Kate Johnson

June 07, 2017

CHICAGO — First-line use of abiraterone acetate (Zytiga, Janssen) was underscored for advanced metastatic prostate cancer in the presentation of the pivotal STAMPEDE and LATITUDE trials here at the at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.

But one of the immediate questions raised by comparing the two studies was how the data apply to nonmetastatic disease.

As previously reported by Medscape Medical News, STAMPEDE included patients with both metastatic and nonmetastatic prostate cancer. However, LATITUDE, a phase 3 trial of abiraterone plus predinisone (AAP) added to androgen deprivation therapy (ADT), included men with only high-risk metastatic disease.

This study, which was published simultaneously in the New England Journal of Medicine, included 1199 patients receiving first-time ADT. The patients were randomly assigned to receive in addition either AAP or placebos.

Docetaxel was not included as part of the ADT regimen because enrollment for the trial was completed before there was evidence to support this approach, explained investigator Karim Fizazi, MD, PhD, head of the Department of Cancer Medicine at Gustave Roussy, University Paris-Sud, in Villejuif, France.

Dr Karim Fizazi

At the first planned interim analysis, the independent data and safety monitoring committee recommended that the trial be unblinded to allow crossover of placebo-treated patients to abiraterone. The recommendation was based on positive findings for the coprimary endpoints: radiographic progression-free survival (rPFS) and overall survival (OS).

At a median follow-up of 30.4 months, the results showed a significant 38% reduction in the risk for death in the abiraterone group compared to the placebo arm (OS, 66% vs 49%; hazard ratio [HR], 0.62; P < .0001), reported Dr Fizazi. The median OS was 34.7 months in the control group; it was not reached in the experimental group.

Abiraterone was also associated with a 53% improvement in rPFS, which occurred at a median of 33.0 months compared to 14.8 months in the placebo group (HR, 0.47; P < .001).

"And this good news did not come alone," added Dr Fizazi. "All our secondary endpoints were met," he noted, including time to progression of prostate-specific antigen (PSA) levels, pain progression, next symptomtic skeletal event, chemotherapy, and subsequent prostate cancer therapy.

The overall safety profile of ADT + AAP was "consistent with prior studies of patients with metastatic castration-resistant prostate cancer," he said. Adverse events of grades 3 and 4 were more common in the abiraterone group vs the placebo group (63% vs 48%), particularly grade 3 hypertension, which occurred in 20% vs 10% in the ADT plus placebo group, and hypokalemia of grades 3 and 4, which occurred in 10% and 0.8% in the abiraterone group vs 1% and 0.2% in the placebo group.

Speaking about LATITUDE and STAMPEDE during a press briefing at the meeting, ASCO expert Sumanta Kumar Pal, MD, said, "It's remarkable to see the similarity in survival benefit across the two studies in the metastatic population," but he made a distinction between these patients and the patients with nonmetastatic disease in STAMPEDE. "I would argue that further study is needed to determine appropriate candidates in nonmetastatic disease."

Dr Sumanta Kumar Pal

A breakdown of STAMPEDE's patients showed that among the 52% of patients who had metastatic disease, the addition of abiraterone was associated with a clear OS advantage (HR, 0.61; 95% confidence interval [CI], .49 - 0.75).

However, in the other half of the participants who had nonmetastatic or locally advanced disease, the CI crossed 1 (HR, 0.75; 95% CI, 0.48 - 1.18). "To me, that suggests that we haven't completely defined the benefit of abiraterone in that population," said Dr Pal.

His reasoning was echoed by Tanya Dorff, MD, from Keck School of Medicine, University of Southern California, Los Angeles, who was the discussant for STAMPEDE.

Responding to the comments, STAMPEDE investigator Nicholas James, MBBS, PhD, from Queen Elizabeth Hospital in Birmingham, United Kingdom, said concern that the HR crosses 1 "is a misinterpretation of how the forest plot should be read." He added that study investigators' tests for heterogeneity showed that the benefit of abiraterone "was similar for metastatic and nonmetastatic patients. We saw the same magnitude of effect, and so we think the effect applies across the whole trial population."

Eric Small, MD, from the University of California, San Francisco, who was discussant for the LATITUDE trial, was less concerned. "The use of abiraterone together with ADT is a new standard of care for patients with untreated high-risk metastatic prostate cancer ― and potentially for all patients with untreated metastatic prostate cancer," he concluded.

"The benefit appears to be the same as that seen with docetaxel, but use of abiraterone avoids chemotherapy, avoids (rare) neutropenic complication/treatment-associated deaths, replaces short-term IV treatment with long-term oral treatment, and may be more appropriate in the elderly or debilitated," Dr Small commented.

Approached for comment, Thomas Flaig, MD, from the University of Colorado School of Medicine, in Aurora, told Medscape Medical News: "Several questions remain to be answered.

"Firstly, can we select patients based on clinical or molecular features who are most likely to benefit from either abiraterone or docetaxel in this setting?" he said. And secondly, "Should docetaxel and abiraterone be combined up front with ADT in high-risk patients?" he asked.

"How will we reconcile the patient population differences in these two trials in clinical practice?" he continued, noting that STAMPEDE included a more heterogeneous and lower-risk population than LATITUDE.

"We have to keep in mind that many of the patients in this clinical setting are elderly and may have other comorbid illness. One of the most exciting aspects of these new data is the potential for broad application of more effective therapy (abiraterone acetate) for hormone-sensitive, advanced prostate cancer patients, including patients who might not have otherwise received docetaxel," Dr Flaig commented.

LATITUDE was funded by Janssen Research and Development. STAMPEDE was funded by grants from Cancer Research UK, the Medical Research Council, and Janssen, with additional contributions to the STAMPEDE protocol from Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis. Dr Fizazi has a consulting or advisory role with Janssen Oncology, Bayer, Astellas Pharma, Sanofi, Orion Pharma GmbH, Curevac, AstraZeneca, ESSA, Clovis Oncology. He has also received expenses from Amgen and honoraria from Janssen, Sanofi, Astellas Pharma, Takeda, Merck, and Amgen. Dr James has a consulting or advisory role with Sanofi, Bayer, Merck, Astellas Pharma, and Janssen; is on the speakers' bureau for Pierre Fabre, Ferring, Sanofi, Astellas Pharma; has received compensation for expenses from Sanofi and honoraria from Sanofi, Bayer, Oncogenex, Janssen, Astellas Pharma, Pierre Fabre; and has received research funding (institutional) from Janssen, Astellas Pharma, Pfizer, Sanofi, and Novartis. Dr Pal has received honoraria from Astellas Pharma, Medivation, Novartis; has had consulting or advisory roles with Astellas Pharma, Aveo, Bristol-Myers Squibb, Exelixis, Genentech, Myriad Pharmaceuticals, Novartis, Pfizer; and has received research funding from Medivation. Dr Small owns stock and other ownership interests in Fortis Therapeutics and Harpoon Therapeutics; has a consulting or advisory role with Fortis Therapeutics and Gilead Sciences; and has received research funding (institutional) from Janssen. Dr Dorff has received honoraria from Astellas Pharma, Dendreon, Exelixis, Medivation, and Pfizer; has a consulting or advisory role with Bayer, Dendreon, Eisai; EMD Serono, and Genentech; serves on the speakers' bureau for Astellas Pharma, Dendreon, Exelixis, and Pfizer; and receives research funding from Bristol-Myers Squibb. Dr. Flaig was not directly involved in either trial but has served as a local principal investigator and has received funds from Cougar/Janssen for clinical trial–related expenses for other abiraterone trials.

American Society of Clinical Oncology (ASCO) 2017 Annual Meeting. Abstract LBA3 (LATITUDE trial), presented June 4, 2017, and abstract LBA5003 (STAMPEDE trial), presented June 3, 2017.

N Engl J Med. Published online June 4, 2017. Full text

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