Use of the PAM50 signature helped identify patients with recurrent prostate cancer who would benefit from a combination of hormone therapy added to radiotherapy, like CyberKnife.
For patients with recurrent prostate cancer, those with a certain subtype had clinically meaningful benefits when apalutamide (Erleada) was added to salvage radiotherapy after radical prostatectomy, a randomized trial showed.
Among 295 patients with recurrent prostate cancer and no signs of metastasis, those with a luminal B subtype as stratified by the PAM50 gene signature had a 5-year biochemical progression-free survival (PFS) rate of 72% with added apalutamide versus 54% with placebo (HR 0.45, 95% CI 0.24-0.86, P=0.0062), reported Daniel Spratt, MD, of Case Western Reserve University in Cleveland, at the American Society for Radiation Oncologyopens in a new tab or window annual meeting.
In contrast, no benefit was observed among patients with a non-luminal B subtype, with nearly identical 5-year biochemical PFS rates between the apalutamide and placebo arms (70% vs 71%; HR 0.95, 80% CI 0.65-1.41, P=0.44).
Results were similar for metastasis-free survival (MFS). Among luminal B patients, the 5-year MFS rate was 95% with hormone therapy and 82% with placebo (HR 0.27, 95% CI 0.07-0.95, P=0.029), while no difference between groups was seen in the non-luminal B group (90% vs 89%; HR 1.06, 95% CI 0.41-2.78, P=0.90).
“PAM50 represents the first, and actually, only prospectively validated predictive biomarker to guide the use of hormone therapy in prostate cancer,” Spratt said.
Study discussant Karen Hoffman, MD, MPH, of the University of Texas MD Anderson Cancer Center in Houston, noted that “given the heterogeneity of prostate cancer, it is critical that we personalize therapy based on the individual biology of the cancer.”
“The PAM50 molecular subtype will be clinically available soon,” she added, “and then we’ll need to decide, do we take this information to clinic? How does this change our practice?”
This trial should impact how we give androgen deprivation therapy (ADT) to patients with a prostate-specific antigen (PSA) level less than 1.0 ng/mL after surgery, she said, adding that luminal B patients should receive ADT, while ADT should be considered selectively for non-luminal B patients.
As for the role PAM50 can potentially play in other disease settings, Hoffman said future work is needed to understand how it will perform in patients with recurrent prostate cancer and PSA levels over 1.0 ng/mL or those with nodal involvement, and those with localized prostate cancer or oligometastatic prostate cancer.
Study Rationale and Design
In explaining the rationale behind this trialopens in a new tab or window, Spratt noted that recurrence after radical prostatectomy for men with intermediate- and high-risk prostate cancer ranges from 40% to 80%.
“To improve outcomes for these patients, we typically deploy postoperative radiation, now using what is termed early secondary radiation that used to be called salvage radiation,” Spratt said. “This is now preferred over adjuvant radiation for most of these patients.”
While hormone therapy is also an option, it is “the number one driver of quality-of-life decline,” Spratt noted, and “we still have zero prospectively validated predictive biomarkers to guide hormone therapy across all of prostate cancer.”
Ten years ago, Spratt and his colleagues developed a novel luminal-basal classification system adapted from the PAM50 classifier that categorized breast cancer into luminal A, luminal B, HER2, and basal subtypes. As explained in a 2017 studyopens in a new tab or window, they hypothesized that since prostate and breast cancer are both hormonally driven tumors, the PAM50 algorithm could identify luminal- and basal-like subtypes of prostate cancer, and these subtypes would differ in prognosis and response to treatment.
The current trial enrolled men who underwent surgery with a PSA level of 0.1-1.0 ng/mL and without evidence of nodal or distant metastasis. The 295 eligible patients were randomized to receive a standard course of secondary radiation therapy with 6 months of either apalutamide or placebo.
The arms were well balanced, with a median age of 65 years; 50% had positive surgical margins, 51% had pathologic T3 disease, 86% had an entry PSA level of <0.5 ng/mL, and 43% had the luminal B subtype.
The study design involved first testing efficacy within the luminal B subtype (which was hypothesized to have greater benefit), followed by the evaluation of the non-luminal B group. If the lower limit of the 80% confidence interval for the hazard ratio in the placebo group was <0.77, the researchers would be unable to completely rule out a benefit in that population.
As for safety, there were more grade ≥3 adverse events observed in the apalutamide arm compared with the placebo arm (32% vs 23%), mainly driven by rash (5% vs 0%) and hypertension (13% vs 5%). Cardiac disorders and falls were rare in both arms.