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•This systematic review characterized the comparative efficacy of combination approaches in men with hormone-sensitive metastatic prostate cancer. In all, seven trials met eligibility criteria using either docetaxel, abiraterone acetate, enzalutamide, or apalutamide in combination with ADT. All agents, in combination with ADT, were shown to be superior to ADT alone; enzalutamide + ADT had the lowest absolute hazard ratio compared with ADT only. Enzalutamide appeared to be associated with better overall survival compared with docetaxel in men with low-volume disease, but there was no difference in other comparisons.
•The authors concluded that combination therapy with any of docetaxel, abiraterone acetate, enzalutamide, or apalutamide provides a significant overall survival benefit when compared with ADT alone.
– Gautam Jayram, MD
Urology
Written by Fred Saad MD, FRCS
For over 70 years, androgen deprivation therapy (ADT) has been the standard of care for metastatic castration-sensitive prostate cancer (mCSPC). Over time, almost all will progress to a metastatic castration-resistant prostate cancer (mCRPC) state and eventually die of the disease. Several new agents have enabled men with mCRPC to live longer with a better quality of life; however, the improvements in outcomes have been relatively modest. The addition of some of these agents to ADT in the setting of metastatic hormone-sensitive prostate cancer has resulted in significantly improved outcomes. This meta-analysis confirms that all the combinations are better than ADT alone in mCSPC.
Should everyone be treated? I believe and agree with the authors that all patients with high-risk and/or high-volume mCSPC should be offered immediate additional therapy with ADT. However, for low-burden metastatic disease, the hormonally based therapies appear to be the preferred option and some patients may not need lifelong combination therapy. Personalizing the approach for these patients will be our next challenge. Until then, options may include sequential treatment in patients who rapidly achieve undetectable serum PSA levels with ADT plus local therapy. The other choice may be an intensive approach for all of these patients, with treatment discontinuation after 2 to 3 years of treatment in patients having a complete response. We may actually revisit the intermittent approach for mCSPC using optimal combination therapy. Given the efficacy and long survivals that can be achieved, we will actually need to start considering life expectancy when treating low-volume/low-risk mCSPC. One thing is certain—these advances are pushing the field forward and this is great news for our patients.
CONTEXT
There have been substantial changes in the management of men with metastatic hormone-sensitive prostate cancer (mHSPC) over the past 5 yr, with upfront combination therapies replacing androgen-deprivation therapy (ADT) alone. A range of therapies have entered the space with no clear answer regarding their comparative efficacy.
OBJECTIVE
To perform a systematic review and network meta-analysis to characterise the comparative efficacy of combination approaches in men with mHSPC.
EVIDENCE ACQUISITION
We searched multiple databases and abstracts of major meetings up to June 2019 for randomised trials of patients receiving first-line therapy for metastatic disease, a combination of ADT and one (or more) of taxane-based chemotherapy, and androgen receptor-targeted therapies. The primary endpoint was overall survival (OS) and we evaluated progression-free survival as a secondary outcome. We performed subgroup analysis based on the volume of disease.
EVIDENCE SYNTHESIS
We found seven trials that met our eligibility criteria using either docetaxel, abiraterone acetate, enzalutamide, or apalutamide in combination with ADT. All agents in combination with ADT were shown to be superior to ADT alone; enzalutamide + ADT had the lowest absolute hazard ratio compared with ADT only (hazards ratio 0.53, 95% confidence interval 0.37-0.75), and an estimated 76.9% probability that it is the preferred treatment to prolong OS compared with other combination treatments, or with ADT alone. Enzalutamide appeared to have better OS compared with docetaxel in men with low-volume disease, but there was no difference in other comparisons.
CONCLUSIONS
Combination therapy with any of docetaxel, abiraterone acetate, enzalutamide, or apalutamide provides a significant OS benefit when compared with ADT alone. We did not identify significant differences in OS between different combination therapies. Subtle differences between these options provide clinicians considerable flexibility when selecting options for individual patients.
PATIENT SUMMARY
Many men with metastatic, hormone-sensitive prostate cancer should be managed with upfront combination therapy instead of androgen-deprivation therapy alone. Clinicians may consider many factors during the decision-making process, and thus management should be tailored for patients individually.
European Association of Urology
Indirect Comparisons of Efficacy Between Combination Approaches in Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review and Network Meta-Analysis
Eur Urol 2019 Oct 31;[EPub Ahead of Print], NJ Sathianathen, S Koschel, IA Thangasamy, J Teh, O Alghazo, G Butcher, H Howard, J Kapoor, N Lawrentschuk, S Siva, A Azad, B Tran, D Bolton, DG Murphy
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.