Dose-Escalation Strategy Feasible With Novel Radionuclide Treatment in mCRPC

Scott Tagawa, MD

Dose escalation of the novel radionuclide treatment ¹⁷⁷Lu-PSMA-617 is safe up to 22.2 GBq per cycle with fractionated dosing, showing promising early efficacy and tolerability in patients with progressive metastatic castration-resistant prostate cancer (mCRPC), according to phase I data presented at the 2018 ESMO Congress.

Enrollment criteria included progression on at least 1 potent androgen receptor—targeted agent and docetaxel and an ECOG performance status between 0 and 2. Twenty-nine patients were treated in the study.

Treatment was a single cycle of ¹⁷⁷Lu-PSMA-617 at a fractionated dose on day 1 and day 15 starting at 7.4 GBq, with planned escalation up to 22.2 GBq in a 3+3 modified strategy. The primary endpoint was determination of dose-limiting toxicity (DLT) and recommended phase II dose with secondary efficacy endpoints.

Findings show that there were no DLTs at any planned dose level. With follow-up ongoing, 44.8% of patients had prostate specific antigen (PSA) levels decrease >50%. Most common treatment-related adverse events (AEs) were xerostomia and fatigue, explained lead study author Scott T. Tagawa, MD.

OncLive: Please provide some background to this study.

In an interview with OncLive during ESMO, Tagawa, an assistant professor of Medicine, medical director, Genitourinary Oncology Research Program, assistant attending physician, Weill Cornell Medicine/NewYork-Presbyterian Hospital, discussed this emerging modality for patients with mCRPC.Tagawa: Overall, we know that prostate cancer is a radiosensitive disease. We cure some men with localized radiation, and we help others tremendously. You see decreased pain for bone metastasis. The vast majority, approximately 90% of patients, will express prostate-specific membrane antigen (PSMA). This is more or less exclusive to prostate cancer but is expressed throughout the body as well.

Over the last 15 years, we have been able to utilize radiolabeled antibodies to attack this disease. What we have shown over time, with a series of phase I/II trials, is that higher doses lead to more responses in terms of lower PSA and longer OS. By delivering the same total dose in a fractionated pattern, we can lower the rate of toxicity. In parallel, several small molecules have been developed against PSMA and have been delivered in other countries. In a nonprospective manner, we got results last year. No one has ever done a phase I dose-escalation study. We decided to do that, taking our overall data with the antibodies over 15 years, and combine it with the available data by researchers from Germany, Austria, etc. We used a phase I protocol.

Is dose escalation a common approach in the prostate cancer space?

What else would you like to add?

We took patients with mCRPC who had progressed following at least 1 novel antiangiogenic agent. There were other strict criteria as well. We used a 3+3 design, similar to what is used per cycle. We enrolled across all 6 cohorts without hitting the DLT. Rather than amending protocol, we decided to stop there and transition to a phase II study. Overall, what we see with the phase I results are no acute toxicities. We didn't hit any DLTs. Some patients had nausea and other low-grade adverse events, and the majority of them were grade I. There are data for dose-escalation approaches. In some studies, we see an OS benefit. However, in most studies, we see at least a slight PFS benefit. These strategies have been done with radiolabeled antibodies. Despite an unknown number, perhaps more than 1000 patients who have received this therapy, no one has done a prospective dose-escalation study. We all find this drug and target very exciting. It's nice to know there are 2 ongoing randomized studies in this space. We see a fairly good response rate measured by PSA and a reasonably good PFS in the absence of high-grade toxicities. These are all nonrandomized trials, so that's something to consider. Overall, we have an unmet need in this space in terms of tumor-targeted therapy. Once we get this kind of drug approved, we can move it to an earlier treatment setting.

Tagawa ST, Vallabhajosula S, Jhanwar Y, et al. Phase I dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 799PD.