Real-world comparison of Docetaxel versus new hormonal agents in combination with androgen-deprivation therapy in metastatic hormone-sensitive prostate cancer descrying PSA Nadir ≤ 0.05 ng/ml as marker for treatment response

After obtaining a positive vote of the local ethical committee (vote number: 1395/2020) a retrospective single-center study was performed at the Medical University Innsbruck, Austria. A total of 42 men diagnosed with mHSPC between 2014 and 2020 were included. All patients were eligible to receive a first-line therapy consisting of ADT combined with either Docetaxel (6 cycles á 75 mg/m² KOF 3-weekly) or a novel hormonal therapy (NHT) (AAP or Apa). Patient data were extracted into an excel spreadsheet and follow-up was conducted until a cut-off date (December 31, 2021). Clinical outcome was analyzed by assessing overall survival (OS), progression-free survival 1/2 (PFS1/2) and time to progression (TTP).

Baseline patient characteristics were tabulated separately for patients treated with NHTs vs. Docetaxel, using absolute and relative frequencies for categorical variables. For continuous variables, the median as well as minimum to maximum (Min–Max) parameters were used. Clinical outcomes OS, PFS1/2 and TTP were analyzed using Kaplan–Meier survival analysis, and the influence of various factors on survival was tested using log-rank tests. Univariate and multivariable-adjusted hazard ratios (HRs) were obtained from Cox proportional hazards models. Multivariable adjustment was done for age and PSA levels at therapy start, the only variable for which we detected a statistically significant difference between the NHT and Docetaxel groups. PFS was assessed from the starting date of combination therapy while TTP refers to the beginning of ADT. Due to the highly skewed distribution of most of the analyzed continuous biomarkers, those variables were dichotomized for the survival analysis using clinically meaningful cut-off values. All statistical tests were two-sided at a significance level of 0.05. SPSS, version 26.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis.

All patients had an initial histopathological diagnosis of adenocarcinoma of the prostate and presented with mHSPC. Two cohorts were formed based on the systemic therapy added to ADT (NHT + ADT vs Docetaxel + ADT). Cohort 1 consisted of 24 patients (10 AAP, 14 Apa), while cohort 2 included 18 patients treated with 6 cycles Docetaxel in addition to ADT. Baseline patient characteristics were well balanced between groups (Table1). The only variable for which groups differed significantly were PSA levels at therapy start (1.6 ng/ml vs. 6.07 ng/ml, p = 0.01). Median age at diagnosis was 69.7 years with a median PSA of 29.3 ng/ml at primary diagnosis. The majority of patients presented with high-risk, locally advanced PCa comprising 71.4% with ISUP 4 or 5 in primary biopsy. Of note, 75% of the patients had a positive digital rectal examination (DRE) status. Most patients had a good performance status reflected by a Charlson Comorbidity Index (CCI) of 8.6 not differing among groups, indicating that CCI did not influence therapy selection in our collective. Of importance, we modified the CCI by 6 points remitting due to malignancy, as it was a constant variable in all patients. 42.1% of patients underwent a previous local therapy (radical prostatectomy (RPE) or external beam radiation therapy (EBRT)), while 57.9% presented with de-novo metastatic disease. In addition, patients were classified according to the volume status defined by CHAARTED as well as the LATITUDE risk criteria as previously described emphasizing that high risk/high volume patients were well balanced among the treatment groups [3, 4]. Concerning metastatic load, we observed that the Docetaxel group had a higher, but not statistically significant, metastatic status (bone: 66.7% vs 83.3%, lymph nodes: 62.2% vs 83.3%, visceral: 20.8% vs 22.2%). Furthermore, the Docetaxel group included more de-novo metastasized patients compared to the NHT group (72.2% vs 45.8%, p value: 0.120).

Therapy outcomes of patients stratified according to systemic therapy are displayed in Fig. 1. Interestingly, we observed a trend towards better clinical outcomes in terms of OS, PFS 1 and 2, and TTP in the NHT group however without reaching statistical significance possibly caused by the limited statistical power due to limited sample size (OS: p_{log-rank test} = 0.189, Hazard ratio (HR) = 2.99, 95% CI 0.54–16.57; PFS1: p_{log-rank test} = 0.082, HR = 2.35, 95% CI 0.86–6.42; PFS2: p value: 0.093, HR = 0.28, 95% CI 0.06–1.40; TTP: p_{log-rank test} = 0.055, HR = 2.53, 95% CI 0.92–6.94). Results did not substantially change when adjusting models for age and PSA levels at treatment start (OS: HR = 4.96, 95% CI 0.67–36.52, p = 0.116; PFS1: HR = 2.48, 95% CI 0.88–6.97, p = 0.085; PFS2: HR = 0.67, 95% CI 0.07–6.14, p = 0.720; TTP: 2.64, 95% CI 0.94–7.38, p = 0.065).

Up to now, PSA still represents the most important serum biomarker for initial PCa detection and monitoring [7]. PSA Nadir, defined as the lowest measured PSA during therapy, represents an important marker for clinical response after local therapy as well as during systemic treatment [8, 9]. In our work the PSA-Nadir relates to the lowest PSA-value since beginning of the systemic therapy and not to the PSA after the initial local treatment. Importantly we found that the PSA level at primary diagnosis was not correlated to OS (p value: 0.52), PFS1 (p value: 0.55), or TTP (p value: 0.45). A PSA decline of more than 50% (PSA50) was achieved in the majority patients during therapy (91.7% NHT vs. 94.4% Docetaxel), implying that PSA50 often used in clinical trials is not a reasonable marker to predict treatment response in our population. Thus, we determined a PSA Nadir of ≤ 0.05 ng/ml as cut-off level and were able to demonstrate a significantly prolonged PFS1 and TTP (p value: < 0.001) in those patients who reached a PSA Nadir of ≤ 0.05 ng/ml during therapy (Fig. 2).

Based on our previous study describing an increase in TSH levels as predictive biomarker for therapy response in metastatic castration resistant PCa (mCRPC) during AAP, we analyzed TSH changes in the present cohort [10]. TSH increase was defined as increase of any TSH levels within 3 months after initiation of treatment. A TSH increase was achieved in 76.2% of the NHT and in 58.8% of the Docetaxel group (p value: 0.2). Indeed, a TSH increase observed within 3 months after therapy start resulted in prolonged TTP (p value: 0.06, Fig. 3A). Next, we assessed the neutrophil–lymphocyte ratio (NLR) before and 4–6 weeks after treatment start as potential biomarker. However, in contrast to other studies [11, 12] we were not able to find a correlation of either pre-therapy NLR, or NLR change during therapy with OS (p value: 0.55), PFS (p value: 0.122) or TTP (p value: 0.113), Fig. 3B). Furthermore, we could not demonstrate a correlation between lactate dehydrogenase levels (LDH) and OS (p value: 0.3), PFS1 (p value: 0.285) or TTP (p value: 0.51), Fig. 3C). Concerning alkaline phosphatase (AP) there was a trend towards a shorter OS for elevated AP levels before treatment start (p value: 0.07), Fig. 3D). Elevated LDH and AP levels before therapy were observed slightly more often in the Docetaxel group (LDH: 55.6% vs 45.8%, AP: 55.6% vs 45.8%). Analyzing various clinical parameters, we found that CCI was correlated to OS (p_{cox-regression OS=} 0.028) highlighting CCI as a prognostic factor also in mHSPC.