Remission Depth in Metastatic Hormone-Sensitive Prostate Cancer Is Associated With Prognosis in Patients With Initial Prostate-Specific Antigen Values Above 100 Ng/ML

Introduction: Recently, new drugs have caused a paradigm shift in the treatment of metastatic hormone-sensitive prostate cancer (HSPC). Meanwhile, research has identified several prognostic factors of metastatic HSPC. Objective: The present study focused on remission depth in metastatic HSPC and evaluated its association with remission depth. Method: We analyzed 427 patients diagnosed with metastatic HSPC with serum initial prostate-specific antigen (PSA) > 100 ng/ml. The nadir serum PSA value was used as a marker of remission depth for each duration to castration resistance by using receiver operating characteristic (ROC) curves. Cox proportional hazards regression was used to assess for any correlation of progression-free survival (PFS) and overall survival (OS) with the nadir PSA level. Results: The cut-off value for the nadir PSA level per time to castration resistance (TTCR) at three, five, seven, and nine years was calculated. The nadir PSA value alone was able to predict prognosis because of its high sensitivity, high specificity, and high AUC in ROC analysis. The nadir PSA level can be an independent prognostic marker not only for TTCR but also for OS on multivariate analysis. Conclusion: We identified the cut-off value for nadir PSA per TTCR period in patients with metastatic HSPC. The nadir PSA value alone can predict prognosis; this demonstrates utility in routine clinical practice due to its simplicity and accuracy.

The search for prognostic factors of metastatic HSPC has been proceeding in parallel with these developments and several prognostic markers have been identified [7][8][9][10][11].One of these prognostic markers [12][13][14] is the nadir prostate-specific antigen (PSA) level.Previous studies examining the serum nadir PSA level used various cut-off values, with most using 0.2 ng/ml, the conventional cut-off value [15,16].However, the reason for choosing this value was never made explicit.
Remission depth is an important prognostic factor in patients with hematological malignancies [17].Achieving a deep response can lead to a good clinical prognosis [18][19][20].The current methods of assessing the prognosis of hematological malignancies include polymerase chain reaction (PCR) analysis, which can be used to assess the treatment effect in patients with chronic myeloid leukemia (CML) in routine clinical practice.PCR analysis is highly sensitive and is associated with the prognosis of CML, although, in patients with epithelial-derived malignancies, a serum tumor biomarker might be more useful as a marker of remission depth.However, serum tumor biomarkers have low sensitivity for most epithelial-derived malignancies, which differ from hematologic malignancies in lacking a useful method of detecting fine, residual cancer cells, i.e., remission depth.Only prostate cancer has a highly sensitive serum tumor biomarker, PSA [21].For example, the serum PSA level immediately after a radical prostatectomy reflects residual prostate cancer, and the serum nadir PSA value is useful as a post-prostatectomy prognostic marker 1 1 1 1 [22].The present study examined the use of the nadir serum PSA level as a marker of remission after treatment.
The present study assessed the association between prognosis and remission depth in metastatic HSPC by analyzing the serum nadir PSA cut-off level as a remission depth marker for time to castration resistance (TTCR) by using receiver operating characteristic (ROC) curves.

Patients
Of 542 patients with iPSA > 100 ng/ml who were initially treated at Tokyo Metropolitan Tama Medical Center between April 1st, 2002 and March 31st, 2021, 427 had at least one metastasis.These 427 patients were eligible for this study and enrolled, and their follow-up data were retrieved from the hospital medical records between June 1st and July 31st, 2022.Authors had access to information that could identify individual participants during or after data collection.The present retrospective study was performed in compliance with the ethical standards of the Declaration of Helsinki and was approved by the ethics review board at Tokyo Metropolitan Tama Medical Center (4-3).Comprehensive informed consent was obtained from all the participants.

Treatment protocol
The patients had received androgen-deprivation therapy with or without irradiation against bone metastases.CRPC was defined as two consecutive increases in PSA or a clear, radiological finding of progressive disease.After diagnosis of CRPC, patients received systemic chemotherapy (docetaxel and/or cabazitaxel) and/or second-generation androgen deprivation therapy.

Data
The following data were collected from the medical records: age; initial PSA; nadir PSA; hemoglobin; LDH; ALP; total Gleason score; metastasis site; EOD; and treatment history.

Statistics
The nadir PSA cut-off value was determined using ROC curve analysis.PFS was defined as the time from diagnosis to biochemical or radiological failure.OS was defined as the time from diagnosis to death from any cause.The distribution of PFS and OS was mapped using the Kaplan-Meier method.Cox proportional hazards regression analysis was performed to analyze independent predictors of PFS and OS.All statistical analyses were performed using the JMP® software package (SAS Institute, Cary, NC), and p <0.05 was considered to indicate statistical significance.

Correlation analysis
Table 2 shows the results of our analysis of the correlation between several factors and nadir PSA.All the nadir PSA cut-off values correlated with initial PSA, extent of disease (EOD) score, hemoglobin, albumin, lactate dehydrogenase, alkaline phosphatase, and the CHAARTED and LATITUDE criteria.PSA, prostate-specific antigen

Univariate and multivariate analyses
Univariate analysis revealed that the nadir PSA value, hemoglobin, albumin, lactate dehydrogenase, alkaline phosphatase, EOD, and the CHAARTED and LATITUDE criteria were associated with PFS (Table 3).Age, nadir PSA, hemoglobin, albumin, lactate dehydrogenase, alkaline phosphatase, EOD, and the CHAARTED and LATITUDE criteria were associated with OS (Table 4).Multivariate analysis using Cox's proportional hazards analysis revealed that the nadir PSA value was an independent predictor of PFS and OS.Hemoglobin, albumin, alkaline phosphatase, EOD, liver metastasis, and the LATITUDE criteria were also independent predictors of PFS while hemoglobin, lactate dehydrogenase, alkaline phosphatase, and the LATITUDE criteria were associated with OS.

Discussion
The present report is the first to predict the prognosis of individual patients with metastatic HSPC by remission depth.The nadir PSA cut-off value for each TTCR (three, five, seven, and nine years) was determined using ROC curves.The TTCR was able to be predicted using the serum PSA nadir value, i.e., remission depth; as the nadir PSA level decreased, the TTCR tended to increase, with the target nadir PSA value for the seven-and nine-year TTCR being the same, indicating that most patients without progression to CRPC for seven years would be CRPC-free after nine years.
Several, previous reports used nadir PSA 0.2 ng/ml as a cut-off value, but this comes with some limitations in the clinical setting.First, the cut-off value (0.2 ng/ml) merely predicts a good or bad prognosis but cannot predict the specific prognosis.Second, this cut-off value has already been used as one of several prognostic factors in a multivariate model to predict prognosis.In our study, the target value for each TTCR was determined using ROC curves.Our results suggested that the nadir PSA value alone can predict prognosis without using a model with multiple factors because of its high sensitivity, high specificity, and high AUC on ROC analysis.
Some newly developed drugs have been approved for front-line therapy against metastatic HSPC.However, there is as of yet no evidence-based recommendation for choosing among these options [23].The nadir PSA level thus remains an accurate and reliable prognostic marker and can facilitate choosing an appropriate drug depending on the life expectancy of each patient.It has the additional benefit of being useful in the clinical setting because of its simplicity.
Of the 170 patients with a PSA value < 0.21 ng/ml, 35 (20.6%) failed to achieve 0.1 ng/ml or lower.Similarly, of the 135 patients with PSA < 0.1 ng/ml, 37 (27.4%)failed to achieve PSA < 0.036 ng/ml.These findings indicate the difficulty of lowering the nadir PSA value to extend the TTCR by two years.The newly developed drugs might be able to lower the nadir PSA value and extend the TTCR but may come at a higher cost; androgen receptor-axis-targeted (ARAT) therapies, for example, are ten times as expensive as the vintage hormonal therapies [1,4,5].Our cohort comprised 413 patients (97.0%) receiving vintage hormonal therapies as their first-line therapy.Of these patients, 39.8, 31.6, and 23.0% were able to achieve a nadir PSA value <0.21, 0.1, and 0.036 ng/ml, respectively, suggesting that vintage hormonal therapy is adequate for some patients with metastatic HSPC.However, the clinical use of the nadir PSA value for predicting the effect of vintage hormonal therapies early in their administration is limited because the median time to nadir PSA was 9.9 months (range: 1.0-57.8months) or later than the start of ARAT therapy.The effect of delaying ARAT therapy on the clinical efficiency of anti-HSPC treatment is unclear.
Interestingly, low nadir PSA improved both PFS and OS, indicating that the response to the initial treatment for metastatic HSPC can predict the response to subsequent therapies.Recently, Miyake et al. reported no difference between the length of OS in patients after CRPC onset with their TTCR [24].In other words, TTCR has the greatest impact on OS.It is important to achieve as long a remission period as possible with the initial treatment to improve the OS rate.
Our results are meaningful in two respects.First, the nadir PSA value can serve as a reliable prognostic marker of OS.Second, the choice of an appropriate drug can be made based on OS.
The present study analyzed the prognosis of a very large cohort of patients with advanced cancer.The median OS was 58.8 months and worse than in several, previous studies [25].The latter, however, had small sample sizes and included patients with a low serum initial PSA level.
The prognosis of metastatic prostate cancer is classified according to several factors.Serum iPSA is considered a poor prognostic factor [8,26,27] although this finding was contradicted by a recent study reporting that serum iPSA is not a prognostic factor in patients with PSA>100 ng/ml [28].The latter finding is controversial because it was based on a small number of patients.In our cohort, the iPSA level proved to be a poor prognostic factor when using the median cut-off value of 300 ng/ml.
The present study has several limitations.First, it was retrospective and monocentric.Second, most of the patients had received androgen-deprivation therapy as the primary treatment while only a small percentage received ARAT therapy.This is not in line with current treatment trends.To address this issue, the cut-off value should be determined using a cohort receiving ARAT therapy.

Conclusions
Our study identified the nadir PSA cut-off value for several TTCRs in patients with metastatic HSPC.Low nadir PSA improved both PFS and OS, indicating the response to the initial treatment for metastatic HSPC.Initial treatment for HSPC should be selected to achieve a low nadir PSA as much as possible.
The nadir PSA value alone can predict prognosis and is useful in routine clinical practice because of its simplicity and accuracy.Further research is necessary to determine whether choosing a drug on the basis of the predicted life expectancy can improve treatments.