clinical topic updates

Update on Combinations and Therapeutic Sequencing in Advanced Prostate Cancer

by Oliver Sartor, MD

Overview

Efforts are under way to determine the optimal sequencing, layering, or combination of therapies to treat different groups of patients with advanced prostate cancer. Rational combination therapies have the potential to inhibit disease progression and improve clinical outcomes.

Expert Commentary

Oliver Sartor, MD

C. E. and Bernadine Laborde Professor of Cancer Research
Medical Director, Tulane Cancer Center
Assistant Dean for Oncology
Tulane University School of Medicine
New Orleans, LA

“We are in the midst of a paradigm shift in prostate cancer treatment, and these new studies of combination therapies have changed the way we view and approach advanced disease, including nmCRPC.” 

Oliver Sartor, MD

The recent changes in the treatment of prostate cancer have been quite dramatic. This evolution really began in 2015 with the success of upfront androgen deprivation therapy (ADT) plus docetaxel in patients with high-volume, metastatic hormone-sensitive prostate cancer (mHSPC). Another major advance occurred in this setting in 2017 with ADT plus abiraterone. Then, at the 2019 American Society of Clinical Oncology Annual Meeting, we had 2 more breakthrough studies in mHSPC reporting on the use of ADT plus enzalutamide and ADT plus apalutamide, both of which were strongly positive for overall survival benefits and a number of secondary end points. We also learned that the triplet regimen of enzalutamide plus ADT plus docetaxel was not really any better than ADT plus docetaxel alone. 

We have been working to change the natural history of castration-resistant prostate cancer (CRPC) over the last 10 to 15 years with treatments such as abiraterone, enzalutamide, cabazitaxel, docetaxel, radium-223, and sipuleucel-T. One of the most recent alterations to the treatment landscape involves assessing CRPC based on the presence or absence of metastatic disease on conventional imaging. In this context, castration resistance means that the prostate-specific antigen (PSA) is rising despite a castration level of testosterone. 

A series of trials in patients with nonmetastatic CRPC (nmCRPC) examining enzalutamide, apalutamide, and darolutamide—all 3 of which now have US Food and Drug Administration approval—have shown that the time to metastases was substantially prolonged within the group of patients with nmCRPC and a PSA doubling time of 10 months or less. I think that all of these trials will show survival benefits with subsequent additional follow-up. Shorter time to metastasis is a surrogate for a number of poor outcomes, including decreased survival. With the approval of these 3 agents in the nonmetastatic space, the question now becomes: When should clinicians use them? I envision that they will be used in patients with more rapid PSA progression. Each agent is fairly well tolerated; apalutamide has some reports of rash and hypothyroidism and enzalutamide has some reports of fatigue. The darolutamide trials look quite good in terms of side effects, but we know that, with clinical experience, there may be adverse events that are not appreciated initially. 

In summary, we are in the midst of a paradigm shift in prostate cancer treatment, and these new studies of combination therapies have changed the way we view and approach advanced disease, including nmCRPC.

References

American Urological Association. Castration-Resistant Prostate Cancer (2018). https://www.auanet.org/guidelines/prostate-cancer-castration-resistant-guideline. Accessed August 7, 2019.

Chi KN, Agarwal N, Bjartell A, et al. First results from TITAN: a phase III double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT). Abstract presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 5006.

Crawford ED, Petrylak DP, Shore N, et al; Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR II) Group. The role of therapeutic layering in optimizing treatment for patients with castration-resistant prostate cancer (Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II). Urology. 2017;104:150-159. 

Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.

Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352-360.

Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474.

James ND, Sydes MR, Clarke NW, et al; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177. 

Kim W, Ryan CJ. Quo vadis: advanced prostate cancer-clinical care and clinical research in the era of multiple androgen receptor-directed therapies. Cancer. 2015;121(3):361-371. 

Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746.

Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. Abstract presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract LBA2. 

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