Results

Patient baseline characteristics

A total of 82 patients with histologically confirmed PDA were included across seven high-volume urological centers in Germany. The median age at diagnosis was 69 years (IQR 65–73 years), and the median PSA at the time of diagnosis was 9.7 ng/mL (IQR 6.3–13.8 ng/mL). At the time of diagnosis, the majority of patients presented with high-risk (47/82, 57.3%) or intermediate-risk (28/82, 34.2%) disease. Preoperative staging revealed that eight patients (8/82, 9.8%) had synchronous metastatic disease at the time of diagnosis. In patients with synchronous metastatic disease, the median PSA was 17.3 ng/mL (IQR 8.55–199.9 ng/mL), with five patients showing PSA levels below 20 ng/mL. Further baseline characteristics are listed in Table 1.

a) Patient and tumor-specific characteristics at the time of biopsy (n=82) | 
Median age, years (IQR*) | 69 (65–73)
Median PSA# at diagnosis, ng/ml (IQR) | 9.7 (6.3–13.8)
Median prostate volume, cm3 (IQR) | 48 (40–64)
Clinical T-stage (DRE+), n(%) | cT1c | 36 (43.9)
cT2a | 12 (14.6)
cT2b | 11 (13.4)
cT2c | 8 (9.8)
cT3 | 8 (9.8)
Unknown | 7 (8.5)
ISUP at biopsy, n (%) | 1 | 11 (13.4)
2a | 16 (19.5)
3 | 22 (26.8)
4 (Gleason 8) | 21 (25.6)
4 (Gleason 9) | 11 (13.4)
10 | 1 (1.2)
D’Amico risk classification, n (%) | Low risk | 7 (8.5)
Intermediate risk | 28 (34.2)
High risk | 47 (57.3)
Evidence of PDA, n (%) | Yes | 40 (48.8)
No | 42 (51.2)
Consecutive therapy, n (%) | Surgery | 68 (82.9)
Radiotherapy | 6 (7.3)
Systemic therapy (primary metastatic disease) | 8 (9.8)
b) Tumor-specific characteristics of patients with PDA undergoing surgery (n = 68)
ISUP at final pathology, n (%) | 1 | 3 (4.4)
2 | 16 (23.5)
3 | 30 (44.1)
4 (Gleason 8) | 6 (8.8)
4 Gleaswon 9) | 12 (17.7)
10 | 1 (1.5)
T-stage, n (%) | pT2b | 10 (14.7)
pT2c | 23 (33.8)
pT3a | 16 (23.5)
pT3b | 19 (27.9)
N-stage, n (%) | pN0 | 51 (75.0)
pN+ | 17 (25.0)
Resection status, n (%) | R0 | 53 (77.9)
R+ | 15 (22.1)
Proportion of PDA on final histopathology, n(%) | ≤ 5% | 27 (39.7)
6% − 49% | 20 (29.4)
≥ 50% | 21 (30.9)

Local treatment and pathologic findings

Among non-metastatic patients (n = 74, 90.2%), RP was the predominant local therapy (68/74, 91.9%), while 6 patients (6/74, 8.1%) underwent definitive radiotherapy. Postoperative pathological analysis revealed lymph node-positive disease in 18 patients (18/68, 26.5%) and positive surgical margins in 15 patients (15/68, 22.1%). Most patients were diagnosed with ISUP 3 (30/68, 44.1%) or 4 (19/68, 27.9%). Extraprostatic extension and seminal vesicle invasion were observed in 16 (16/68, 23.5%) and 19 (19/68, 27.9%) patients, respectively.

At the time of prostate biopsy, 40 patients (40/82, 48.8%) had PDA; 30 (30/40, 75.0%) of whom underwent surgery. Final histopathology after RP, however, showed an additional 38 cases (38/68, 55.9%) of PDA that had been previously missed by biopsy. There were no patients with PDA at the time of biopsy, but without PDA at the time of RP. In the current cohort, only 7 patients (8.5%) were classified as low-risk. In this subgroup, PDA could be identified by biopsy in 4 patients (57.1%). All low-risk patients underwent local therapy (RP: n = 6/7, 85.7%; Radiotherapy: n = 1/7, 14.7%). At the time of RP, 3 additional cases without PDA at the time of biopsy could be found.

Oncologic outcomes

Median follow-up for the entire cohort was 36 months (IQR 20–54 months). Including censoring of patients alive at last follow-up, at the 10-year landmark, median OS and CSS were not reached in the overall cohort. Seven patients (7/82, 8.5%) died during the observation period, and 24 (24/82, 29.3%) experienced BCR. Of these 24 patients, 21 (21/24, 87.5%) had previously undergone surgery. Among previously non-metastatic patients who ultimately required systemic therapy during follow-up, the median interval from local treatment to initiation of systemic therapy was 23 months (IQR 5–31 months) (Fig. 1).

Fig. 1: Kaplan–Meier analysis examining the systemic therapy-free survival of patients diagnosed with prostatic ductal adenocarcinoma

Predictors of unfavorable outcomes

In separate univariable Cox regression analyses, both preoperative and postoperative ISUP ≥ 4 were significantly associated with an increased risk of systemic therapy initiation. Specifically, a preoperative ISUP ≥ 4 showed a hazard ratio (HR) of 3.36 (95%CI1.24–9.14, p = 0.017), while a postoperative ISUP ≥ 4 demonstrated an HR of 5.06 (95%CI1.79–14.2, p = 0.002). No significant associations were observed for age, PSA at diagnosis, or pathological lymph node status (Table 2).

 | Hazard ratio | 95% Confidence interval | p-value
a) Overall cohort
T-stage | pT2 | REF | – | –
pT3a | 0.26 | 0.30–2.28 | 0.225
pT3b | 1.91 | 0.61–5.99 | 0.265
N-stage | pN0 | REF | – | –
pN+ | 3.66 | 1.18–11.4 | 0.025
ISUP at biopsy | ≤ 3 | REF | – | –
≥ 4 | 3.22 | 1.27–8.20 | 0.014
ISUP at final pathology | ≤ 3 | REF | – | –
≥ 4 | 4.15 | 1.50–11.4 | 0.006
PSA at diagnosis | ≤ 20 | REF | – | –
> 20 | 2.01 | 0.77–5.25 | 0.152
Proportion of PDA on final histopathology | ≤ 5% | REF | – | –
6% − 49% | 0.82 | 0.15–4.54 | 0.816
≥ 50% | 2.82 | 0.92–8.65 | 0.070
b) Non-metastatic patients undergoing surgery
T-stage | pT2 | REF | – | –
pT3a | 0.33 | 0.03–3.24 | 0.344
pT3b | 2.42 | 0.63–9.26 | 0.198
N-stage | pN0 | REF | – | –
pN+ | 3.92 | 1.19–12.9 | 0.024
ISUP at biopsy | ≤ 3 | REF | – | –
≥ 4 | 2.97 | 0.87–10.2 | 0.084
ISUP at final pathology | ≤ 3 | REF | – | –
≥ 4 | 2.96 | 0.94–9.37 | 0.065
PSA at diagnosis | ≤ 20 | REF | – | –
> 20 | 1.93 | 0.51–7.30 | 0.331
Proportion of PDA on final histopathology | ≤ 5% | REF | – | –
6% − 49% | 0.84 | 0.15–4.71 | 0.846
≥ 50% | 1.78 | 0.50–6.30 | 0.374

Systemic therapy and response

Overall, 24 patients (24/82, 29.3%) received systemic therapy during follow-up. Additionally, 4 patients previously received ADT within 6 months after local therapy for immediate adjuvant or early salvage radiotherapy. In the first-line, non-curative setting, 14 patients received ADT monotherapy, while 7 patients underwent additional ARPI therapy. 3 patients underwent first-line chemotherapy with docetaxel. Median time to second-line therapy differed by therapeutic modality: 27.2 months (95%CI12–41.6 months) for ADT monotherapy, 10.9 months (95%CI5–16.6 months) for ADT/ARPI-therapy (p = 0.085), and 6.1 months (95%CI1.5–10.8 months) for ADT/chemotherapy (p = 0.033).

In the subgroup of patients with low-risk disease, 28.7% (n = 2/7) underwent further systemic therapy, one after 41 months, the other after 188 months.