Bone marker data support mCRPC combination Tx

Markers of bone metabolism improved in men with metastatic castration-refractory prostate cancer (mCRPC) who received radium-223 (Xofigo) in addition to enzalutamide (XTANDI) compared with enzalutamide alone.

In a phase II trial, a suggestion of improved PSA progression-free survival (PFS) was also observed with the combination, reported Benjamin L. Maughan, MD, PharmD, at the European Society for Medical Oncology annual congress in Munich.

The data provide a rationale for combining the agents in men with progressive mCRPC, said Dr. Maughan, of Huntsman Cancer Institute, University of Utah, Salt Lake City.

Radium-223 dichloride is a radioisotope that emits cytotoxic alpha particles with a high affinity for the bone matrix. It was approved by the FDA in 2013 for the treatment of metastatic prostate cancer to bone in the absence of visceral metastases on the basis of the phase III ALSYMPCA trial, which showed an overall survival (OS) benefit with the use of the radioisotope.

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Data from the phase II study presented here build upon the safety data from the same trial presented earlier, at the 2018 American Society of Clinical Oncology annual meeting in Chicago.

“We showed that the combination of enzalutamide plus radium was no more toxic than you would expect with enzalutamide alone in terms of noncytopenia toxicities and cytopenias compared with radium-223 as seen in the ALSYMPCA trial. That’s what we benchmarked it against,” Dr. Maughan told Urology Times. “We also noted that there was no increased fractures with radium-223; in fact, there were no fractures in either arm with up to 12.1 months of follow-up in this study.”

As part of the study, levels of bone formation markers were measured in sera collected at baseline and at the end of treatment or until disease progression or unacceptable toxicities. A total of 49 men were recruited for the study; 35 received radium-223 at a standard dosage (six treatments of 55 kBq/kg IV every 4 weeks) plus enzalutamide, 160 mg/day, and 14 received enzalutamide alone.

Patients included had histologically documented castration-resistant adenocarcinoma of the prostate and life expectancy ≥6 months. They had metastatic disease as evidenced by both lymphadenopathy and bony metastases or just bony metastases on baseline bone scan and/or computed tomography scan or magnetic resonance imaging of the abdomen and pelvis.

With the exception of one patient in each arm, all patients were treated with bone-modifying agents such as zoledronic acid for the duration of the study.

The ratio of N-telopeptide in the radium-223 plus enzalutamide group relative to the enzalutamide alone arm, the primary objective, was 0.61 (p<.001). Other bone metabolism markers were also significantly improved in the combination arm, including bone-specific alkaline phosphatase (ratio: 0.38; p<.001) and procollagen intact N-terminus (ratio: 0.52; p<.001). The level of C-telopeptide was also lower in the combination arm versus enzalutamide alone, but the difference narrowly missed significance (ratio: 0.61; p=.06). The change in morphine use from baseline was similar in each group. Improvement in bone metabolism markers was shown in a prior SWOG trial (PMID 24565955) to correlate with OS, noted Dr. Maughan.

Continue to the next page for more.PSA50 and PSA90 response rates were numerically greater in the radium-223/enzalutamide arm versus enzalutamide alone but these were not statistically significant (67% vs. 33%; p=.082; and 48% vs. 17%; p=.083, respectively). The median PSA PFS at 1 year was longer in the combination arm (HR=0.62; p=.27) though it was also not statistically significant. No difference in OS emerged at 1 year.

“Bone markers have been associated with OS, specifically with radium therapy and other bone-directed therapies,” said Dr. Maughan. “OS data are not mature yet. We didn’t necessarily expect it to be. First, this was a very small study so it would be difficult to demonstrate a difference in OS but also it’s a relatively short follow-up” for this specific patient population.

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The data suggest potential additive efficacy between radium and enzalutamide that account for the PSA PFS difference between the two arms, he added.

These data gathered from this phase II study will be validated by an ongoing phase III study comparing radium-223 plus enzalutamide with enzalutamide alone (NCT02194842).

Bayer provided funding for the study.