Are More Indications for Local Therapy of Prostate Cancer on the Horizon?

We now know better than to treat everyone with low-risk prostate cancer with definitive local therapy.  But, we also know there is a clear benefit to radical prostatectomy over watchful waiting for those with high-risk disease who are healthy enough to benefit from such an intervention.1  Additionally, there is data from multiple randomized trials to show that adding androgen deprivation therapy (ADT) to definitive external beam radiation (EBRT) leads to a survival benefit.2, 3  Collectively, these data support the concept that both local and systemic therapy has the potential to offer benefit to patients who harbor biologically more aggressive disease.

More recently, there has been increasing data to show that these concepts may extend beyond localized prostate cancer to the metastatic hormone-sensitive disease state.  Intensification of systemic therapy by adding docetaxel4,5 or abiraterone acetate6, 7 to standard ADT has led to new accepted standards of care.  Additionally, the concept of cancer self-seeding8 lends theoretical support for ablation of the primary lesion even in the metastatic setting.  Multiple retrospective databases/registries have shown data linking control of the prostate cancer primary with longer overall survival.9, 10, 11  However, the question of local therapy for patients with metastatic prostate cancer remains yet incompletely answered from randomized, prospective trials. 

Recently, the HORRAD trial reported on the first randomized controlled trial to provide some data on the topic.12  In this trial, 432 patients with bone metastatic prostate cancer and prostate-specific antigen (PSA) level >20 ng/mL were randomized to ADT with EBRT vs. ADT alone.  The primary endpoint of overall survival was not significantly different (p=0.40) between arms; however, it is important to recognize that the median PSA level was 142 ng/mL and 67% of patients had >5 osseous metastases.  As a result, it may be reasonable to determine that primary EBRT for patients with very high PSA levels and higher volumes of bone metastatic prostate cancer is unlikely to offer a survival benefit.

This leaves the question open about the role of local therapy for patients with lower volumes of metastatic prostate cancer.  We recognize that there may be differences in clinical outcomes and that certain treatments may offer benefits in certain settings and not in others.  A perfect example is the clear overall survival benefit for docetaxel for patients in the metastatic prostate cancer subgroup of the STAMPEDE trial5 as well as the high-volume metastatic prostate cancer subgroup of the CHAARTED trial.13  On final analysis, it became very clear that there would not be a survival benefit from the low-volume metastatic disease subgroup from the CHAARTED trial, defined by the patient lacking visceral disease and harboring <4 osseous metastases or no bone metastasis in the appendicular skeleton.

Subsequently, the STAMPEDE trial just published data on a comparison between men who received ADT with 55 Gy of EBRT daily in 20 fractions over 4 weeks or 36 Gy of EBRT in 6 fractions weekly over 6 weeks vs. ADT alone.14  Although ADT with EBRT improved failure-free survival (HR 0.76, 95% CI 0.68-0.84; p<0.0001), it did not improve overall survival (HR 0.92, 95% CI 0.80-1.06; p=0.266) over ADT alone.  Interestingly, 40% of men in the trial had low-volume metastatic prostate cancer using the CHAARTED definition above.  For this low-volume disease subgroup, an overall survival improvement was seen in the patients who received ADT with EBRT compared to those with ADT control alone (HR 0.68, 95% CI 0.52-0.90; p=0.007).  The study could also be deemed a negative trial, although the results from the low-volume disease subgroup warrant further exploration and are worth discussion with select patients.

There are currently multiple ongoing trials attempting to determine the benefit of local therapy in patients with metastatic hormone-sensitive prostate cancer.  The PEACE-1 trial (NCT01957436) is a 4-arm randomized trial using ADT plus docetaxel as the control and is actively testing both the addition of local EBRT and also abiraterone acetate.  The SWOG 1802 (NCT03678025) trial has recently just opened to accrual.  This trial is unique in that it allows the investigator to choose any standard acceptable systemic therapy for either arm, any form of local therapy (e.g. radical prostatectomy, EBRT) for the definitive therapy arm and even oligometastatic-directed therapy is allowed for the definitive therapy arm.  Both of the above randomized, phase III trials are evaluating overall survival as the primary endpoint.  However, multiple other smaller trials are ongoing, with attached links below.

Ultimately, the concept of local prostate cancer ablation has much promise even in this presumed incurable metastatic disease population.  The data from the low-volume subgroup of patients in the STAMPEDE trial, who received EBRT, lends promise for the potential success of future trials of patients who meet select eligibility criteria.  If it is possible to garner benefit from EBRT in the low-volume subgroup in that trial, would we see even greater, definitive benefit if a trial focused on even lower-volume disease patients, used combinations of the most efficacious systemic therapies, treated the primary lesion with higher doses of radiation or definitive surgery and also addressed oligometastases with metastasis-directed therapy?  This topic will be discussed in a future article and will focus on the use of next-generation PET imaging, such as fluciclovine or prostate-specific membrane antigen (PSMA)-targeted radiotracer approaches, to identify oligometastases for directed ablation.

Local therapy trials for patients with metastatic hormone-sensitive prostate cancer that are actively accruing

  • Phase III PEACE–1: ADT + Docetaxel +/- Local EBRT +/- Abiraterone acetate (NCT01957436)
  • Phase III SWOG 1802: Standard systemic therapy +/- definitive local therapy (NCT03678025)
  • Phase II LoMP II: Cytoreductive prostatectomy vs. cytoreductive EBRT (NCT03655886)
  • CRADT: Cystoprostatectomy vs. EBRT combined with ADT for cT4 bladder invasive prostate cancer (NCT03482089)
  • Radical prostatectomy for very high-risk and oligometastatic prostate cancer (NCT02971358)
  • Phase II VA: Systemic and tumor-directed therapy for oligometastatic prostate cancer (NCT03298087

Written by: Evan Yu, MD

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