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The nadir prostate-specific antigen (PSA) value 6 months after definitive radiotherapy (RT) had a significant association with long-term outcomes in localized prostate cancer, an analysis of almost 10,000 patients showed.

A 6-month PSA value ≥0.1 ng/mL as much as doubled the hazard ratio for metastasis-free survival (MFS) at 12 months. The hazard for prostate cancer-specific mortality (PCSM) and for overall survival (OS) increased by as much as 70-80% as compared with patients who had lower PSA values. Hazards remained elevated whether patients received RT alone or with androgen deprivation therapy (ADT).

Outcomes at 5 years also favored patients who had a 6-month PSA nadir <0.1 ng/mL, reported Christopher J. Sweeney, MBBS, of the University of Adelaide in Australia, and co-authors in the .

"The ability to have an early marker of treatment activity is appealing in localized [prostate cancer], where the natural history of the disease means it may take several years to demonstrate a benefit in PCSM or OS," the authors wrote of their findings. "Biochemical recurrence in men undergoing RT is the earliest clinically used marker of efficacy but has been only weakly correlated with PCSM or OS at the patient or trial level."

"Our data have immediate clinical relevance since a PSA at 6 months after RT is measured in routine clinical practice and could provide an early readout of treatment efficacy, particularly where novel systemic agents are tested along with ADT and RT in high-risk disease," they added.

Closer inspection of the data showed that a PSA nadir <0.1 ng/mL at 6 months post-RT "offers no or minimal prognostic value" after RT alone or with short-term ADT (stADT), noted the author of an .

"Most of the prognostic information can be captured from the baseline characteristics, and patients not achieving a very low PSA nadir still generally appeared to manifest favorable long-term outcomes," wrote Daniel E. Spratt, MD, of UH Seidman Cancer Center and Case Western Reserve University in Cleveland. "The prognostic value of PSA nadir post-RT appears primarily confined to the RT plus ltADT [long-term ADT] subgroup, although nearly 90% of patients with high-risk prostate cancer treated with lower-dose RT plus ltADT, even with a nadir PSA >0.1 ng/mL, did not die of prostate cancer 10 years post-treatment."

However, he continued, the predictive value of the PSA nadir warrants further consideration. Patients who have a suboptimal PSA response might benefit from intensified treatment with androgen receptor pathway inhibitors (ARPIs). However, most high-risk patients do not appear to benefit from such intensification as a result of favorable contemporary outcomes with RT plus ltADT.

"Consequently, early PSA response to ADT, irrespective of RT timing, could potentially guide more personalized treatment intensification strategies, which carry physical and financial toxicities," Spratt observed. "This hypothesis, while compelling, necessitates formal validation through completed randomized trials, and one should not assume that this subgroup will preferentially benefit from ARPI treatment intensification and use of this as a presumed predictive biomarker."

The emergence of prostate-specific membrane antigen (PSMA) PET/CT imaging for staging high-risk disease has led to of about 1% at 6 years. In contrast, the landmark STAMPEDE trial of abiraterone (Zytiga) plus ADT for high-risk prostate cancer had a 6-year PCSM of 15%.

"These clearly are very different patient populations," Spratt continued. "Thus, as we look to design future trials in high-risk prostate cancer in the era of PSMA PET/CT, we must leverage the prognostic tools we have available to de-escalate therapy for most men with high-risk prostate cancer ... PSA nadir may be one additional variable to consider."

Several studies have sought to extract prognostic information about high-risk prostate cancer from post-RT PSA values. The largest of the studies was a pooled analysis of 2,400 patients enrolled in evaluating RT and stADT. The results showed that a PSA >0.1 ng/mL after neoadjuvant ADT and before RT was highly prognostic.

Sweeney and colleagues reported data from the (ICECaP) initiative, which comprises individual patient data from 25 randomized trials of local therapy for prostate cancer. Previous analyses of ICECaP data established and that lacked sufficient power to serve as a surrogate for OS.

The current analysis included 9,660 patients treated with RT alone (n=2,376), RT plus stADT (n=5,658), or RT plus ltADT (n=1,626). Each patient's lowest PSA value within 6 months after completing RT was recorded and categorized as <0.1 or ≥0.1 ng/mL. The primary outcomes were 12-month MFS, PCSM, and OS.

The data showed that 98% of patients treated with RT alone had a PSA nadir ≥0.1 ng/mL at 6 months, as did 84% of those who received RT plus stADT, and 77% of patients who received RT plus ltADT. A 6-month PSA nadir ≥0.1 ng/mL increased the hazard ratios for all three 12-month outcomes following RT with or without ADT:

• RT alone: MFS (HR 2.24); PCSM (subdistribution HR 1.82); OS (HR 1.72)
• RT plus stADT: MFS (HR 1.27); PCSM (subdistribution HR 2.10); OS (HR 1.26)
• RT plus ltADT: MFS (HR 1.58); PCSM (subdistribution HR 1.97); OS (HR 1.59)

MFS at 5 years remained superior in patients who had a 6-month PSA nadir <0.1 ng/mL: RT, 91% vs 79%; RT with or without stADT, 83% vs 76%; RT with or without ltADT, 87% vs 74%.

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