177Lutetium-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer; Randomized Controlled Phase 3 Trial Data is Pending and Novel Combinations are Being Tested

177Lu-PSMA-617 has been introduced before in this column as a PSMA-targeted radioligand therapy.1 A Phase II Australian trial treated 30 men with metastatic castration-resistant prostate cancer who had variable lines of exposure to agents such as abiraterone, enzalutamide, docetaxel and/or cabazitaxel.Seventeen (57%) patients achieved a prostate-specific antigen (PSA) decline ≥50%. Fourteen (82%) of 17 patients with measurable disease had an objective response. Toxicities were generally mild with grade 1 dry mouth in 26 (87%) patients, grade 1/2 transient nausea in 15 (50%) patients and grade 1/2 fatigue in 15 (50%) patients. Grade 3/4 events were rare, but thrombocytopenia did reach that level in 4 (13%) patients.

There are two large, randomized, controlled trials ongoing with 177Lu-PSMA-617 at this time. The first is the VISION trial (NCT03511664), an international Phase III trial that enrolled approximately 750 patients with progressive metastatic castration-resistant prostate, who received 1-2 lines of previous taxane therapy as well as previous novel hormonal therapy (e.g. abiraterone, enzalutamide). If a patient received only one line of previous taxane therapy, the patient must have been either deemed ineligible or unwilling to receive a second taxane. 68Ga-PSMA PET positivity at baseline was mandated for eligibility. The randomization was 2:1 177Lu-PSMA-617 plus best standard of care vs. non-chemotherapy best standard of care. The primary endpoint will be overall survival, and a positive trial has high potential to lead to a new regulatory approval.

Given the recent results from the CARD trial,3 it is reasonable to support the immediate use of cabazitaxel in the metastatic castration-resistant prostate cancer patient who has received prior docetaxel and one prior novel hormonal therapy. Hence, the TheraP trial (NCT03392428), is a randomized, Phase II, cooperative group trial from Australia and New Zealand (ANZUP 1603) that enrolled patients in the post-docetaxel setting that were suitable for cabazitaxel. Approximately 200 patients with PSMA PET avid disease were randomized 1:1 to cabazitaxel 20 mg/m2 versus 177Lu-PSMA-617. The primary endpoint of this trial is the PSA response rate, but overall survival is another important endpoint.

One advantage to 177Lu-PSMA-617 is that it is very well-tolerated, making it amenable for rationale combination therapy trials. For example, poly (ADP-ribose) polymerase (PARP) inhibitors and immune-oncology agents are being investigated in combination clinical trials with 177Lu-PSMA-617. Other methods of targeting PSMA with antibody-based radioligand therapy are also being combined with the 177Lu-PSMA-617 small-molecule approach.

In summary, 177Lu-PSMA-617 has much promise to become a standard agent for use for patients with metastatic castration-resistant prostate cancer. As usual, the initial randomized trials are restricted to heavily pre-treated, post-chemotherapy disease states. However, as we have seen with docetaxel and the novel hormonal agents, it will not be surprising to soon see clinical trial development in the pre-chemotherapy disease state. Additionally, combination efforts offer hope for additive or synergistic efficacy, and we should support clinical trial accruals to those efforts. Below, I highlight multiple clinical trials with 177Lu-PSMA-617 that are actively accruing patients.

Clinical Trials with Radioligand therapy targeting PSMA:

• LuPARP trial - 177Lu-PSMA-617 with olaparib (NCT03874884)
• PRINCE trial – 177Lu-PSMA-617 with pembrolizumab (NCT03658447)
• Antibody with small molecular combination - 177Lu-PSMA-617 with 177Lu-J591 (NCT03545165)
• Lu-PSMA trial - Radiometabolic 177Lu-PSMA-617 (NCT03454750)
• Fractionated 177Lu-PSMA-617 trial (NCT03042468)

Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine,  Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center

References:

1. Yu, E. (2018). From the Desk of Evan Yu: “Prostate-specific Membrane Antigen (PSMA)-targeted Radioligand Therapies are Finally Arriving.”. Retrieved 6 January 2020

2. Hofman, Michael S., John Violet, Rodney J. Hicks, Justin Ferdinandus, Sue Ping Thang, Tim Akhurst, Amir Iravani et al. "[177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study." The Lancet Oncology 19, no. 6 (2018): 825-833.

3. de Wit, Ronald, Johann de Bono, Cora N. Sternberg, Karim Fizazi, Bertrand Tombal, Christian Wülfing, Gero Kramer et al. "Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer." New England Journal of Medicine (2019).

Further Related Content:
Watch: The VISION Trial: Radionuclide Therapy Plus Standard Therapy for Metastatic Castration Resistant Prostate Cancer - Oliver Sartor and Michael Morris