Niraparib/Radium-223 Combo Shows Tolerability in Early-Phase CRPC Trial

The combination of niraparib (Zejula) and radium-223 dichloride (Xofigo) was found to be safe and tolerable in patients with castration-resistant prostate cancer (CRPC) in a phase 1b trial (NCT03076203), according to William K. Kelly, DO, warranting further exploration.

Using the Time-to-Event Continual Reassessment Method (TITE-CRM), investigators identified the maximum-tolerated dose (MTD) of the combination based on toxicities observed over 12 weeks of treatment. Patients were divided into 2 cohorts, those who were chemotherapy-exposed (n = 15) versus chemotherapy-naïve (n = 15). These patients received 6 cycles radium-223 along with 1 of 3 doses of niraparib: 100 mg, 200 mg, or 300 mg.

“This is a really important trial design—what we call the TITE-CRM trial design. It's unique because typically in a phase 1 study, you [test] 3 patients, wait 1 month, and then you can escalate [treatment],” explained Kelly. “However, with these drugs, especially with radium-223, we know [the toxicities] are delayed. As such, we had to come up with a design to show the longitudinal effects of the combination, overall. That’s actually how we defined the doses.”

Kelly noted that chemotherapy-naïve patients exhibited the strongest clinical response to the combination. One of 7 patients treated with the niraparib MTD of 200 mg experienced a 50% or higher reduction in prostate-specific antigen (PSA) at 12 weeks. Seventy-one percent of these patients experienced a ≥30% reduction in alkaline phosphatase levels (ALP) with 43% achieving at least a 50% reduction in ALP, overall.

The treatment-emergent toxicities helped to determine dosage and were noted by Kelly as being manageable. Some of these adverse effects (AEs) included anemia (10%), decreased platelets (7%), a decrease in white blood cells (3%), and nausea (3%).

In an interview with OncLive, Kelly, a professor of medical oncology and urology at Thomas Jefferson University and director of the Division of Solid Tumor Oncology at Sidney Kimmel Cancer Center, discussed the early data seen with radium-223 plus niraparib and the next steps for this regimen in CRPC.

OncLive: Could you discuss the overall role of radiopharmaceuticals in prostate cancer?

Kelly: Radium-223 is an alpha emitter and is approved for patients with metastatic castrate-resistant prostate cancer with symptomatic bone metastases, as shown in the ALSYMPCA trial. It’s a common radiopharmaceutical that we use in our patients with advanced disease.

Could you provide the rationale and background for the study presented at ASCO?

Research suggests that PARP1 and PARP2 are key regulators of the androgen receptor (AR) signaling pathway and it is important in the transition to lethal CRPC. We have [results from] several trials that have shown the benefits of PARP inhibitors in advanced prostate cancer, even improving survival. Niraparib itself is a potent, selective PARP1/2 inhibitor with a favorable safety profile and it has shown single-agent activity in patients with metastatic CRPC. In this study, we wanted to see whether we could safely combine these 2 drugs together in patients with advanced disease.

What was the design of the trial and the methods implemented?

This was a unique trial design; it was a phase 1b trial with patients with progressive prostate cancer. One of the issues with radium-223 is that the [toxicities] don't usually present until later on. As such, we used a TITE-CRM method to help us identify the MTD or the toxicities over a 12-week period. We essentially had standard doses of the radium-223 and we had 3 dose levels of oral niraparib: 100 mg, 200 mg, and 300 mg daily. Patients were allowed to receive 6 cycles of radium-223, which is the standard dosing. Once patients completed treatment with the combination, they were allowed to continue on the niraparib alone.

What were the findings of this study?

They were very interesting. We were able to put 15 patients on each arm: the prior chemotherapy [arm] (n = 15) and the chemotherapy-naïve [arm] (n = 15). Overall, these patients had good performance status. We found that the MTD was 100 mg per day in the chemotherapy-exposed arm and 200 mg daily in the chemotherapy-naïve arm. We did see clinical activity with [this combination], which was very interesting. We saw the most clinical activity in the chemotherapy-naïve arm.

We looked at the 200 mg dose level, [which] 7 patients [had received]. We did have 1 patient who had a ≥ 50% decline in PSA [at 12 weeks], 5 of the 7 subjects had a ≥30% decline in ALP, which is another marker we looked at when we used radium-223. Forty-three percent of the patients actually achieved a ≥50% reduction in ALP, overall. All 7 patients experienced either an ALP decline or a PSA decline, which suggests that there is clinical activity there.

Were any notable safety signals observed?

It was the typical toxicities that we see in patients [on this type of regimen]: anemia, decrease white blood cell counts, decreased platelets, and a little bit of nausea. However, all these events [were manageable]. The MTD [AEs] were really hematologic, and that's how we defined it; that describes why there are 2 different dose levels between the chemotherapy-naïve group and those who had prior chemotherapy.

What are the clinical implications of these findings?

These patients were unselected for DNA damage repair abnormalities. We are going to go back and see whether any of those patients had any DNA repair abnormalities. Just with the number of patients who did see responses, there is probably added activity with the combination. An expansion phase 2 study using the combination in chemotherapy-naïve patients who have been tested and do not have DNA repair abnormalities is currently ongoing.

Reference

Kelly WK, Leiby B, Einstein DJ, et al. Radium-223 (Rad) and niraparib (Nira) treatment (tx) in castrate-resistant prostate cancer (CRPC) patients (pts) with and without prior chemotherapy (chemo). J Clin Oncol. 2020;38(suppl 15):5540. doi: 10.1200/JCO.2020.38.15_suppl.5540