The Oligometastatic-Directed Therapy Trend in Prostate Cancer: Are We Being Precocious or Premature?

The identification of oligometastatic prostate cancer is becoming more feasible due to improved imaging technologies. For example, 11C-choline PET/CT imaging has approximately 50% sensitivity for detection at a prostate-specific antigen (PSA) level of 1.5-2.0 ng/mL.1 However, 11C-choline PET/CT imaging is not widely available, as it requires an on-site cyclotron for production. Prostate-specific membrane antigen (PSMA) small molecules tagged with either 68Gallium or 18Fluoride are also highly sensitive with detection felt to begin at PSA levels of 0.2-0.5 ng/mL.2-4  PSMA PET imaging is also not yet widely available. Fluciclovine PET/CT imaging was recently approved by the United States Food and Drug Administration (FDA) for the detection of recurrent prostate cancer. Fluciclovine PET/CT carries the ability to detect prostate cancer starting at a level of around 0.5 ng/mL,5-10 and it is becoming widely available for use. 



Early detection of oligometastatic prostate cancer may lend feasibility to metastasis-directed therapy with the goal of achieving improved clinical outcomes.  The recent identification of metastasis to metastasis expansion of disease lends credence to this treatment paradigm.11 Still theoretical, one can hypothesize that the acquisition of new and potentially dangerous mutations in malignant clones might be decreased with oligometastatic-directed therapy, and eradication of systemic therapy-resistant clones could lead to improved overall patient outcomes. There is even a glimmer of hope that unique patients with early metastatic disease, initially presumed to only be “micro-metastatic” in nature, possibly could be cured with metastasis-directed therapy.

Fortunately, the field is starting to accumulate some early clinical trial experiences to help bolster support for larger efforts that could provide more validated and clinically-significant endpoints. A recently published randomized Phase II trial, termed the ORIOLE12 trial, utilized conventional imaging and identified one to three metastases in 54 men with recurrent hormone-sensitive prostate cancer. The patients were randomized in a 2:1 ratio to receive stereotactic ablative radiation (SABR) or observation. The primary outcome measure of PSA progression at six months occurred in 7/36 (19%) randomized to SABR vs. 11/18 (61%) randomized to observation (p=0.005). Median progression-free survival was also improved with SABR (NR vs. 5.8 months; hazard ratio [HR] 0.30; 95% confidence interval [CI], 0.11-0.81; p=0.002). Impressively, there were no significant grade 3 or greater toxicities noted.

Another randomized control trial, termed STOMP,13 administered metastasis-directed therapy for presumed biochemically-recurrent prostate cancer patients subsequently found to have three or fewer metastases on 11C-choline PET/CT imaging. The primary endpoint of androgen deprivation therapy (ADT)-free survival was triggered by the initiation of ADT, defined by symptomatic progression, progression to ≥3 metastases and/or local progression of a known metastasis. The radiographic progression events could be determined by 11C-choline PET/CT imaging. Eligible patients were randomized to observation vs. metastasis-directed therapy with a strong trend in favor of ADT-free survival for those receiving metastasis-directed therapy. Median ADT-free survival was 13 vs. 21 months (p=0.11) for those receiving observation vs. oligometastasis-directed therapy. Additionally, biochemical recurrence-free survival was significantly improved for those receiving metastasis-directed therapy with HR 0.53 (95% CI 0.30-0.94; p=0.03). Even without proven long-term benefit from metastasis-directed therapy, the data from the STOMP trial serves as a welcome reference for the patient who is conscientious about deferring the potential side effects of ADT.

With the increasing use of “next-generation PET imaging” technologies, it is important to understand the benefits and risks of tailored therapy in response to findings on these scans. Efficacy, safety, and quality of life, not of the PET imaging modality itself, but of the downstream site-directed and systemic therapeutics used in response to imaging findings, need to be determined. Although patients and physicians have already embarked on treating people in this fashion, at this time we have only early hints of benefit and no data proving definitive long-term gains for our patients. Rolling out metastasis-directed therapy as a conclusive standard of care would be premature at this point in time. As a field, we need to accrue aggressively to well-designed prospective clinical trials to decisively prove this concept of oligometastatic-directed therapies as valuable for our patients.

Oligometastatic-directed therapy trials for patients with prostate cancer:

  • Randomized Phase 3: Metastasis directed radiotherapy +/- ADT identified by PSMA PET (ADOPT) (NCT04302454)
  • Metastasis-directed therapy in castration-refractory prostate cancer (MEDCARE) (NCT04222634)
  • Phase 2: Metastasis directed therapy with ADT and abiraterone acetate for fluciclovine PET/CT identified oligometastases (FLU-BLAST-PC) (NCT04175431)
  • Phase 2: SBRT with ADT, abiraterone and apalutamide for PSMA PET detected metastases (NCT03902951)
  • Randomized Phase 2: SBRT with or without durvalumab (POSTCARD) (NCT03795207)
  • Randomized Phase 3 SWOG 1802: Standard systemic therapy +/- definitive local therapy with optional oligometastatic directed therapy as detected by conventional imaging (NCT03678025)
  • Randomized Phase 2: Metastasis directed therapy +/- whole pelvic radiation for oligorecurrent prostate cancer identified by choline or PSMA PET (STORM) (NCT03569241)
  • Randomized Phase 2: Abiraterone +/- SBRT for oligometastatic castration-resistant prostate cancer (ARTO)(NCT03449719)
  • Phase 2: Newly diagnosed oligometastatic prostate cancer treated with radical prostatectomy, metastasis-directed SBRT, ADT, abiraterone and apalutamide (NCT03298087)
  • Salvage lymph node dissection of PSMA PET identified prostate cancer with recurrence after radical prostatectomy (NCT02974075)

Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine, Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center

References:

1. Giovacchini, Giampiero, Maria Picchio, Elisa Coradeschi, Valentino Bettinardi, Luigi Gianolli, Vincenzo Scattoni, Cesare Cozzarini et al. "Predictive factors of [11 C] choline PET/CT in patients with biochemical failure after radical prostatectomy." European journal of nuclear medicine and molecular imaging 37, no. 2 (2010): 301-309.

2. Afshar-Oromieh, A., Uwe Haberkorn, M. Eder, Michael Eisenhut, and C. M. Zechmann. "[68 Ga] Gallium-labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18 F-FECH." European journal of nuclear medicine and molecular imaging 39, no. 6 (2012): 1085-1086.

3. Eiber, Matthias, Tobias Maurer, Michael Souvatzoglou, Ambros J. Beer, Alexander Ruffani, Bernhard Haller, Frank-Philipp Graner et al. "Evaluation of hybrid 68Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy." Journal of nuclear medicine 56, no. 5 (2015): 668-674.

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5. Savir-Baruch, Bital, Lucia Zanoni, and David M. Schuster. "Imaging of prostate cancer using fluciclovine." PET clinics 12, no. 2 (2017): 145-157.

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7. Odewole, Oluwaseun A., Funmilayo I. Tade, Peter T. Nieh, Bital Savir-Baruch, Ashesh B. Jani, Viraj A. Master, Peter J. Rossi et al. "Recurrent prostate cancer detection with anti-3-[18 F] FACBC PET/CT: comparison with CT." European journal of nuclear medicine and molecular imaging 43, no. 10 (2016): 1773-1783.

8. Nanni, Cristina, Lucia Zanoni, Cristian Pultrone, Riccardo Schiavina, Eugenio Brunocilla, Filippo Lodi, Claudio Malizia et al. "18 F-FACBC (anti1-amino-3-18 F-fluorocyclobutane-1-carboxylic acid) versus 11 C-choline PET/CT in prostate cancer relapse: results of a prospective trial." European journal of nuclear medicine and molecular imaging 43, no. 9 (2016): 1601-1610.

9. Nanni, Cristina, Riccardo Schiavina, Eugenio Brunocilla, Stefano Boschi, Marco Borghesi, Lucia Zanoni, Cinzia Pettinato, Giuseppe Martorana, and Stefano Fanti. "18F-fluciclovine PET/CT for the detection of prostate cancer relapse: a comparison to 11C-choline PET/CT." Clinical nuclear medicine 40, no. 8 (2015): e386-e391.

10. Ren, Jingyun, Leilei Yuan, Guanghua Wen, and Jigang Yang. "The value of anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PET/CT in the diagnosis of recurrent prostate carcinoma: a meta-analysis." Acta radiologica 57, no. 4 (2016): 487-493.

11. Gundem, Gunes, Peter Van Loo, Barbara Kremeyer, Ludmil B. Alexandrov, Jose MC Tubio, Elli Papaemmanuil, Daniel S. Brewer et al. "The evolutionary history of lethal metastatic prostate cancer." Nature 520, no. 7547 (2015): 353-357.

12. Phillips, Ryan, William Yue Shi, Matthew Deek, Noura Radwan, Su Jin Lim, Emmanuel S. Antonarakis, Steven P. Rowe et al. "Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial." JAMA oncology (2020).

13. Ost P, Reynders D, Decaestecker K, et al. "Surveillance or metastasis-directed therapy for oligometastastic prostate cancer recurrence: A prospective, randomized, multicenter phase II trial." J Clin Oncol 36 (2018): 446-53.