Chemo Triumphs in Second-Line Metastatic Prostate Cancer

Pam Harrison

December 26, 2019

Chemotherapy with cabazitaxel (Jevtana, Sanofi-Aventis) beat treatment with an androgen-signaling inhibitor in the second-line treatment of metastatic castrate-resistant prostate cancer (mCRPC).

The first-line treatment for these patients was with docetaxel and then with one of the androgen-signaling inhibitors, either abiraterone (multiple brands) or enzalutamide (Xtandi, Astellas).

However, there was evidence of rapid disease progression, and so second-line treatment with either cabazitaxel or the other androgen-signaling inhibitor was initiated.

The results showed that men who received carbazitaxel had more than double the rate of imaging-based progression-free survival (PFS; median, 8.0 months vs 3.7 months) and significantly improved overall survival (OS; median, 13.6 months vs 11 months).

"Cabazitaxel remained superior regardless of the androgen-signaling-targeted inhibitor received," note the investigators, led by Ronald de Wit, MD, PhD, Erasmus Medical Center, Rotterdam, the Netherlands.

These findings come from the European CARD trial, which was published on December 26 in the New England Journal of Medicine.

"The CARD trial shows convincingly that cabazitaxel is the preferred therapeutic option over second-line androgen-signaling inhibitors in patients with metastatic castration-resistant prostate cancer who had rapid disease progression while they were receiving first-line androgen-signaling inhibitors," say experts in an accompanying editorial.

"Hence, these results are practice-changing," comment Mario Eisenberger, MD, and Emmanuel Antonarakis, MD, both from the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.

Other Options to Consider

However, the editorialists stopped short of recommending that all men with mCRPC who are treated with first-line abiraterone or enzalutamide preferentially receive cabazitaxel, because they felt that certain patients who have a more favorable prognosis might wish to choose an alternative approach.

For example, patients who have a more durable response to first-line abiraterone or enzalutamide, lasting at least 18 months — especially before they receive chemotherapy — might wish to rely on their physician's preference for treatment, in conjunction with appropriate biomarker assessment.

On the other hand, until recently, the choice of either abiraterone followed by enzalutamide or enzalutamide followed by abiraterone has often been preferred over taxane-based chemotherapy after first-line treatment failure because of the ease of administration of these agents and a perception that androgen-signaling inhibitors are roughly as effective as the taxanes.

This may no longer be the case, because preliminary data suggest that the efficacy of sequential androgen-signaling-inhibitor treatment for patients who are no longer deriving benefit from their initial agent is modest and short-lived — "suggesting clinically significant cross-resistance between different androgen-signaling inhibitors," Eisenberger and Antonarakis note.

Given the results of the CARD trial, "it would seem that men treated with androgen-signaling inhibitors before the development of castration-resistant prostate cancer are not likely to benefit from this class of drugs if used subsequently," they state.

"The CARD trial...shows that cross-resistance between agents targeting the androgen receptor is a factor that is likely to have a substantial effect on the planning of future research examining systemic treatments in patients with this disease," they also suggest.

Details of the CARD Trial

The CARD trial was conducted in 255 men with mCRPC. The median age of the cohort was 70 years, but almost one third of the patients were 75 years of age or older.

All patients had received first-line treatment with docetaxel and an androgen-signaling-targeted inhibitor (either abiraterone or enzalutamide), but they showed evidence of rapid disease progression.

They were randomly assigned to receive second-line treatment with either cabazitaxel or the other androgen-signaling-targeted inhibitor.

Cabazitaxel was administered at a dose of 25 mg/m2 given intravenously every 3 weeks along with oral prednisone, 10 mg a day. Patients in the cabazitaxel group were also premedicated with an antihistamine, dexamethasone, and a histamine2-receptor antagonist. Prophylactic granulocyte colony–stimulating factor was given before each cycle.

In the other arm, patients received either oral abiraterone, 1000 mg/day, plus oral prednisone, 5 mg twice a day, or oral enzalutamide, 160 mg/day.

"A treatment cycle was 3 weeks in both trial groups," the investigators note.

Patients received treated until there was evidence of disease progression on imaging or unacceptable toxic effects occurred.

The primary endpoint of the study was imaging-based PFS — often referred to as radiographic PFS, although they are not exactly the same thing, the authors comment. The study was designed to address a number of secondary endpoints as well, they add.

At a median follow-up of 9.2 months, the median imaging-based PFS was 46% longer in the cabazitaxel group, at 8 months, compared with 3.7 months in the androgen-signaling-inhibitor group (P < .001), the study authors report.

The vast majority of patients in both arms experienced disease progression by study endpoint, but the median PFS rate was 4.4 months in the cabazitaxel arm vs only 2.7 months in the androgen-signaling-inhibitor arm (P < .001), they add.

Secondary Endpoints

All secondary endpoints were also better among patients treated with cabazitaxel compared with those who received either abiraterone or enzalutamide.

For example, median OS was 36% longer, at 13.6 months, in the cabazitaxel group, compared with 11 months in the abiraterone or enzalutamide arm.

PSA response was not available for all patients, but among those for whom it was measured, the results favored the chemotherapy group: 35.7% of cabazitaxel patients experienced a reduction in PSA levels of at least 50% from baseline, compared to only 13.5% of patients in the androgen-signaling-inhibitor group (P < .001).

"Among patients with measurable disease at baseline, the percentage of patients with a tumor response was 37% with cabazitaxel and 12% with an androgen-signaling-targeted inhibitor (P = .004)," de Wit and colleagues observe.

Pain response was not evaluated in all patients, but among those for whom it was, the results showed a confirmed pain response in 45% of those treated with cabazitaxel, compared with 19.3% of those treated with either abiraterone or enzalutamide.

More than half of patients in the androgen-signaling-inhibitor group were estimated to have experienced a symptomatic skeletal event at 18 months, compared to slightly more than one quarter, at approximately 29%, of those who received cabazitaxel.

In contrast, the incidence of serious adverse events of any grade was virtually identical in both groups, at 38.9% in the cabazitaxel group vs 38.7% for those treated with either abiraterone or enzalutamide.

Importantly, there was more crossover in the androgen-signaling-inhibitor group ― 33% of these patients crossed over to receive cabazitaxel, compared to about 23% of cabazitaxel patients who crossed over to abiraterone or enzalutamide.

Thus, the fact that cabazitaxel reduced the risk for death from any cause by 36% compared with either abiraterone or enzalutamide despite the high crossover is perhaps all the more remarkable, the authors comment.

The study was sponsored by Sanofi, manufacturer of cabazitaxel. De Wit reports receiving grant support, honoraria, and advisory fees from Sanofi, grant support and advisory fees from Bayer, and honoraria and advisory fees from Merck. He also received advisory fees from Janssen, Clovis Oncology, and Roche. Many coauthors also report relationships with industry, as detailed on the journal's website. Antonarakis reports relationships with Janssen, Astellas, Sanofi-Genzyme, Dendreon, Pfizer, ESSA, AstraZeneca, Clovis, Merck, Johnson & Johnson, Genentech, Novartis, Bristol-Myers Squibb, and Amgen. Eisenberger reports nonfinancial support and other support from Sanofi outside the submitted work.

N Engl J Med. Published online December 26, 2019. Abstract, Editorial

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