Although findings from the phase 3 PEACE-3 trial (NCT02194842) demonstrated a progression-free survival (PFS) benefit with radium-223 (Xofigo) plus enzalutamide (Xtandi) in patients with bone-predominant metastatic castration-resistant prostate cancer (mCRPC), its applicability to contemporary patients—many of whom have received prior enhanced hormonal therapy—is uncertain, according to Qian (Janie) Qin, MD. Likewise, ongoing studies may further clarify radium-223’s role in this evolving treatment landscape.
“There [are] certainly ongoing trials [evaluating] radium-223 that will help us answer some important questions, although the sequencing question remains a challenge,” Qin shared with OncLive®. “However, [selection is still] very patient dependent and is somewhat of a clinical judgment.”
Meanwhile, the radioligand therapy lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) is increasingly being considered as an earlier treatment option for mCRPC following data from the phase 3 VISION (NCT03511664) and PSMAfore (NCT04689828) studies.
In the interview, Qin discussed the limited applicability of PEACE-3 results to current patients with mCRPC who have received prior enhanced hormonal therapy, the ongoing uncertainty regarding the optimal sequencing of radium-223, and whether lutetium Lu 177 vipivotide tetraxetan should be considered an additional, viable treatment option in the first line.
Qin is an assistant professor in the Department of Internal Medicine at UT Southwestern Medical Center and the Eugene P. Frenkel, MD Scholar in Clinical Medicine at Harold C. Simmons Comprehensive Cancer Center in Dallas, Texas.
OncLive: Although results from the phase 3 PEACE-3 trial support the use of radium-223, plus enzalutamide, and a bone-protecting agent for patients with mCRPC, has the application of this regimen been clearly defined?
Qin: [PEACE-3] enrolled patients [who] had mCRPC with bone metastases, were asymptomatic or mildly symptomatic, with no known visceral [metastases] and had [received] no prior treatment with enzalutamide or radium-223. They were then [randomly assigned] to [receive] either radium plus enzalutamide or enzalutamide monotherapy.
The challenge is that, if we look at the baseline characteristics, these patients also did not previously receive an enhanced hormone therapy such as abiraterone acetate [Zytiga]. Nowadays, in the modern era, most patients, if not all, should have received an enhanced hormone therapy in the metastatic hormone-sensitive prostate cancer [mHSPC] setting.
The question is: how applicable [are] these results for our patients who had enhanced hormone therapy in the mHSPC setting, and [are] being [randomly assigned] to radium-223 plus enzalutamide vs enzalutamide alone.
That is the challenging part in terms of how applicable [PEACE-3] is to our current patient population, although it did show quite a significant PFS benefit. We certainly saw some overall survival [OS] benefit as well, pending the final OS analysis.
Have subsequent trials with radium 223 helped delineate its optimal role? If not, how are you currently navigating the situation in your own clinical practice?
Selection is still a clinical question based on the patient characteristics, comorbidities, etc. If a patient is in that metastatic setting with bone-predominant metastasis, and does not need chemotherapy, for example, I would think about radium-223. Given the safety profile of the combination—especially if they have slowly [increasing] prostate-specific antigen [levels], where even an enhanced hormone therapy switch from abiraterone to enzalutamide, for example, is something reasonable to consider—it’s not unreasonable to [consider] based on [PEACE-3], data.
There are ongoing radium-223 trials currently. I’m not sure they’ll truly help answer the sequencing question at this time, but [they are] looking at different combinations with radium-223. The DORA trial [NCT03574571], for example, is a phase 3 [study] looking at radium-223 plus docetaxel vs docetaxel [alone]. It will be important to see the readout from [this study].
There’s also the [phase 1/2] AlphaBet trial [NCT05383079] looking at the combination of radium-223 and lutetium Lu 177 vipivotide tetraxetan in mCRPC]. There [are] certainly trials [evaluating] radium-233 that could help us answer some important questions, although the sequencing question remains a challenge.
Where are we using radioligand therapies like lutetium Lu 177 vipivotide tetraxetan based on prior clinical trials?
The currently approved [radioligand therapy] is lutetium Lu 177 vipivotide tetraxetan. This agent was [FDA-]approved for patients who have mCRPC after enhanced hormone therapy and taxane-based chemotherapy, based on [data from] the phase 3 VISION trial, so that’s where I was using it.
More recently, the PSMAfore study was read out. This is the study enrolling patients with mCRPC who had previously [received] enhanced hormone therapy but [were] taxane-naive. These patients were randomly assigned 1:1 to lutetium Lu 177 vipivotide tetraxetan vs a change in their enhanced hormone therapy.
PSMAfore showed significant radiographic PFS [rPFS] benefit for patients on the lutetium-177 arm, although it did not show an OS benefit. Part of that is probably because there was a very high crossover to lutetium Lu 177 vipivotide tetraxetan that probably affected our OS outlook. Regardless, the rPFS benefit was quite significant.
Based on this, and a quite tolerable safety profile, the FDA actually extended [the indication for]lutetium Lu 177 vipivotide tetraxetan for patients who have mCRPC after enhanced hormonal therapy, but before taxane therapy. As long as these patients are appropriate to delay taxane chemotherapy, we can use this therapy in the pre-taxane arena.
I have started to look at lutetium Lu 177 vipivotide tetraxetan in the first line for mCRPC. Now, in that setting, it’s quite crowded [given] the availability of our therapies. We just talked about radium-223 plus enzalutamide; [this regimen] could be considered [for first-line treatment, as could certain] PARP inhibitor combinations.
Again, the choice is dependent on the patient [and whether] they have specific hormone receptor alterations, bone-predominant disease, bone and soft tissue disease, [etc]. All these [factors] come into play when we are choosing the right treatment for a patient.