ASCO 2019: Considerations for Systemic Therapy in Optimal Management of Oligometastatic Disease

Chicago, IL (UroToday.com) Prostate cancer commonly spreads through metastasis to metastasis seeding.1 It is important to remember that metastatic tumor cells can be genetically different from the primary tumor.1 Downregulation of androgen receptor in lymph node metastases vs. the primary tumor has been observed even in hormone-naïve castrate-resistant prostate cancer (CRPC) patients.2 A study by Haffner has shown that the lethal clone-causing metastasis appears to originate from the prostate itself.3 

Charles Ryan, MD, described the “1.439 billion cell rule,” as he has named it. According to this rule, this number manifests the “point of no return,” where oligometastasis becomes just “metastases.” This rule can be used as opposed to the crude determination of low vs. high volume disease, which is not biological. This number stems from a calculation made in a study by Amber E de Groot et al.4

Figure 1 –Calculation behind the 1.439 billion cell rule:


There are many studies showing the advantage of androgen deprivation therapy (ADT) plus radiotherapy, as the ADT is used for the treatment of the occult disease. ADT + radiotherapy has been shown to be better than radiotherapy alone in localized disease.5 It also enhances radiotherapy efficacy, and it is given as treatment in metastatic prostate cancer. If we can manage to successfully treat oligometastatic disease, we can postpone the time until long-term ADT is initiated, and we might be able to introduce intermittent instead of continuous ADT.

Next, Dr. Ryan discussed some of the systemic therapies which can potentially be used in the setting of oligometastatic disease. The first drug discussed was docetaxel. Low volume patients in the CHARRTED study did not show any overall survival benefit when treated with docetaxel. This observation was also shown in the GETUG AFU-15 study, comparing ADT+docetaxel to ADT alone.6 Next, abiraterone was discussed. This drug is most likely to be prescribed in a lower metastatic volume setting. However, the STAMPEDE6 data showed no overall survival advantage with abiraterone in low-risk metastatic patients.

The goals of therapy for the oligometastatic disease are to (Figure 2):
  1. Cure patients currently considered uncurable – ideally, the goal should be to have had a normal life expectancy on zero treatment. However, it will be enough to have a “functional” cure, which will delay disease progression and cancer-specific death
  2. To defer ADT initiation
  3. To prolong survival
Figure 2 - Goals of care in oligometastatic disease:


In summary, oligometastasis is a “new” clinical state, but not unique from a systemic therapy perspective. Combined therapy (e.g., with radiotherapy) may allow discontinuing systematic therapy or giving intermittent instead of continuous therapy. While Docetaxel is likely not beneficial in this setting, abiraterone, enzalutamide, apalutamide, and Darolutamide might be appropriate candidates, requiring further research.

Presented by: Charles J. Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, University of Minnesota, Minneapolis, MN 

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

References:
  1. Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015 Apr 16;520(7547):353-357. doi: 10.1038/nature14347. Epub 2015 Apr 1.
  2. Fleischmann A, Rocha C, Schobinger S,et al. Androgen receptors are differentially expressed in Gleason patterns of prostate cancer and down-regulated in matched lymph node metastases. Prostate. 2011 Apr;71(5):453-60. doi: 10.1002/pros.21259. Epub 2010 Sep 28
  3. Haffner MC, Mosbruger T, Esopi DM, et al. Tracking the clonal origin of lethal prostate cancer. J Clin Invest. 2013 Nov;123(11):4918-22. doi: 10.1172/JCI70354. Epub  2013 Oct 25.
  4. de Groot AE, Roy S, Brown JS, et al. Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis.Mol Cancer Res. 2017 Apr;15(4):361-370. doi: 10.1158/1541-7786.MCR-16-0436. Epub 2017 Feb 16.
  5. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002 Jul 13;360(9327):103-6.
  6. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017 Jul 27;377(4):338-351. doi: 10.1056/NEJMoa1702900. Epub 2017 Jun 3.