Local Therapy in Metastatic Prostate Cancer: Treating the Primary or Oligometastatic Sites. What's the Evidence?
By: Bogdana Schmidt, MD, MPH | Posted on: 01 Sep 2022
Annually in the United States 8% of men diagnosed with prostate cancer present with metastatic disease, for which 5-year survival is a disappointing 30%.1,2 Definition of oligometastatic disease is evolving as our imaging modalities become more sensitive at detecting sites of metastasis. Furthermore, the upper limit on the number of lesions defined as “oligo,” ranges from 3 to 5 and typically describes lymph node and bony metastasis. Staging with 68Ga-prostate-specific membrane antigen positron emission tomography/CT appears to show the highest detection rates of metastases compared to other imaging modalities.3 Although to date there are no randomized data demonstrating a better clinical outcome by using 68Ga-prostate-specific membrane antigen positron emission tomography/CT for oligometastatic disease, it can be assumed that the higher detection rate will allow more patients to be diagnosed earlier in the metastatic course. With a known stage migration effect, it is important to consider what goals of treatment we are seeking in these patients and what the role of therapy is.3
Conventionally, metastatic hormone sensitive prostate cancer is approached systemically with androgen-deprivation therapy (ADT) with or without chemotherapy or secondary androgen-receptor blockade—without local treatment to the primary tumor or metastasis-directed therapy (MDT). Trials evaluating the use of abiraterone + prednisone, enzalutamide, and, most recently, darolutamide in combination with ADT and docetaxel demonstrate improvement in overall survival (OS). However, these trials suggest greater benefit for higher volume metastatic disease and may indicate overtreatment in the oligometastatic setting.4 Accumulating evidence suggests that local treatment to the primary and MDT could delay disease progression and/or the need for systemic therapy, with a subsequent improvement in quality of life.
Numerous retrospective studies demonstrated an associated survival benefit in local therapy with radical prostatectomy (RP). Culp et al used the SEER (Surveillance, Epidemiology, and End Results) registry from 2004 to 2010 to assess cancer-specific mortality (CSM) in men who underwent local therapy, including RP or brachytherapy, compared with no local therapy. Men treated with RP had a 62% decreased risk of CSM (HR 0.38, 95% CI 0.27–0.53, p <0.001), and men who underwent brachytherapy had a 32% decreased risk (HR 0.68, 95% CI 0.49–0.93, p=0.018). RP was associated with decreased CSM across all metastasis stages.5 Satkunasivam et al compared intensity-modulated radiation therapy, conformal radiation therapy, and RP with patients who did not receive local treatment, demonstrating CSM HR 0.48 (95% CI 0.27–0.85, p = 0.01) for RP, HR 0.38 (95% CI 0.24–0.61, p <0.001) for intensity-modulated radiation therapy, and HR 0.85 (95% CI 0.64–1.14, p = 0.3) for conformal radiation therapy.6 While these retrospective studies suggest a benefit to prostatectomy, they lack granularity in systemic treatment data and consistency in radiation dosing, and carry the inherent selection bias of such registries.
Prospective surgical trials are challenging, but recently TRoMbone, a prospective, randomized, nonblinded trial demonstrated the feasibility and safety of addition of RP in newly diagnosed oligometastatic, locally resectable prostate cancer to ADT ± docetaxel chemotherapy compared to systemic therapy alone. They recruited 50 patients within 14 months and established that surgery was safe and had similar impact on early functional outcomes as surgery for men with localized disease.7 SWOG (Southwest Oncology Group) 1802 and SIMCAP (Surgery in Metastatic Carcinoma of Prostate) are ongoing randomized trials to prospectively evaluate the role of local treatment to the prostate. Radiotherapy to the prostate is another means of local treatment and has been evaluated by 2 prospective randomized trials, HORRAD and STAMPEDE. A meta-analysis of these trials showed the addition of prostate radiotherapy to ADT did not improve OS (HR 0.92, 95% CI 0.81–1.04, p = 0.195); however, a 7% improvement in 3-year OS was seen among men with fewer than 5 bony metastases (Table 1).8
Table 1. Role of local therapy (randomized trials)
|Study Name||Inclusion||Phase||Design||Participants||Primary Endpoint||NCT||Results|
|TRoMbone||M1b (≤ 3 mets)||Feasibility||RP-eLND + SOC vs SOC||51||Feasibility||ISRCTN 15704862||Feasible to randomize with acceptable short-term outcomes|
|SWOG 1802||M1||Phase 3||SOC vs SOC + definitive local (RP or RT)||1,273||OS||NCT03678025||Expected October 2031|
|SIMCAP||M1||Phase 2.5||SOC vs SOC + RP||190||FFS at 2 yrs, if phase 3, OS||NCT03456843||Expected September 2022|
|STAMPEDE (arm H)||M1||Phase 2 and phase 3||ADT and prostate RT vs ADT alone||1,032||OS||NCT 00246476||RT improved FFS (HR 0.76, 95% CI 0.68–0.84,
p <0.0001) not OS (HR 0.92, 95% CI 0.80–1.06
p = 0.266)
|HORRAD||M1b||Phase 2||ADT and prostate RT vs ADT alone||432||OS||SRCTN06890529||Median OS 45 mos (95% CI 40.4–49.6) in ADT + RT vs
43 mos (95% CI 32.6–53.4) in ADT alone (p = 0.4)
|eLND, extended lymph node dissection. FFS, failure-free survival. mets, metastases. RT, radiotherapy. SOC, standard of care. STAMPEDE, Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy. TRoMbone, Testing Radical prostatectomy in Men with prostate cancer and oligometastases to the Bone.|
Data from prospective trials exploring the role of MDT in the setting of oligometastatic prostate cancer patients are accumulating. The STOMP trial, a phase II, multicenter, randomized study of 62 patients who developed recurrence in 3 or fewer sites after primary treatment comparing MDT to all lesions (either metastasectomy or stereotactic body radiation therapy) vs surveillance alone demonstrated that patients receiving MDT experienced a longer ADT-free survival (21 vs 13 months), with 5-year ADT-free survival of 8% in patients under surveillance alone and 34% for the MDT arm (HR 0.57, 80% CI 0.38-0.84, log-rank p = 0.06). While suggesting benefit to MDT, STOMP was intended to inform additional phase 3 studies and was not powered to detect difference in survival.9 The ORIOLE trial, a phase II, multicenter, randomized study of 54 men with recurrent hormone-sensitive prostate cancer and 3 or fewer metastases detected by conventional imaging compared stereotactic ablative radiotherapy (SABR) vs surveillance. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing surveillance (p = 0.005). SABR improved median progression-free survival (not reached vs 5.8 months; HR 0.30, 95% CI 0.11-0.81, p = 0.002) (Table 2).10
Table 2. Role of MDT (randomized trials)
|Study Name||Inclusion||Phase||Design||Participants||Primary Endpoint||NCT||Results|
|STOMP||N1 + M1 ≤3 lesions by choline PET||Phase 2||Arm A: observation, arm B: SBRT or surgery to metastasis; ADT at progression||62||ADT-free survival||NCT01558427||Arm A: 13 mos vs arm B: 21 mos (HR 0.6, 80% CI: 0.40-0.90, p = 0.11). 5-yr ADT-free survival of 8% vs 34% (HR 0.57, 80% CI 0.38-0.84, p = 0.06)|
|ORIOLE||M1 ≤3 lesions||Phase 2||Observation vs SABR||54||PFS||NCT02680587||Progression at 6 mos 7/36 pts (19%) SABR vs 11/18 (61%) observation, (p = 0.005); SABR improved PFS, not reached vs 5.8 mos HR 0.3, 95% CI: 0.11-0.81, p = 0.002|
|ORIOLE, Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer. PET, positron emission tomography. PFS, progression-free survival. SBRT, stereotactic body radiation therapy. STOMP, Surveillance or metastasis-directed Therapy for Oligometastatic Prostate cancer recurrence.|
With improvement in imaging technologies, we are increasingly identifying men with oligometastatic prostate cancer as a distinct entity. Treatment for these patients remains controversial as our ability to target discrete sites of disease improves. Prior thinking that this is an early glimpse into a systemic disease where treatment of isolated lesions is futile is being contested by our ability to aggressively treat sites of metastasis. Numerous other cancers (breast, ovarian, colorectal, etc) are routinely managed with multimodal treatments directed at the primary site, sites of metastasis, and systemic chemo-/hormonal therapy, and this may become our new standard of care with prostate cancer. To best serve our patients, we should assess and treat them in a multidisciplinary setting including medical oncology, radiation oncology, and urologic oncology, and rely on prospective trials to guide our practice.
- Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33.
- Cancer of the Prostate—Cancer Stat Facts. SEER. Accessed July 8, 2022. https://seer.cancer.gov/statfacts/html/prost.html.
- Lancia A, Zilli T, Achard V, et al. Oligometastatic prostate cancer: the game is afoot. Cancer Treat Rev. 2019;73:84-90.
- Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142.
- Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol. 2014;65(6):1058-1066.
- Satkunasivam R, Kim AE, Desai M, et al. Radical prostatectomy or external beam radiation therapy vs no local therapy for survival benefit in metastatic prostate cancer: a SEER-Medicare analysis. J Urol. 2015;194(2):378-385.
- Sooriakumaran P, Wilson C, Rombach I, et al. Feasibility and safety of radical prostatectomy for oligo-metastatic prostate cancer: the Testing Radical prostatectomy in men with prostate cancer and oligo-Metastases to the Bone (TRoMbone) trial. BJU Int. 2022;130(1):43-53.
- Burdett S, Boevé LM, Ingleby FC, et al. Prostate radiotherapy for metastatic hormone-sensitive prostate cancer: a STOPCAP systematic review and meta-analysis. Eur Urol. 2019;76(1):115-124.
- Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018;36(5):446-453.
- Phillips R, Shi WY, Deek M, et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 2020;6(5):650-659.