Radical prostatectomy (RP) vs. radiation therapy (RT) in high-risk prostate cancer (HR-PCa): Randomized comparison emulated with individual patient data (IPD) from two phase III randomized controlled trials (RCTs).

In general, standard of care (SOC) treatment options for high-risk prostate cancer (HR- PCa) include: radiotherapy (RT) with long-term androgen deprivation (LT-ADT) or radical prostatectomy (RP) with selective use of postoperative RT +/- androgen deprivation therapy (ADT). Retrospective population-based and multicenter studies have evaluated the optimal approach but have produced divergent results. Thus, the present study performed an emulated randomized comparison of RT vs. RP in high-risk prostate cancer based on patients who were included in randomized controlled trials.

To do this, the researchers used data from randomized controlled trials found in Medline on HR-PCa that included an RT or RP-based SOC treatment arm. As an inclusion criterion, the authors required similar experimental treatment and contemporaneous recruitment in the same country to reduce possible bias, which led to the identification of two studies, namely: i) NRG/RTOG 0521 (RT + LT-ADT +/- 6 cycles of docetaxel [sweet]); ii) CALGB 90203 (PR +/- 6 cycles of neoadjuvant docetaxel and ADT). Considering inherent differences in the criteria for biochemical recurrence between TR and PR, the researchers adopted as the primary outcome the cumulative incidence weighted by inverse probability of treatment (IPTW) of distant metastasis (DM), considering deaths as concurrent events. Consequently, mortality after distant metastasis was analyzed in order to create a standardized metric of deaths likely to be attributed to prostate cancer. Finally, to assess possible residual selection bias, the investigators analyzed deaths without distant metastasis to capture deaths that would not be associated with cancer.

From the point of view of the results, a number of 1,290 patients (RT = 557; PR = 733) were included, with a median follow-up time of 6.4 years. Before weighting by the IPTW, patients undergoing PR were significantly younger and had lower baseline PSA compared to patients treated with RT, with 18% receiving adjuvant therapy and 44% salvage therapy in the PR group. Regarding the cumulative incidence of distant metastasis, it was observed that it was significantly lower in patients undergoing RT compared to those treated with PR (DM at 8 years: 16% vs. 23%; p=0.01; hazard ratio for underdistribution [sHR] 0.48 [95% CI: 0.34-0.69], p<0.001). Mortality rates after distant metastasis at 8 years were 10% in the RP group vs. 8% in the RT group (p=0.72). However, patients treated with RT had a significantly higher risk of death without distant metastasis (HR 2.09 [1.01-4.34], p=0.048), with early differences observed. In the comparison between the groups, the cumulative incidence of distant metastasis at 8 years was 18% vs. 21% when comparing the SOC RT+LT-ADT group with the Doce+ADT+RP group (sHR 0.75 [0.45-1.24], p=0.26).

In conclusion, the present study demonstrated that patients with HR-PCa included in the randomized controlled trials had a significantly lower incidence of distant metastasis with a RT-based strategy, when compared with RP. In addition, the researchers pointed out that a longer follow-up would be necessary to assess deaths attributed to prostate cancer. Despite the advantages of the comparison (use of data from cooperative randomized controlled trials, contemporaneous recruitment in the same country, inclusion of patients suitable for chemotherapy, and adjustments by IPTW), there seems to be unmeasured residual bias, as evidenced by the higher number of early deaths without distant metastasis in the RT group. The use of postoperative radiation therapy and ADT+Doce can mitigate the differences between RP and RT+LT-ADT.