ESMO 2018: Improving Outcome by Optimizing Combination and Sequencing of Treatments

Munich, Germany ( There are currently four approved systemic therapies by biologic domain in advanced prostate cancer:

  1. Novel androgen signaling inhibition – abiraterone and enzalutamide
  2. Chemotherapy – docetaxel, cabazitaxel
  3. Immunotherapy – Sipuleucel T
  4. Bone-targeting agents – Radium 223

It is possible that we will see the emergence of fifth ”systemic” therapy, defined as the treatment of the primary tumor in the oligometastatic setting. This refers to the STAMPEDE trial assessing radiotherapy to the primary tumor in newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), recently presented in ESMO 2018, and published in the Lancet journal.1 Though not positive for unselected patients, this study did show positively clear results for a subset of patients with the low metastatic burden of disease.

Determining the efficacy of individual therapeutic agents will efficiently lead to their approval and may rank them in order of efficiency. However, it may not inform us about impactful sequences or combinations and strategy for their allocation over time to maximize benefits.

The challenges that are encountered nowadays include the fact that the patients which are treated in phase 3 randomized trials are selected by “crude” prognostic criteria. Furthermore, patients are treated in a strategy of “one size fits all” and therefore, the selection of therapy by objective criteria or predictors is not enabled. Lastly, the design of practice changing studies does not account for interactions between the various treatment domains, making sequencing empirical and combinations a concern.

In advanced prostate cancer, there is an enriched genomic alteration landscape, making it too late for treatment with androgen signaling inhibition, and for most targeting agents. This is in contrast to the very limited genetic landscape of localized prostate cancer. The increase in mutation frequency and copy number alterations that are associated with more advanced prostate cancer makes choosing treatment difficult.

Currently, there is no good evidence to support a difference in survival in metastatic hormone-sensitive prostate cancer (HSBC) if treated with abiraterone or docetaxel. In a study comparing docetaxel to abiraterone head to head in 566 mHSPC patients, no difference in overall survival was noted.2

It is important we understand that whether choosing one dug over the other is a matter of sequencing, or access, or both? The availability of the drug needs to be accounted for, its window of opportunity, and patient vulnerability and frailty. Can biology guide us in determining the appropriate sequence a priori? In any case, starting treatment earlier rather than later is probably advised.

There are currently many ongoing chemotherapy-based combinatorial trials with many different variations of combinations with the results eagerly awaited, even though many chemotherapy combination trials in the past were negative.

There are also trials that combine one of the new androgen receptor targeting agents with additional drugs. One such example is the ERA 223 trial, presented in ESMO 2018.3  In this trial, metastatic castrate-resistant prostate cancer (mCRPC) patients with the bone predominant metastatic disease were randomized to either abiraterone + prednisone + radium 223 or abiraterone + prednisone + placebo. The primary endpoint was symptomatic skeletal events free survival (SSE-FS). This was a negative trial demonstrating similar median SSE-FS of 22.3 months (95% CI 20.4−24.8) for abiraterone + prednisone + Radium 223, and 26 months (95% CI 21.8−28.3) with abiraterone + prednisone + placebo. Importantly, fractures occurred in 29% and 11% of patients treated with abiraterone + prednisone + Radium 223, and abiraterone + prednisone + placebo, respectively. Other studies analyzed and compared abiraterone + Olaparib (a PARP inhibitor) vs. abiraterone + placebo.4

Summarizing this discussion, Dr. Edstathiou reiterated that physicians need to make the most of the evolving data being published and adapt their practice accordingly. Patients must be monitored diligently, and their needs have to be respected.

Presented by: Eleni Efstathiou, MD, Ph.D., Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Houston, US

1. Parker CC et al. LANCET 2018
2. Sydes et al. Annals of Oncology 2018
3. Smith et al. ESMO 2018
4. Efstathiou et al. ASCO 2016

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany

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