with 0.2 < PSA < 4 and with PSA > 4 were included in the PSA > 0.2 arm.
Saad et al. [24], in 2025, published a post hoc analysis on ARANOTE trial (patients with mHSPC who received darolutamide). They published data on OS and PFS for patients who received darolutamide using a PSA nadir cutoff of < 0.2 (included in our ≤ 0.2 arm) versus ≥ 0.2 (included in our PSA > 0.2 arm).
Progression-Free Survival
We compared the IPD obtained from the Kaplan–Meier curve for the PFS of the included studies comparing patients who reached a PSA nadir ≤ 0.2 versus patients with PSA nadir > 0.2. We analyzed data from 1104 patients (819 with PSA nadir ≤ 0.2 and 285 with PSA nadir > 0.2). In terms of median PFS (mPFS), the PSA nadir ≤ 0.2 arm had an advantage: mPFS not reached (NR) versus 12.1 months HR 0.19 (95% CI 0.16–0.23, p < 0.0001) (Fig. 2).
Fig. 2.
PFS analysis comparing PSA nadir ≤ 0.2 versus PSA nadir > 0.2 of included trials
Overall Survival
We compared the IPD obtained from the Kaplan–Meier curve for the OS of the included studies comparing patients who reached a PSA nadir ≤ 0.2 versus patients with PSA nadir > 0.2. We collected data from 1638 patients, 965 of them with PSA nadir ≤ 0.2 and 673 with PSA nadir > 0.2. In terms of median OS (mOS), the PSA nadir ≤ 0.2 arm had an advantage compared with the PSA nadir > 0.2: mOS 92.8 months versus 34 months (HR 0.27, 95% CI 0.22–0.33, p < 0.0001) (Fig. 3).
Fig. 3.
OS analysis comparing PSA nadir ≤ 0.2 versus PSA nadir > 0.2 of included trials
Exploratory Endpoint: Odds Ratio
In terms of OR we compared data regarding the number of patients that reached PSA nadir values of ≤ 0.2 versus > 0.2 for clinical features described in the enrolled trials (Gleason score < 8 versus ≥ 8), high-volume disease versus low-volume disease, and synchronous versus metachronous disease. Having nPSA ≤ 0.2 is less frequent in high-volume versus low-volume patients (OR 0.274, 95% CI 0.20–0.37, p = 0.002) and in patients with de novo metastatic versus metachronous metastatic (OR 0.44; 95% CI 0.25–0.75, p = 0.02). No significant differences were found analyzing Gleason score > 8 versus Gleason score < 8 (OR 0.82; 95% CI 0.62–1.10, p = 0.95) (Fig. 4).
Fig. 4.
Odds ratio analysis of the included studies: probability of reaching a PSA nadir ≤ 0.2 considering clinical characteristics. Exposed: patients who reached a PSA nadir ≤ 0.2; comparator: patients with a PSA nadir > 0.2
Exploratory Endpoint: Sensitivity Analysis
To address study-level heterogeneity, a Cox proportional hazards model stratified by study was conducted. The pooled unstratified analysis showed a significant survival advantage for PSA nadir ≤ 0.2 ng/mL cohort (HR 0.23, 95% CI 0.22–0.33, p < 0.0001). Once we had stratified the model by individual study, the prognostic value of having a deep biochemical response was consistent with that result (stratified HR 0.17, 95% CI 0.14–0.23, p < 0.0001), confirming the prognostic significance of the PSA nadir ≤ 0.2 ng/mL. The same result was obtained for PFS (pooled HR 0.19 (95% CI 0.16-0.23, p < 0.0001) (stratified HR 0.17, 95% CI 0.14–0.23, p < 0.0001). Furthermore, we conducted sensitivity analysis with KM curves for PFS and OS excluding data from studies that used PSA < 0.1 ng/ml as a cutoff, and the overall results were consistent with other analyses favoring PSA ≤ 0.2 ng/mL cohort (PFS HR 0.15 95% CI 0.11–0.2, p < 0.0001; OS HR 0.22 95% CI 0.16–0.3; Fig. S2). The last sensitivity analysis was conducted excluding studies that involved patients who received chemotherapy and including patients who received ADT + ARPI, obtaining consistent results in terms of OS (HR 0.2 95% CI 0.16–0.25, p < 0.0001); none of the patients of the included studies for PFS received chemotherapy.
Risk of Bias Assessment Results
The overall risk of bias was rated as low in one study [24] and moderate in seven studies [12–16, 18, 23]. The moderate risk of bias was driven by the retrospective nature of the real-world studies: inherent limitations in study participation, potential unmeasured confounders, and varying follow-up schedules for progression-free survival assessment. Furthermore, two studies [13, 23] were downgraded to a moderate risk in the prognostic factor measurement domain due to the adoption of a ≤ 0.1 ng/mL PSA nadir cutoff, instead of the ≤ 0.2 ng/mL threshold investigated in our analysis. All studies demonstrated a low risk of bias regarding statistical analysis and reporting. The overall summary of the risk of bias assessment is reported in Fig. 5, while the domain-level evaluation for each individual study is detailed in Fig. S4.
Fig. 5.
Summary of the risk of bias assessment across all included studies, evaluated using the Quality in Prognosis Studies (QUIPS) tool. The bar chart shows the proportion of studies assessed as having a low (green) or moderate (yellow) risk of bias across the six specific methodological domains. D1: study participation; D2: study attrition; D3: prognostic factor measurement; D4: outcome measurement; D5: study confounding; D6: statistical analysis and reporting
Discussion
The results of our meta-analysis, based on IPD from eight prospective and retrospective clinical studies, strongly confirm the prognostic role of PSA nadir in patients with mHSPC treated with docetaxel or ARPIs. Specifically, achieving a PSA nadir ≤ 0.2 ng/mL was significantly associated with improved OS and PFS, underscoring its potential utility as an early indicator of treatment efficacy.
In our analysis, median PFS was not reached in patients who achieved a PSA nadir ≤ 0.2 ng/mL, whereas median OS was 92.8 months, compared with 34 months in those who did not reach this threshold. These findings suggest that a deep and early biochemical response may signal higher sensitivity to treatment, regardless of the regimen used. These data are comparable to the recent post hoc analysis of CHAARTED trial, which showed that patients with a PSA nadir < 0.2 had significantly longer median OS in both the ADT + docetaxel (100.3 versus 45.4 months) and ADT alone (116.8 versus 31.8 months) arms [19].
These results are consistent with previous reports. In the LATITUDE study, Matsubara et al. conducted a post hoc analysis exploring the association between PSA kinetics and clinical outcomes in patients treated with abiraterone and prednisone in addition to ADT. In that cohort, more than half of patients treated with abiraterone achieved a PSA nadir ≤ 0.2 ng/mL, with clear benefits in terms of OS and radiographic PFS (rPFS). Specifically, reaching a PSA ≤ 0.1 ng/mL within 6 months was associated with a more than 50% reduction in the risk of death compared with nonresponders [13].
Another important contribution comes from the study by Wenzel et al., which found that achieving a PSA nadir ≤ 0.2 ng/mL was significantly associated with improved OS, regardless of treatment modality (ADT, ADT + ARPI, or ADT + docetaxel). In particular, patients who reached a nadir ≤ 0.2 ng/mL within 6 months had a median OS not reached, versus 45.6 months in those with higher PSA nadirs. The study also showed that this threshold retains prognostic value in subgroups with high-volume disease and synchronous metastases, strengthening its clinical relevance in complex and real-world settings [14].
More recently, a retrospective analysis demonstrated that patients achieving a PSA ≤ 0.2 ng/mL within 9 months of therapy initiation (ADT +/− other treatments) had 55% reduced risk of progression and 54% reduced risk of death. In contrast, a percent PSA reduction (e.g., PSA90) was less predictive and discriminative rather than PSA nadir, with no significant impact on disease progression. This reinforces the assumption that the absolute value of PSA nadir is a more reliable prognostic marker than percentage reductions from baseline [25].
Our analysis also considered the association between selected clinical characteristics and the likelihood of achieving a PSA nadir ≤ 0.2 ng/mL. In this exploratory, unadjusted association, patients with high-volume disease and synchronous (de novo) metastases were less likely to achieve a deep biochemical response, probably due to the negative prognostic implications of these features. Conversely, Gleason score was not significantly associated with achieving PSA nadir ≤ 0.2 ng/mL in our analysis (OR 0.84; 95% CI: 0.58–1.22), indicating a lack of statistical significance. This finding contrasts with previous literature data, which suggests that higher Gleason scores, particularly ≥ 9, are linked to lower rates of deepening biochemical response. The discrepancy in these findings may be due to the limited sample size, differences in study populations characteristics, or variability in study designs among the included cohorts [26, 27].
One of the main strengths of this meta-analysis is the use of reconstructed IPD, which allowed for the integration of heterogeneous studies by harmonizing endpoints and enabling stratification into clinically meaningful subgroups. This approach increased statistical power and improved the clinical applicability of the findings. However, it has some limitations, including the lack of data on time to PSA nadir (TTN) (this is a reconstructed IPD meta-analysis and extracting TTN data from the survival curves published was not feasible), and the inclusion of both prospective and retrospective studies with incomplete data, which may have introduced heterogeneity and affected the reliability of the estimates. Another important limitation is the different cutoffs for PSA nadir in the included studies, which could have partly affected results. Nevertheless, PSA nadir-based outcomes regarding phase III trials on combining ADT, ARPI, and chemotherapy in mHSPC, or PARPi and ARPI [28], are not available and could be interesting for further analysis. Immortal time bias is another important limit of this meta-analysis: we excluded studies with fixed timepoint nadir, and this means that we only included data on patients who lived long enough to reach a nadir, making survival curves look longer (patients who died before having a nadir were excluded), but this is true both for PSA nadir < 0.2 and PSA nadir > 0.2.
Overall, these findings regarding the value of PSA nadir have practical implications. PSA nadir could be adopted as an early marker to guide therapeutic decisions, both at baseline and during follow-up. Patients achieving a PSA nadir ≤ 0.2 ng/mL within 6–12 months may be considered to have a favorable prognosis and may be evaluated in future prospective studies for therapy deescalation or less invasive monitoring. In an era focused on personalized therapy, PSA nadir emerges as an accessible, low-cost, and validated marker with potential to help to refine decision-making.
Looking ahead, several unresolved questions remain. The optimal PSA nadir threshold in clinical practice is yet to be clearly defined: while 0.2 ng/mL is widely used, lower rates (< 0.1 or even < 0.02 ng/mL) may provide improved prognostic stratification. Furthermore, the role of time to PSA nadir as an independent prognostic factor requires further exploration, as does the predictive value of PSA nadir and time to PSA nadir in distinguishing between therapeutic responses (ARPI versus docetaxel or triplet therapy). Another noteworthy aspect evaluation for future analysis concerns the role of local therapies (radiotherapy or surgery of T in oligometastatic disease, or radiotherapy on metastases in oligometastatic disease) in reducing PSA and its relationship with outcomes [29].
Finally, integrating PSA nadir into comprehensive prognostic models—including radiologic, genomic, and clinical parameters—could represent a further step toward individualized management of mHSPC.
Conclusions
This IPD-based meta-analysis strongly confirms the prognostic value of PSA nadir in patients with mHSPC treated with docetaxel or ARPIs. Achieving a PSA nadir ≤ 0.2 ng/mL was significantly associated with improved OS and PFS, highlighting its relevance as an early marker of treatment efficacy.
Moreover, clinical features such as high-volume disease and synchronous metastases were associated with a lower probability of achieving this threshold, supporting the use of PSA nadir as a potential tool for prognostic stratification.
Given its accessibility, ease of monitoring, and strong correlation with clinical outcomes, PSA nadir could be effectively integrated into therapeutic decision-making for mHSPC, contributing to more personalized treatment. Future meta-analyses as well as prospective studies could be directed to understand whether the prognostic impact of PSA nadir change if measured at precise timepoints (e.g., assessing nadir strictly at 6 months). Prospective studies are needed to validate the optimal cutoff and clarify the role of time to nadir.
Supplementary Information
Below is the link to the electronic supplementary material.
Funding
Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement. No external funding was used in the preparation of this manuscript.
Declarations
Conflicts of interest
Mattia Alberto Di Civita, Laura Pappalardo, Danila De Angelis, Marco Stellato, Luca Zacco, Simone Rota, Eleonora Gusmaroli, Valentina Guadalupi, Iolanda Speranza, Michela Roberto, Elena Verzoni, Giuseppe Procopio, and Daniele Santini declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.
Ethics approval, consent to participate, consent for publication
Not applicable.
Availability of data and material, code availability
Not applicable.
Authors' contributions
Conceptualization, M.A.D.C. and D.D.A.; methodology, M.A.D.C.; formal analysis, M.A.D.C.; resources, M.A.D.C. and D.D.A.; data curation, D.S. and L.P. and G.P. and E.V.; writing-original draft preparation, M.A.D.C. and L.P. writing-review and editing, M.S. and S.R. and G.V. and L.Z. and E.G. visualization, I.S. and M.R. supervision, D.S. and E.V. and G.P. All authors have read and agreed to the published version of the manuscript.
Footnotes
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