TITAN Solidifies Place for Apalutamide in Metastatic CSPC

Pam Harrison

June 06, 2019

CHICAGO — New data show efficacy for the next-generation androgen receptor inhibitor apalutamide (Erleada, Janssen) in the treatment of metastatic hormone-sensitive prostate cancer, which would be a new indication for the drug.

The first efficacy data in this patient population show that the drug extended both radiographic progression-free survival (rPFS) and overall survival (OS) compared with placebo when both were added onto standard androgen deprivation therapy (ADT).

Last year, apalutamide became the first treatment to be approved by the US Food and Drug Administration for use in nonmetastatic, castration-resistant prostate cancer, having shown a benefit on the new endpoint of metastasis-free survival in the SPARTAN study.

The new data comes from the TITAN trial, which was conducted in a later stage of the disease in men with metastatic castrate-sensitive prostate cancer (mCSPC) who were already on ADT.

"The rationale behind the TITAN study was [the idea that] direct inhibition of the androgen receptor by apalutamide may provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes," explained study author Kim Chi, MD, medical oncologist at BC Cancer Agency in Vancouver, Canada.

"And the TITAN study met its dual primary endpoints, demonstrating significant benefit with apalutamide plus ADT in an all-comer population with metastatic CSPC," he concluded.

The study was presented here at the annual meeting of the American Society of Clinical Oncology, and concurrently published online in the New England Journal of Medicine.

Commenting on the new data at the meeting, discussant Michael Carducci, MD, AEGON professor in prostate cancer research at Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, said that this study confirms that the current standard for mCSPC should be a combination of ADT plus chemotherapy or an androgen receptor inhibitor such as enzalutamide (Xtandi, Astellas) and abiraterone (Zytiga, Janssen) and now, also apalutamide.

What About ADT Alone?

Also commenting on the TITAN trial, Celestia Higano, MD, professor of oncology and urology at the University of Washington in Seattle, noted that the oncology community now has a variety of drugs that they can use together with ADT, all of which have been shown to be superior than ADT alone.

"Thus, one of the questions we have is: 'Do we have to eliminate ADT alone as a therapeutic option for patients with mCSPC?' " Higano asked.

In her opinion, the answer to this question is no, at least not for selected patients.

"The patients I would select for ADT alone would be an older man who has recurrent prostate cancer, for example, who has not been on ADT in the past; in such a patient, you start his ADT, and after 7 months his PSA is undetectable on ADT alone," said Higano, who was not involved with the current study.

Higano also noted that she chose the 7 months purposely because in the SWOG-9346 trial, "we found that those who became undetectable at the 7-month time frame had a very good long-term outcome, with a median survival of 5 years."

"So it's not clear to me that adding one of these other agents to that type of scenario is really worth some of the additional toxicities that we know are associated with them," she concluded.

Study Details

The TITAN study involved 525 patients who were randomly assigned to apalutamide and another 527 to placebo.

"Patients were required to have continuous ADT," Chi noted, "and prior docetaxel for castration-sensitive disease" was permitted (and used by 10%).

Patients randomly assigned to active therapy received apalutamide 240 mg/day given in addition to standard ADT, or to placebo plus ADT.

The two groups were evenly balanced both in baseline characteristics and in disease status. For example, the Eastern Cooperative Oncology Group (ECOG) Performance Status was 0 in 64% of patients, most patients had no pain or only mild pain at baseline, and 63% had high-volume disease.

At the time of the current analysis, the median follow-up for OS was 22.9 months in the additional apalutamide group and 22.4 months in the placebo group.

Median treatment duration was somewhat longer for patients receiving apalutamide at 20.5 months, with 66% of patients still remaining on treatment at the time of analysis.

For placebo controls, the median treatment duration was 18.3 months, with 46% of patients remaining on placebo at the same time point.

"Apalutamide significantly reduced the risk of radiographic progression or death by 52% compared with placebo," Chi reported.

In addition, the drug significantly reduced the risk of death by 33% compared with placebo, with OS rates at 2 years being 82% in the experimental group and 74% in the placebo group (P = .0053).

The median time to radiographic progression was not reached among those randomly assigned to apalutamide vs 22.1 months for those receiving ADT alone.

At 2 years, there was an absolute 20% difference in the rate of rPFS, with 68% of patients in the apalutamide group remaining free of disease progression vs 48% of those on ADT alone.

"The benefit from apalutamide was consistent across subgroups," Chi noted.

This included whether patients had or had not received prior docetaxel, and those with both high- and low-volume disease.

However, in his discussion of the study, Johns Hopkins professor Carducci disagreed with this conclusion, and he cautioned that the addition of apalutamide to ADT did not seem to benefit certain subgroups of patients, such as those who had visceral disease or who had received prior docetaxel.

Secondary endpoints similarly favored apalutamide, Chi added.

For example, the median time to PSA progression had not been reached at the time of analysis for the apalutamide group compared with a median of 12.9 months for those on ADT alone  (P < .001).

At 2 years, 75% of patients in the active treatment group remained PSA progression-free compared with only 36% of those in the control group.

"The incidence of adverse events was roughly the same between apalutamide and placebo," Chi noted, although more patients in the apalutamide group (8%) discontinued treatment than did those on placebo (5.3%), largely because of rash.

Other adverse events, said Chi, included hypothyroidism, which was largely grade 1 and did not require intervention. Incidence rates of fatigue, fall, fracture, and seizures were similar between the two treatment groups.

In keeping with the AE profile, health-related quality of life was preserved from baseline, with no change from baseline in patients who received additional apalutamide; this was similar to that seen among placebo controls, Chi noted.

Chi reports receiving honoraria from Astellas, Bayer, Janssen, and Sanofi, and has served as a consultant or on the advisory board for Amgen, Astellas, Bayer, ESSA, Janssen, Lilly/ImClone, and Sanofi. He also reports receiving research funding from Astellas, Bayer, Bristol-Myers Squibb, Lilly/ImClone, Merck, Roche, Sanofi, and Tokai Pharmaceuticals.

Carducci reports having served as a consultant for Pfizer, Roche/Genentech/ Foundation Medicine, and AbbVie and has received research funding from EMD Serrano, Pfizer, and Effector.

Higano declares she has served as a consultant, or on the advisory board, for Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Janssen, Myriad Genetics, Pfizer, and Tolmar. She has also received research funding from Aragon Pharmaceuticals, Astellas, AstraZeneca, Bayer, Dendreon, Emergent BioSolutions, Hinova Pharmaceuticals, Medivation, and Pfizer; and travel expenses from Astellas, Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Hinova Pharmaceuticals, Menarini, Myriad Genetics, and Pfizer.

American Society of Clinical Oncology (ASCO) 2019 Annual Meeting: Abstract 5006. Presented May 31, 2019.

NEJM. Published online May 31, 2019. Abstract

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