UCLA-led research has shown that adding hormone therapy to postoperative radiotherapy (PORT) does not improve survival for most men who have undergone surgery for prostate cancer but may benefit those with a high postoperative prostate specific antigen (PSA) level.
The results of the POSEIDON study, a meta-analysis of individual patient data, are published The Lancet and were presented by first author Amar Kishan, professor and executive vice chair of radiation oncology at the David Geffen School of Medicine at UCLA, during the plenary session of the American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco.
He explained that although hormone therapy has been shown to improve outcomes when combined with radiotherapy in men whose prostates are still intact, it is unclear whether it has a similar benefit for men who need radiotherapy for recurrence after radical prostatectomy.
“Our findings show that for most men with detectable but low PSA levels (<0.5 ng/mL), after surgery to remove the prostate, post-operative radiotherapy is highly effective on its own,” said Kishan. “By safely omitting hormone therapy in these patients, we can potentially spare them months of treatment that may substantially affect their quality of life without extending survival.”
The study included data for 6057 men with prostate cancer who participated in six randomized Phase III clinical trials comparing PORT alone to PORT combined with either short-term (4–6 months) or long-term (24 months) hormone therapy.
Kishan and colleagues report that after a median nine years of follow-up, there were no significant difference in overall survival (OS) between the men who received PORT alone and those who were also given hormone therapy. The estimated 10-year OS rates were 83.6% and 84.3%.
When stratified by pre-PORT PSA level, there was still no significant difference between the two treatment strategies for men with PSA levels up to 0.50 ng/mL.
However, for those with a PSA of 0.51–1.00 ng/mL, the 10-year OS rate was significantly lower for the men who did not receive hormone therapy relative to those who did, at 76.4% versus 80.9%. There was also a significant difference for men with a PSA level above 1.00 ng/mL, at 72.4% and 80.5%, respectively.
Kishan told Inside Precision Medicine that there are two possible reasons why the benefit of hormone therapy only appears at higher PSA levels.
“First, at a higher PSA, there is a greater bulk of cancer present (by definition, PSA is proportional to tumor burden). If the cancer is still confined to the prostate bed, then the radiosensitizing effect of the added hormone therapy may make radiation more effective at killing a larger number of tumor cells.
“Second, patients with higher PSAs may also be those who are likely to have disease outside the prostate bed as well. The added hormone therapy would suppress (but not kill) disease outside the radiation target, and even if it’s not a permanent effect, that might help drive an observed benefit.”
He also notes that “any PSA above 0.5 ng/mL would be considered late salvage radiotherapy. Hopefully patients are being referred at lower PSAs; in my practice, at least 85-90% are seen with a PSA ≤0.5 ng/mL.”
For the general patient with a PSA level of 0.5 ng/mL or lower, Kishan believes that the study provides evidence to shift standard practice toward radiotherapy alone but he cautions that “there may be selected patients with multiple high risk features, or a rapid PSA doubling time, or perhaps a very young patient, in whom we might have a discussion about the pros and cons.”
The study also examined the duration of hormone therapy. Short-term therapy did not improve OS, though it slightly reduced the risk for metastases. Long-term therapy showed a small survival benefit, particularly for men with higher PSA levels (>1.6 ng/mL) after prostatectomy. However, the team’s statistical analysis demonstrated that extending short-term therapy to long-term therapy did not further improve survival, although it did modestly lower the risk of metastasis.
Although PSA levels can guide treatment decisions, Kishan and co-authors say that there is a still an unmet need to identify biomarkers to predict potential hormone therapy benefit.
“There were promising data presented at the ASTRO conference from the NRG GU-006 BALANCE trial, which suggested the PAM50 classifier may be predictive,” said Kishan. “PAM50 divides prostate cancer into Luminal A, Luminal B, and Basal subtypes based on gene expression. Luminal B tumors exhibit high androgen receptor activity and poor prognosis.”
In addition, Kishan and colleagues are planning an analysis of their randomized trial of Prostate-Specific Membrane Antigen measurement before salvage radiotherapy, which is the largest trial to date looking at the utility of an imaging biomarker to help with salvage radiation.
