Sequential 177Lu-PSMA-617 Plus Docetaxel Under Examination in Metastatic Hormone-Naïve Prostate Cancer

Arun Azad, MBBS, PhD, FRACP, discusses the rationale that inspired the launch of the UpFrontPSMA trial, and highlights past and future research directions with 177Lu-PSMA-617 in the treatment of patients with prostate cancer.

Several prospective trials, such as the phase 2 TheraP study (NCT03392428), have demonstrated encouraging data with 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC). Now, research is examining the efficacy of the radionuclide earlier on in the disease process—specifically in patients with metastatic hormone-naïve prostate cancer (mHNPC), according to Arun Azad, MBBS, PhD, FRACP.

177Lu-PSMA-617 is a very active treatment for [patients with] mCRPC, and now we are testing it earlier in the disease spectrum. We know that docetaxel is more efficacious when you use it earlier rather than later, and we know that intensifying upfront systemic therapy for metastatic prostate cancer is a very effective strategy,” Azad said. “We are trying to intensify that further so that we can deliver better outcomes and better therapies for men with newly diagnosed, high-volume mHNPC.”

In the phase 2 UpFrontPSMA trial (NCT04343885), investigators will examine sequential 177Lu-PSMA-617 and docetaxel vs docetaxel alone in patients with mHNPC. The study will enroll 140 patients who will be randomized 1:1 to receive either 177Lu-PSMA-617 at a dose of 7.5 GBq every 6 weeks for 2 cycles, followed by docetaxel at a dose of 75mg/m2 every 3 weeks for 6 cycles, or docetaxel alone. Additionally, all patients will receive continuous androgen deprivation therapy (ADT).

In an interview with OncLive®, Azad, a medical oncologist at the Peter MacCallum Cancer Centre and an associate professor at the University of Melbourne, discussed the rationale that inspired the launch of the UpFrontPSMA trial, and highlighted past and future research directions with 177Lu-PSMA-617 in the treatment of patients with prostate cancer.

OncLive®: What was the rationale for combining 177Lu-PSMA-617 with docetaxel in mHNPC as part of the UpFrontPSMA trial?

Azad: This is a randomized, open-label phase 2 trial that is sponsored by Peter McCallum Cancer Center, my home institution, here, in Melbourne, Australia. [The trial] is looking at patients with newly diagnosed mHNPC, for whom the standard of care treatment is ADT, or hormonal therapy, plus docetaxel for 6 cycles. In these patients, we are looking at the addition of 2 cycles of 177Lu-PSMA-617 radionuclide therapy in the experimental arm; those men will receive ADT plus 2 cycles of 177Lu-PSMA-617, plus 6 cycles of docetaxel vs ADT plus 6 cycles of docetaxel in the control arm.

To be eligible, the patients must have high-volume disease on their prostate-specific membrane antigen [PSMA] PET scan, which means at least 4 bone metastases with at least 1 outside of the pelvis or spine, and/or visceral metastases. They must also have high PSMA expression on their PET scan. The study will recruit 140 men at 12 sites across Australia, and it is a follow-up to the TheraP trial that was presented by my colleague at Peter McCallum, Professor Michael Hofman, who is nuclear medicine physician. [Results from that trial] showed that 177Lu-PSMA-617 for 6 cycles was superior to cabazitaxel in [patients with] more advanced mCRPC.

The rationale for [the UpFrontPSMA] study is to bring 177Lu-PSMA-617 forward in the treatment paradigm for prostate cancer. We have seen that docetaxel chemotherapy and androgen receptor pathway inhibitors, like abiraterone acetate [Zytiga] and enzalutamide [Xtandi], are efficacious in mCRPC, and then when brought forward, have been more efficacious in terms of their absolute benefit. We are obviously hoping we will see the same thing with 177Lu-PSMA-617 in this trial.

Could you expand on the end points of this study?

The primary end point [for this study] is undetectable prostate-specific antigen [PSA] at 12 months; that [means] a PSA of less than or equal to 0.2 ng/mL. [Additionally,] we have other key secondary end points, which include overall survival, but also radiographic progression-free survival, objective response rate, PSA response rates, quality of life, and safety.

What is the overall objective of this research?

The overall goal for this research is to improve outcomes for patients with newly diagnosed mHNPC. For many decades, all we treated [these patients] with was ADT. That [approach] was efficacious initially, but invariably—particularly men with higher volume or higher burden disease— they will develop castration resistance, which is a highly lethal form of the disease, within a median of approximately 18 to 24 months.

Then, we saw that the addition of docetaxel and the androgen receptor pathway inhibitors, such as abiraterone, enzalutamide, and apalutamide [Erleada], to ADT, further improved outcomes in patients with mHNPC. [However,] patients with newly diagnosed, higher volume, or high burden disease, the men who we are recruiting to this study, still have relatively poor clinical outcomes. The goal is to try and bring new therapies into that space to further improve outcomes for those patients.

What previous data support the use of 177Lu-PSMA-617 plus docetaxel?

177Lu-PSMA-617 has been used for quite some time now in different parts of the world, largely for [patients with] mCRPC. Interestingly, many of the studies that were done globally [with the agent], were not prospective. Retrospective data were published [with this approach and showed] efficacy. The work that [came] out of Peter McCallum Cancer Center by Dr Hofman,which was initially a pilot study of 50 patients, and then, the 200-patient TheraP study, the real beauty of that work was that it was prospective. Then, therapy was randomized against control with cabazitaxel, which is obviously a standard of care, and a proven agent.

That has unleashed, and will unleash, a wave of other studies. For example, the phase 3 VISION trial [NCT03511664], which will report out perhaps even as early as later this year, is looking at later-stage use of 177Lu-PSMA-617 vs standard of care in [patient with] mCRPC.

Bringing it forward is now a logical step for 177Lu-PSMA-617. We have done that with all these other therapies like docetaxel and the androgen receptor pathway inhibitors. In some respects, there is a bit of an unknown; it is somewhat of a risk when you take something into a different point within the therapeutic armamentarium for a particular disease. [However,] this makes sense because of the greater efficacy we have seen in bringing other systemic agents forward.

Are any other efforts being made with the radionuclide?

In addition to the UpFrontPSMA trial, at Peter McCallum Cancer Center, we have even taken it a step further and brought in 177Lu-PSMA-617 for high-risk, localized prostate cancer as a pre-surgical treatment, as a proof of concept, to see whether we can deliver decent high doses of radiation to the prostate before surgery. Also, the phase 2 ENZA-p trial [NCT04419402] is looking at first-line mCRPC treatment with enzalutamide with or without 177Lu-PSMA-617.

The story I am trying to tell here is that 177Lu-PSMA-617 is efficacious in mCRPC, and more data are coming out. As we wait for those findings, [the agent] is moving forward, and you can see a whole spectrum of studies are going on here. UpFrontPSMA is clearly one of [these efforts], and it will be exciting to see these studies read out over the next 3 or 4 years.


  1. Azad A, Dhiantravan N, Emmett L, et al. UpFrontPSMA: A randomized phase II study of sequential 177Lu-PSMA617 and docetaxel versus docetaxel in metastatic hormone-naïve prostate cancer (mHNPC). J Clin Oncol. 2021;39(suppl 6):TPS180. doi:10.1200/JCO.2021.39.6_suppl.TPS180