Radionuclide-Containing Combo Slows Metastatic Prostate Cancer, Improves Survival

Men with castration-resistant prostate cancer (CRPC) and asymptomatic or mildly symptomatic bone metastases lived significantly longer when they received enzalutamide (Xtandi) plus radium-223 (Ra-223, Xofigo), a large randomized trial showed.

Median radiographic progression-free survival (rPFS), the primary endpoint, improved from 16.4 months with enzalutamide along with 19.4 months with the addition of Ra-223. Median overall survival (OS) improved from 35.0 to 42.3 months with combination therapy.

The improved survival came with increased toxicity, as grade ≥3 drug-related adverse events (DRAEs) increased from 19% to 28%, but relatively few patients discontinued because of DRAEs, reported Silke Gillessen, MD, of the Oncology Institute of Southern Switzerland in Bellinzona, at the European Society for Medical Oncology (ESMO) congress in Barcelona.

“These results support the combination of enzalutamide plus radium-223 plus a bone protecting agent as a potential new first-line mCRPC option for patients with prostate cancer and bone metastases who have not received a prior androgen receptor-pathway inhibitor,” she concluded.

The PEACE-3 trial results are practice changing, with caveats about the need for long-term OS data and missing data on osteonecrosis of the jaw, said ESMO invited discussant Karim Fizazi, MD, of the Gustave Roussy Institute in Villejuif, France.

“Combining enzalutamide and radium clearly improves the primary endpoint of the trial and most likely also overall survival,” said Fizazi. “If you’re using this combination in your practice, please make sure you prescribe a bone-protecting agent. [Bone] symptoms are no longer needed. If you’re using radium-223 historically, this was a need in the first pivotal phase III trial, but this was not the case here, so we can actually probably treat patients without bone pain.” Previous studies were limited to patients with symptomatic bone disease. PEACE-3 enrolled patients with no or minimal symptoms.

“Also, if you’re using enzalutamide in your practice, make sure you measure blood pressure. This is needed, and please treat hypertension,” Fizazi stated.

“More data are needed in PEACE-3, but this is really the first look at the data,” Fizazi said. “As more trials with radium-223 phase III trials are maturing, we need to optimize the best use for radium-223 versus lutetium, which is also a standard of care, and hopefully soon, other radiopharmaceuticals for prostate cancer patients.”

Both abiraterone (Zytiga) and enzalutamide are standard first-line options for mCRPC that has progressed on androgen deprivation therapy (ADT), Gillessen noted. No combination had improved rPFS and OS in the first-line setting. In fact, a randomized trial of abiraterone plus Ra-223 led to worse OS and an increased fracture risk in men with asymptomatic mCRPC as compared with the androgen receptor pathway inhibitor alone.

In the era prior to introduction of androgen receptor pathway inhibitors, Ra-223 improved OS in the phase III ALSYMPCA trial.

Continuing investigation of combination therapy, the PEACE-3 trial enrolled patients with mCRPC and bone metastases, asymptomatic or mildly symptomatic, no prior treatment with enzalutamide or Ra-223, and ongoing ADT. Patients were randomized to receive single-agent enzalutamide or in combination with Ra-223. The primary endpoint was rPFS, and key secondary endpoints included safety, OS, time to next treatment, time to pain progression, and time to first symptomatic skeletal event (SSE).

Use of a bone-protecting agent was mandated after enrollment of the first 119 patients. The trial had an accrual goal of 560 patients, but closed with 446 patients because of slow accrual. Baseline characteristics were well balanced.

The primary analysis showed that the addition of Ra-223 was associated with a 31% reduction in the rPFS hazard ratio (95% CI 0.54-0.87, P=0.0009). A subgroup analysis showed a consistent benefit for the addition of Ra-223. An interim analysis of OS also showed that the combination therapy was associated with a 31% reduction in the hazard ratio (95% CI 0.52-0.90.) The hazard was associated with a P-value of 0.0031, which met the prespecified level for statistical significance of P<0.0034.

The time to next systemic treatment was significantly prolonged in the combination arm. After 24 months, 51% of patients randomized to single-agent enzalutamide had initiated a next systemic treatment as compared with 30% of patients in the combination arm (HR 0.57, 95% CI 0.44-0.75, P<0.0001).

Time to pain progression at 24 months (45% with enzalutamide, 48% with the combination) did not differ significantly between the two groups nor did time to SSE (18% in each arm).

DRAEs (84% vs 71%), serious AEs (43% vs 30%), and serious DRAEs (8% vs 1%) all occurred more often in the combination arm. Grade 3-5 DRAEs occurred in 28% of patients randomized to Ra-223 versus 19% of those who received single-agent enzalutamide. Fatal AEs occurred in 3% of the combination arm and 2% of the enzalutamide arm. Treatment discontinuation related to enzalutamide toxicity was 8% and 7% in the two arms, and 3% of patients in the combination arm discontinued because of Ra-223-associated toxicity.

The most common treatment-emergent AE was hypertension, which occurred in a third of patients in each arm. Treatment-related hypertension occurred in 12% of patients in each group.

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