Management of hormone-naïve oligometastatic prostate cancer

Case presentation

A 64-year-old healthy man was found to have a prostate-specific antigen (PSA) level of 5.7 ng/mL, and prostate biopsy demonstrated grade group 3 prostate adenocarcinoma. Staging imaging with magnetic resonance imaging (MRI) and bone scan were negative, and he had a robot-assisted laparoscopic radical prostatectomy with pathology notable for pT3aN0R0 grade group 4 disease. His PSA was initially undetectable, and 18 months postoperatively became elevated to 1.8 ng/mL, confirmed on subsequent measurement. MRI of the abdomen and pelvis was negative. However, an F-fluciclovine positron emission tomography (PET) showed a solitary bone metastasis in his right fourth rib.

Introduction

The mainstay of treatment for metastatic prostate cancer has historically been lifelong androgen deprivation therapy (ADT). For men with newly diagnosed metastatic disease treated with ADT, the median time to castrate resistance is 11.7 months and median overall survival is 47.2 months.¹ However, newly diagnosed metastatic prostate cancer is heterogeneous, with different natural histories dependent upon disease characteristics. For instance, patients with lymph node–only metastases have significantly better survival compared with those who have bony or visceral metastases.² And men with low-volume metastasis have a more favorable prognosis, with a longer time to development of castrate resistance, compared with patients with high-volume metastasis.³

The concept of oligometastatic disease was first proposed by Hellman and Weichselbaum, who proposed that patients did not all fall into binary categories of either locally confined disease or widespread metastasis.⁴ They suggested that some patients have a distinct low-volume oligometastatic state that may require unique treatment strategies with the potential for cure. Several new findings are changing the treatment paradigm for low-volume metastatic prostate cancer, specifically regarding the role of treatment of the primary tumor, use of metastasis-directed therapy (MDT), and benefit of more sensitive imaging modalities. As 42% to 74% of patients with recurrent or newly diagnosed metastatic prostate cancer present in an oligometastatic state, these advances are potentially relevant to a significant number of men.^3,5

Local tumor control

Local tumor control has been widely studied as a means of improving the prognosis of metastatic cancer. Urologists are familiar with cytoreductive nephrectomy for metastatic renal cell carcinoma, which was associated with improved survival during the cytokine era and is still being studied today.^6,7 The theory behind local tumor control is that proliferation of cells at distant metastatic sites may be dependent on compounds secreted by the primary tumor; thus, controlling the primary tumor may help control distant metastatic disease (the abscopal effect).⁸ Emerging evidence now supports a role for radiation therapy (XRT) to the prostate for men with metastatic disease.

The HORRAD trial randomized 432 men with metastatic castration-sensitive prostate cancer (mCSPC) to ADT vs ADT and prostate XRT.⁹ Though no overall survival benefit was observed, there was a trend toward improved survival in patients with fewer than 5 metastatic lesions (HR 0.68, 0.42-1.10). Subsequently, the STAMPEDE trial (NCT00268476) randomly assigned men with mCSPC to systemic therapy alone vs systemic therapy with XRT to the prostate.⁵ Among 2061 patients and a median follow-up of 37 months, there was no improvement in overall survival with XRT (HR 0.92, P = .266). However, there were improvements in overall survival (HR 0.68, 95% CI, 0.52-0.90; P = .007) and failure-free survival (HR 0.59; 95% CI, 0.49-0.72; P < .0001), defined as the absence of biochemical failure, progression locally or distantly, or death from prostate cancer, in the prespecified subgroup of patients with low-volume metastasis. Per the CHAARTED trial (NCT00309985), high metastatic burden was defined as 4 or more bone metastases with 1 or more outside the vertebral bodies or pelvis, or visceral metastasis, or both; and all others were defined as low metastatic burden.¹⁰

Another analysis of STAMPEDE demonstrated an improvement in failure free survival (adjusted HR 0.48; 95% CI, 0.29-0.79) with prostate radiation specifically among the 177 patients with non-metastatic but lymph node positive prostate cancer.² These data suggest a benefit of prostate XRT to patients with newly diagnosed low-volume metastasis or nonmetastatic but lymph node–positive disease. 

The current European Association of Urology (EAU) Prostate Cancer Guidelines recommend offering prostate radiation in addition to ADT to patients with low-volume metastatic disease.¹¹ The current National Comprehensive Cancer Network (NCCN) Prostate Cancer Guidelines note that prostate radiation to men with low-volume metastatic disease is an option, but do not recommend it for men with high-volume metastasis.¹²

Metastasis directed therapy

In line with Hellman and Weichselbaum’s predictions, several trials have demonstrated a benefit to radiation to metastatic sites. The STOMP trial (NCT01558427) randomized men with biochemical recurrence after primary prostate cancer treatment and 3 or fewer extracranial metastasis on choline PET-CT to surveillance or MDT with either stereotactic body radiotherapy (SBRT) or metastatectomy.¹³ The primary outcome was ADT-free survival. Among 62 men with hormone naïve metastatic prostate cancer who were randomized, those who received MDT had a longer ADT-free survival (21 months vs 13 months, HR 0.60), although this finding was not statistically significant (log-rank, P = .11).

The SABR trial (NCT01446744) was a prospective, single-arm phase 2 study that investigated stereotactic radiation to bony metastatic sites or lymph nodes among patients with 33 oligometastatic hormone-naïve prostate cancer, with no more than 3 metastases per patient.¹⁴ Patients received a single dose of 20 Gy radiation to each metastatic site, and the primary end point was progression-free survival (PFS). At 2 years, local and distant PFS were 93% and 39%, respectively. Importantly, 2-year freedom from ADT was 48% and the treatment was well tolerated.

The ORIOLE trial (NCT02680587) was a prospective, randomized control trial examining the use of SBRT to metastatic sites among men with oligometastatic hormone naïve prostate cancer, with 1 to 3 metastases diagnosed on conventional imaging.¹⁵ The primary outcome was PFS at 6 months, as determined by PSA, imaging findings, symptomatic events, initiation of ADT, or death. Among 54 men randomized to observation or SBRT, at 6 months 61% of controls experienced progression whereas only 19% of the treatment group progressed (P = .005).

Lastly, SABR-COMET was a prospective randomized phase 2 trial that investigated the use of standard-of-care systemic therapy with or without SBRT for patients with oligometastatic cancer, defined as less than 5 metastases, across multiple histologies.¹⁶ Among 99 patients, of whom 16 had prostate cancer, SBRT improved 5-year OS (42.3% vs 17.7%, P = .006) and PFS (17.3% vs 0%, P = .001). Although larger trial results are ongoing, these early trials suggest that MDT can delay the use of ADT for men with oligometastatic prostate cancer and there may also be a survival advantage.

The current NCCN Prostate Cancer Guidelines suggest consideration of SBRT for patients with oligometastatic disease in order to improve PFS.¹² The EAU Prostate Cancer Guidelines acknowledge the current evidence on MDT for men with oligometastatic disease, but state that MDT should be offered only within a clinical trial.¹¹

Imaging

The evidence supporting MDT for men with oligometastatic prostate cancer is particularly relevant given advances in imaging, which are more sensitive for detecting metastatic sites. A recent randomized trial investigated the accuracy of gallium-68 prostate specific membrane antigen (PSMA)-11 PET-CT compared with traditional CT and bone scan imaging in high-risk prostate cancer patients (PSA > 20 ng/dL, ISUP GG3-5 disease, or cT3 disease).¹⁷ Among 302 men, 30% were found to have nodal or distant metastases. PSMA PET had 27% greater accuracy for the diagnosis of metastatic lesions (92% vs 65%, P < .0001) and demonstrated superior sensitivity (85% vs 38%) and specificity (98% vs 91%). As more sensitive imaging techniques are used, an increasing number of men with low-volume metastatic disease will undoubtedly be identified.

Furthermore, in the ORIOLE trial, patients with oligometastatic prostate cancer who had PSMA-PET avid lesions that were treated with SBRT had significantly improved PFS compared with patients with untreated PSAM-PET lesions.¹⁵ Therefore, more sensitive imaging techniques will not only increase the number of patients potentially eligible for MDT, but may also help MDT be more effective. 

Conclusions

There is growing evidence supporting the existence of an intermediate metastatic disease state that lies between organ-confined disease and high-volume metastasis. Metastatic prostate cancer commonly presents with a low-volume burden of disease, for which upfront systemic therapy alone may no longer be adequate or necessary. As the prevalence of oligometastatic prostate cancer increases secondary to the use of more sensitive imaging modalities, further investigation into the treatment of the primary tumor, role of MDT, and other novel treatments, are required.

Smigelski is a chief resident, Chung is a resident, and Anderson is an assistant professor of urology at NewYork-Presbyterian/Columbia University Irving Medical Center, New York, New York.