Apalutamide plus ADT improves OS in men with non-metastatic castration-resistant PCa

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Apalutamide (ERLEADA) combined with androgen deprivation therapy improves overall survival more than androgen deprivation therapy alone in men with non-metastatic castration-resistant prostate cancer at high risk of metastases, according to results from investigators’ final analysis of the phase 3 SPARTAN trial.

Apalutamide, an androgen receptor inhibitor, became the first FDA-approved therapy for non-metastatic castration-resistant prostate cancer in February 2018. In September 2019, the FDA approved apalutamide for the treatment of patients with metastatic castration-sensitive prostate cancer.

Investigators enrolled 1207 patients in the SPARTAN study, who were randomized 2:1 to receive either 240 mg apalutamide orally once daily in combination with androgen deprivation therapy or placebo once daily in combination with androgen deprivation therapy.

The FDA’s first approval of the drug was based on the primary SPARTAN analysis. Investigators found that in a median follow-up of 20 months, treatment with apalutamide significantly delayed development of metastases, as well as the development of symptoms, according to Eric Small, MD, of the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

Small, the lead SPARTAN study investigator, presented the results of this study during the 2020 American Society of Clinical Oncology Virtual Scientific Program.

“What remained unanswered was whether using a novel androgen receptor targeting agent used early before the development of metastases, as opposed to waiting until metastatic castration-resistant prostate cancer, could prolong life,” Small said. “The answer is yes.”

At their final survival analysis with a median follow-up of 52 months, Small and coauthors found that apalutamide significantly increased overall survival from 59.9 months to 73.9 months. That’s an increase of 14 months in median survival, with a hazard ratio for death of 0.78, with P = .0161.

“If you correct for the benefits in survival from crossing over from placebo to apalutamide, the increase in survival goes up to 21 months,” he said.

The combination decreased the risk of death by 22%. And treatment with apalutamide and androgen deprivation therapy significantly delayed patients’ time to cytotoxic chemotherapy compared to placebo in combination with ADT, with a hazard ratio of 0.63 and p value of .0002.

“A fair question that is always raised about studies like this where an active agent is used early, is if overall survival is improved not because earlier is better than later, but because the placebo group ends up not getting any active therapy at all. The study ends up being a study of early treatment versus no treatment,” Small said.

That wasn’t the case in SPARTAN, according to Small.

“Over 80% of placebo patients went on to receive active, life-prolonging, FDA-approved therapy. Around 70% of placebo patients went on to receive abiraterone or other life-prolonging therapy at the time of metastases. All 19% of placebo patients who hadn’t yet progressed at the time of study unblinding went on to receive open-label apalutamide. Parenthetically, in addition to prolonging life, apalutamide also significantly delayed the time to chemotherapy use, a secondary end point of the trial,” he said.

Small said that in his estimation, the data are really important to the practicing clinician and an absolute game-changer for patients with prostate cancer.

“We already knew that apalutamide would delay time to metastases. But there was always this gnawing worry that maybe we were burning that bridge, and that it would ultimately disadvantage the patient to use this therapy early. In fact, the results in SPARTAN were exactly the opposite. Early use prolongs life, even when compared to later use. This means that we can use apalutamide in non-metastatic castration-resistant prostate cancer patients with the full confidence that we are prolonging life and not ‘burning a bridge’ that we will later regret,” Small said.

Apalutamide’s safety and tolerability were consistent across studies. Median treatment duration was nearly 3 times longer, at 33 months, for patients treated with apalutamide plus androgen deprivation therapy compared to 12 months in the placebo group. The most common adverse reactions in the SPARTAN study, occurring in 10% or less of patients were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, falls, hot flush, decreased appetite, fracture, and peripheral edema.

Disclosures: Janssen Research & Development funded the phase 3 trial. Small has ties to Fortis, Harpoon Therapeutics, Janssen, Beigene, Janssen Oncology, Teon Therapeutics, Tolero Pharmaceuticals, and Merck. For full disclosures, click here.