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Two Studies Question the Role of Continuous LHRH Antagonists in Metastatic Castration‑Resistant Prostate Cancer


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In the field of prostate cancer, the use of androgen-deprivation therapy (ADT) in men with metastatic castration-resistant prostate cancer is received wisdom. When experts are asked why ADT is continued once the disease has figured out how to evade hormone suppression, the answer invariably is based on an older meta-analysis, and all the trials of newer agents in metastatic castration-resistant prostate cancer have been conducted with patients on a background ADT in the form of an luteinizing hormone-releasing hormone (LHRH) antagonist. Thus, men with this type of cancer are currently consigned to lifelong ADT if they are treated according to the standard of care.

However, two new (albeit small) studies presented at the 2019 ASCO Annual Meeting challenge this assumption.1,2 In both studies, men with metastatic castration-resistant prostate cancer on more potent suppression with abiraterone acetate plus prednisone were studied without the background LHRH antagonists. Taken together, both studies suggest that withholding ADT (in these studies, LHRH antagonists) in this setting does not compromise outcomes. Further, experts interviewed for this article agree that this approach should be studied with the newer hormonal agents, such as enzalutamide, apalutamide, and darolutamide, not just with abiraterone acetate.

ANDROGEN-DEPRIVATION THERAPY IN PROSTATE CANCER

  • Based on the findings of two studies (one prospective and the other retrospective), androgen-deprivation therapy (ADT) may not be necessary along with potent new drugs for men with metastatic castration-resistant prostate cancer.
  • Larger prospective trials are needed to test this hypothesis.
  • If ADT were withheld in this setting, savings could amount to more than $332 million to the health-care system annually.

Prospective Study

The first study was a prospective, exploratory phase II trial that enrolled 67 patents with asymptomatic or mildly symptomatic treatment-naive metastatic castration-resistant prostate cancer.1 These patients were randomly assigned 1:1 to receive abiraterone acetate and prednisone plus ADT with luteinizing hormone-releasing hormone (LHRH) therapy vs abiraterone acetate plus prednisone with no ADT.

“Abiraterone acetate is a more potent suppressor of testosterone than ADT. We have had several patients who did not want to continue ADT while on abiraterone, and we found that abiraterone acetate plus prednisone was equally effective. Unfortunately, the labeling requires us to continue ADT,” said lead author Carsten H. Ohlmann, MD, of Malteser Hospital, Bonn/Rhein-Sieg, Germany. “We wanted to explore whether you could stop ADT without compromising outcomes. And to my mind, our study challenges the practice of using continuous ADT. It is a small trial not powered for the endpoints, but we have seen no difference in efficacy between the two treatment arms.”


“We wanted to explore whether you could stop ADT without compromising the outcome. And to my mind, our study challenges the practice of using continuous ADT.”
— Carsten H. Ohlmann, MD

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At a median follow-up of 14.9 months, decline in prostate-specific antigen (PSA) level of 50% or more was achieved in 23 of 34 patients (67%) on the ADT-continuing arm vs 24 of 33 patients (72.7%) on the experimental arm. The median serum testosterone level at the end of treatment was exactly the same on both arms: 0.029 ng/mL. The median treatment duration was 266 days on the ADT-continuing arm vs 420 days on the experimental arm. The time to PSA progression was numerically longer on the experimental arm: median of 288 days vs 336 days, respectively. At month 12, the rate of radiographic progression-free survival did not significantly differ between the arms: 0.90 in the ADT-containing arm vs 0.78 in the experimental arm.

Almost all patients had at least one adverse event. Adverse events did not significantly differ between the two treatment arms.

“The main advantages of withholding ADT include less treatment, lower cost, and the ability to control the effects of abiraterone plus prednisone better,” Dr. Ohlmann explained.

“Expected survival in this group of patients is 30 to 36 months. We will follow these patients to determine their outcomes. We are also thinking about studying this approach with enzalutamide, apalutamide, and darolutamide,” he added.

Retrospective Review

“Most studies of newer agents, including abiraterone acetate, have been done with ADT. The thinking is that as testosterone levels rise, they promote the growth of prostate cancer, so the goal is suppression of testosterone. Abiraterone acetate plus prednisone blocks the synthesis of testosterone, so there is no reason to give ADT along with this treatment,” proposed lead author of the second study, Gautam Jha, MD, of the University of Minnesota, Minneapolis.

Gautam Jha, MD

Gautam Jha, MD

“In the 5 to 7 years I have been practicing medicine, I have seen only one treatment failure on abiraterone acetate alone. I am defining treatment failure as a rise in testosterone level above 30 ng/mL,” he said.

Abiraterone acetate and prednisone plus ADT is standard therapy. “In the past several years, I have stopped ADT in patients on abiraterone and followed testosterone levels. Abiraterone alone lowers testosterone to castrate levels,” he continued.

In the retrospective study, testosterone levels were followed in 57 consecutive patients treated at Dr. Jha’s institution with either abiraterone acetate, prednisone, and ADT or abiraterone plus prednisone with no ADT.2 Of these patients, 36 received abiraterone acetate plus ADT; 10 received abiraterone acetate without ADT; and 11 started treatment with abiraterone acetate plus ADT but transitioned to ADT alone. Testosterone levels were drawn every 3 months. The mean duration of therapy with abiraterone acetate was 1 year.

“In the overwhelming majority of patients in both arms (88% and 87%, respectively), the testosterone level was undetectable (ie, < 2 ng/dL),” Dr. Jha said. Only one patient had a detectable testosterone level of more than 30 ng/dL, and that patient was in the arm that received abiraterone acetate alone.

The investigators performed a cost analysis of this study by determining the dollar amount in savings if leuprolide injections were avoided while patients were treated with abiraterone acetate. The sobering finding was that for a total duration of therapy of approximately 61 patient-years, withholding ADT eliminated 244 leuprolide administrations and led to a cost savings of approximately $1.29 million.

“In fact, withholding ADT would translate to an avoidable expense of $55.5 million for 960 patients in the STAMPEDE trial and $34.5 million in the LATITUDE study in the combination therapy arm,” Dr. Jha stated. “By conservative estimates, holding leuprolide during abiraterone therapy could save as much as $332 million annually.”

DISCLOSURE: Dr. Ohlmann disclosed financial support from Janssen-Cilag, sponsor of the prospective study. Dr. Jha reported no conflicts of interest.

REFERENCES

1. Ohlmann CH, Ruessel C, Zillmann R, et al: Abiraterone acetate plus prednisone without continuing LHRH therapy in patients with metastatic chemotherapy-naive castration-resistant prostate cancer: Results from the SPARE trial (NCT02077634). 2019 ASCO Annual Meeting. Abstract 5046. Presented June 1, 2019.

2. Jha GG, Engle J: Suppression of testosterone production using abiraterone acetate with or without androgen deprivation therapy in metastatic castration-resistant prostate cancer. 2019 ASCO Annual Meeting. Abstract 5049. Presented June 1, 2019.


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