AUA 2018: The PROSPER Trial: Chemotherapy-related Endpoints in Patients with Nonmetastatic Castration-resistant Prostate Cancer Treated with Enzalutamide

San Francisco, CA USA ( Earlier this year, at the 2018 GU ASCO conference, the results of two major clinical trials assessing androgen-targeted therapies (ART) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC or M0 CRPC) were released with much interest – with both demonstrating >70% metastasis-free surviva (MFS)l benefit, the results of both studies indicated a drastic shift in the medical management of advanced prostate cancer.

The results of PROSPER, the study in which patients were treated with enzalutamide, demonstrated a 22 month MFS benefit and a trend towards OS benefit (interim analysis). Importantly, there was also a 22 month benefit compared to placebo in terms of time to subsequent therapy (full results of the initial presentation) .

Historically, chemotherapy was the only management option for patients with metastatic or advanced prostate cancer. With the introduction of CHAARTED, docetaxel chemotherapy was available as an option for patients with de novo metastatic hormone-sensitive prostate cancer. However, to date, patients who have failed ART are recommended to proceed to chemotherapy, as there is less cross-resistance with its utilization.

In this abstract by the PROSPER trial collaborators, the focus shifts to chemotherapy related endpoints. Again, while the primary outcome of the original paper was MFS (metastases free survival), secondary outcomes included time to first use of new antineoplastic therapy, time to first use of cytotoxic chemotherapy, chemotherapy-free disease-specific survival (CFDS), chemotherapy-free survival (CFS) and safety.

The patients in both arms were well-balanced. Full inclusion criteria and patient stratification during randomization can be found on our initial coverage. A total of 1401 patients were randomized in a 2:1 Enza/placebo fashion.

Chemotherapy related secondary endpoints:
1. Time to first use of new antineoplastic therapy: HR 0.21; P < .0001 favoring ENZA
- This is time to any secondary treatment, not just chemotherapy!
- Median was not reached for the Enza arm. It was 39.7 months in the placebo arm.
2. Time to first use of cytotoxic chemotherapy: 39.6 vs. 38.9 months, HR 0.38; P < .0001 favoring ENZA
3. Chemotherapy-free disease-specific survival :HR 0.40; P < .0001 favoring ENZA
4. Chemotherapy-free survival: 38.1 vs. 34.0 months, HR 0.50; P < .0001, favoring ENZA

Overall, as described previously, the patients tolerated Enza very well – discontinuation rates were similar in both groups (10% Enza, 8% placebo).

While ENZA continues to outperform placebo in terms of preventing need for cytotoxic chemotherapy, which can have a significant impact on quality of life, it should be noted that even in patients on placebo, patients went ~40 months prior to needing chemotherapy. The absolute benefit was not as impressive as the MFS and OS benefit derived from early enzalutamide.

In the course of discussion, some important points were brought up:
1. Dr. Judd Moul, one of the moderators, commented on a statement first made during the initial ASCO presentation. There was a higher rate of deaths in the treated arm than in the placebo arm in the first 112 days from study cessation. Dr. Shore noted that this was a very small amount and did not represent a large clinical population. Additionally, while the absolute numbers seemed higher in the treatment arm, there was also a 2:1 randomization that should be accounted for!
2. Dr. Eric Small asked about the indication for chemotherapy. Dr. Shore noted, that as an international trial, the discretion to initiate secondary therapies, including chemotherapy, was at the discretion of treating physicians. As chemotherapy is more available than oral agents in most areas of the world, chemotherapy may have been initiated earlier in certain parts. Unfortunately, this cannot be controlled for on a study this scale!

Presenter(s): Neal Shore, MD

Co-Authors: Fred Saad, Maha Hussain, Karim Fizazi, Per Rathenborg, Eren Demirhan, Katharina Modelska, De Phung, Andrew Krivoshik, Cora N. Sternberg

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA

1. C Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. doi: 10.1056/NEJMoa1503747. Epub 2015 Aug 5.

WATCH: Changing the Standard of Care in the M0 CRPC Patient: PROSPER - A Conversation with Cora Sternberg
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