Cribriform prostate cancer is associated with poor outcomes; however, its optimal treatment strategy remains unclear in the absence of randomized data.
To retrospectively analyze the results of the PROTECT randomized clinical trial to establish the association between cribriform-positive and cribriform-negative prostate cancer and 15-year risk of metastasis in patients who underwent active monitoring, surgery, or radiotherapy.
Between 1999 and 2009, the PROTECT phase 3 randomized clinical trial enrolled 1643 men with clinically localized prostate cancer who were randomly assigned to receive active monitoring, surgery, or radiotherapy with neoadjuvant androgen deprivation therapy (ADT). In this secondary analysis of the PROTECT trial, a centralized histopathologic review was conducted on available diagnostic biopsy slides to classify patients as cribriform-positive if they had invasive cribriform carcinoma and/or intraductal carcinoma. Data were collected from January 25, 2024, to October 11, 2024, and were analyzed from October 14, 2024, to January 30, 2025.
Age, prostate-specific antigen (PSA), Gleason score, and cribriform status.
The primary outcome was progression to metastatic disease (bony, visceral, or lymph node metastases on imaging or PSA >100 ng/mL). Multivariable Cox proportional hazards regression models, adjusted for randomization variables, were incorporated to assess 15-year metastasis risk. Cumulative incidence curves were compared using the Gray test. Both intention-to-treat and per-protocol analyses were performed.
Among 712 men (mean [SD] age, 62.0 [5.0] years) whose biopsies were retrospectively reviewed, 93 (13.1%) had cribriform-positive disease and 42 (5.9%) developed metastasis. In the intention-to-treat cohort, cribriform-positive disease significantly increased the risk of metastasis (hazard ratio [HR], 3.61 [95% CI, 1.60-8.11]; P = .003). Radiotherapy with neoadjuvant ADT significantly reduced metastasis risk (HR, 0.35 [95% CI, 0.16-0.78]; P = .04) (15-year cumulative incidence in patients with cribriform-positive disease, 8%), while surgery delayed metastasis but did not significantly improve long-term outcomes compared with active monitoring (HR, 0.52 [95% CI, 0.25-1.08]; P = .09) (15-year cumulative incidence in patients with cribriform-positive disease, 26% for surgery and 25% for active monitoring). Among patients with cribriform-negative disease, incidence of metastasis was low and did not differ by treatment. Similar per-protocol results were noted.
The findings of this secondary analysis of the PROTECT randomized clinical trial suggest that cribriform morphology was a strong, independent predictor of 15-year metastasis among patients with prostate cancer and that radiotherapy with neoadjuvant ADT was associated with a reduced long-term risk of metastasis. Conversely, outcomes were favorable for most patients with cribriform-negative disease, supporting their eligibility for active surveillance.
ClinicalTrials.gov Identifier: NCT02044172
The authors aimed to assess the value of cribriform disease in the natural history of prostate cancer (PCa). They analysed data from the PROTECT randomised clinical trial by performing a central pathology review of the available biopsy slides. This accounted for slightly fewer cases than the original PROTECT cohort.
Overall, 93 men (13.1% of reviewed biopsies) showed cribriform pattern and almost half of them (n=42) developed metastatic disease. The cumulative incidence of metastasis was 9%, 5%, and 4% among patients assigned to active monitoring, surgery, and radiotherapy with neoadjuvant ADT, respectively. Cribriform disease was associated with a more than threefold increase in the risk of metastasis (hazard ratio [HR], 3.61 [95% CI, 1.60-8.11]; P = .003).
Interestingly, the risk of metastasis appeared to have been reduced by radiotherapy with neoadjuvant ADT (HR, 0.35[95%CI,0.16-0.78]; P = .04), but not by surgery when compared with active monitoring (HR, 0.52 [95% CI, 0.25-1.08]; P = .09). However, as the surgery coefficient approached statistical significance, a 15-year restricted mean survival time analysis was performed showing both surgery and radiation with neoadjuvant ADT conferred an average of 2.15 and 2.21 (P = .02 for both) additional metastasis-free years in men with cribriform PCa, respectively.
Among patients with cribriform-negative disease, the cumulative incidence of metastasis did not differ by treatment. Patients with cribriform-negative GS 3 + 4 = 7 disease had metastatic risk similar to that for patients with GS3 + 3 = 6 disease (HR, 1.42 [95% CI, 0.42-4.79]; P = .57).
The first important finding is that no benefit from immediate active treatment was observed in men without cribriform PCa. This indicated that the vast majority of these patients can safely undergo initial surveillance, even if some pattern 4 disease is present.
The second important finding is that cribriform disease is aggressive and increases the risk of metastasis by more than threefold. Lastly, another interesting finding is that radiation combined with androgen deprivation therapy showed advantages in patients with cribriform, not only compared with surveillance but also compared to surgery. However, these advantages were not confirmed in the additional 15-years restricted mean survival analysis. This latter aspect is hypothesis-generating and opens the discussion on the potential role of additional androgen deprivation in possibly controlling micrometastatic spread deriving from cribriform pattern.
Indeed, the PROTECT trial started in the late nineties and it is important to keep in mind that contemporary patients may differ significantly in terms of selection and characterisation due to the use of new imaging including mpMRI and PSMA-PET/CT for diagnostic and/or staging as well as targeted biopsies. In particular, the use of targeted biopsies would have potentially resulted in an increased percentage of cribriform pattern which nowadays may be present in up to 20% of reports. Future studies are eagerly awaited to provide additional evidence.