Commentary

To the Editor, Radical prostatectomy is increasingly being offered to patients with high‐risk localized prostate cancer patients, driven by the evolving concept of multimodality therapy for those demonstrating prostate‐ specific antigen (PSA) persistence or recurrence after surgical resection. In this article, Brodowsky et al. examined the prognostic significance of a “second” biochemical recurrence (sBCR) after salvage radiation therapy (sRT) following primary radical prostatectomy, using a subset of RTOG 9601 study population. The study cohort encompassed 420 patients with tumor stage pT2/T3, pN0, who received sRT with/without hormonal treatment for either persistently elevated PSA postradical prostatectomy or developed (biochemical recurrence [BCR]) with PSA levels between 0.2 and 4.0 ng/ml, then developed secondary BCR after sRT which was defined as a PSA increase of at least 0.3 ng/ml over the first nadir. In total, 55% of the RTOG 9601 study population cohort developed sBCR. The authors found that time to sBCR was an independent predictor of cancer‐specific mortality (CSM), where patients with early sBCR (<3.5 years) had 1.7‐fold higher CSM risk (p = 0.026) than their counterparts with late sBCR (3.5 years). At 10 years, starting at the time of sBCR, CSM rate was 31.3% in the early sBCR group versus 20.0% in the late sBCR group. These findings corroborate the observation from other cohorts that showed patients with high‐risk patients with high‐genomic classifier “GC” risk who did not receive adjuvant radiation therapy (RT) before BCR, had a significantly greater risk of progressing into sBCR or receiving salvage androgen depriviation therapy (sADT) compared to patients with low/intermediate‐GC risk (hazard ratio: 2.64 [1.06–7.06], p = 0.036). In other words, adjuvant RT mitigated the effect of a high GC tumor on the risk of developing sBCR or receiving sADT. Importantly, as GC is a tumor‐based gene expression score that is obtained from molecular analysis of the primary tumor, the information provided by GC is available long before any biochemical event has occurred. Therefore, in combination, these two pieces of information may help us better identify those most at risk of dying from their disease within the broader biochemically recurrent population. While the ARTISTIC meta‐analysis of three randomized trials, RADICALS (ISRCTN40814031), GETUG‐AFU 17 (NCT00667069), and RAVES (NCT00860652), showed that early sRT is not inferior to adjuvant RT, one of the shortcomings of these trials is the low number of patients with multiple adverse pathological features, which affected the applicability of the results from these trials on high‐risk and very high‐risk population. This has been demonstrated previously in retrospective analysis conducted by the same authors and externally validated in another cohort. The current analysis of the RTOG 9601 study population outcomes following sBCR provides useful information for patient counseling in the clinic, emphasizing the need for long‐term monitoring following therapy for localized disease. There is an exigent need to optimize the management of high‐ risk and very high‐risk patients with localized prostate cancer. Thus, using novel imaging such as PSMA PET scan to detect patients with early metastatic disease, and molecular classifiers might help in identifying candidates for early systematic treatment intensification.