Lutetium Lu 177 Vipivotide Tetraxetan Addresses Unmet Need in Taxane-Naive mCRPC

Treatment with lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) continued to improve radiographic progression-free survival (rPFS) compared with standard of care treatment with androgen receptor pathway inhibition (ARPI) in patients with previously treated, taxane-naive metastatic castration-resistant prostate cancer (mCRPC), according to updated data from the second interim analysis of the phase 3 PSMAfore (NCT04689828) trial presented at the 2023 ESMO Congress.¹

Results showed that the hazard ratio (HR) for the primary end point of rPFS was 0.43 (95% CI, 0.33-0.54), in favor of lutetium Lu 177 vipivotide tetraxetan. The median rPFS was 12.02 months (95% CI, 9.30-14.42) and 5.59 months (95% CI, 4.17-5.95) in the lutetium Lu 177 vipivotide tetraxetan and ARPI arms, respectively.

Furthermore, the objective response rate was 50.7% (95% CI, 38.6%-62.8%) in the investigational arm and 14.9% (95% CI, 7.7%-25.0%) in the control arm.

“Many patients never receive a taxane and many patients with prostate cancer never receive chemotherapy,” presenting study author Oliver Sartor, MD, said in an interview with OncLive®. “The idea was to be able to bring the lutetium Lu 177 vipivotide tetraxetan into the pre-taxane space, and that’s what [we] presented here at the 2023 ESMO Congress.”

In the interview, Sartor discussed the significance of the data with lutetium Lu 177 vipivotide tetraxetan in the open-label, multicenter randomized study, highlighted potential next steps with this approach, and expanded on unique adverse effects (AEs) to be aware of when treating patients with this drug. Sartor is the director of radiopharmaceutical trials at Mayo Clinic in Rochester, Minnesota.

OncLive: Could you discuss the historical treatment options in mCRPC, and how recent therapies have changed outcomes for this population?

Sartor: There’s a complex series of treatment choices for mCRPC, and they’re dependent in part upon what you receive prior to getting to that [disease] state. In the old days, you’d have things like androgen deprivation therapy [ADT], and then patients would progress, and then go to secondary ARPI; we saw really good responses [with that approach]. However, we’ve discovered that the ARPI is probably better given [up front].

Now, we’re using the ADT/ARPI combinations, and castrate-resistant disease is very different. In addition to the ARPIs, we also have the possibility of [giving] triplet therapy. What we have called the mCRPC space is very different today than what it used to be.

The treatment choices that we [make] with our patients are dependent on what treatments came before. If you’ve had no evidence of ARPI use, then you probably want to use an ARPI. If you’ve never seen docetaxel, then you might want to consider docetaxel. That’s one of the reasons why the new treatment and the PSMAfore protocol might have real applicability.

We have to look at the present choices of treatment in the context of past treatments, and not only what is approved today, but what might be approved tomorrow.

What led to the investigation of this targeted radioligand therapy in taxane-naive patients in this study?

[We used results from the] past [to] inform the present [trial]. The phase 3 VISION trial [NCT03511664] was conducted in patients who had already had an ARPI and a taxane. The [study authors] were able to demonstrate benefit [there], and that [approach] is now FDA approved.²

Could you provide more detail about the design and methodology of the study, including patient selection?

We wanted everybody in the PSMAfore trial to have had an ARPI and ADT; everybody had to have metastatic disease, as well as a PSMA PET scan that demonstrated [evidence of] PSMA PET positivity. [Approximately] 92% of the patients that [we screened with] PSMA PET qualified for the study. There were [also] usual parameters that covered liver and kidney function, as well as performance status.

The patients had to be considered appropriate for a second-line ARPI. We all know that patients can go straight to a taxane and have very aggressive disease. Patients were randomized between the lutetium Lu 177 vipivotide tetraxetan and the ARPI that they did not receive in the first-line setting.

It was either [hormonal therapy with] abiraterone acetate [Zytiga] or enzalutamide [Xtandi]. The randomization was 1:1 for lutetium Lu 177 vipivotide tetraxetan and a secondary [hormonal agent]. The primary end point was rPFS. We also looked at a variety of secondary end points and exploratory end points, such as toxicity.

Could you walk us through the efficacy results of this study?

The HR for the primary end point of rPFS in the primary analysis was 0.41. The secondary analysis was presented here, with an HR of 0.43, which is essentially the same. Confidence intervals were small and did not [exceed] one. If we want to look at the quantitative estimates, the median was 12.02 months for the lutetium Lu 177 vipivotide tetraxetan and 5.59 months for the secondary treatment. That is a significant difference, more than doubling in the rPFS.

Among the secondary end points, there was a crossover-adjusted overall survival [OS], which showed an HR of 0.80. Those confidence intervals were still pretty big, and they did [exceed] one. Therefore, it is not a statistically significant crossover. We then looked at a whole bunch of other things like health-related quality of life––that was better with lutetium Lu 177 vipivotide tetraxetan. We also looked at time to prostate specific antigen [(PSA) progression] and time to pain progression, which was better with the lutetium Lu 177 vipivotide tetraxetan. Also, the rate of PSA decline was better with lutetium Lu 177 vipivotide tetraxetan and objective response was better with lutetium Lu 177 vipivotide tetraxetan. Notably, AEs were better with lutetium Lu 177 vipivotide tetraxetan.

We had a litany of end points that are positive with lutetium Lu 177 vipivotide tetraxetan as compared with the secondary hormonal [therapy]. The surprise to me was that the grade 3/4 AEs and dose adjustments were all better with lutetium Lu 177 vipivotide tetraxetan. The hormones were dose adjusted 15% of the time. [The dose of] lutetium Lu 177 vipivotide tetraxetan was [adjusted] only about a third of that. That was surprising. The discontinuation rates were also low at 5% in each arm.

Are there any specific AEs that should be known about this combination when you’re thinking about prescribing it?

One of the things we’ve learned about lutetium Lu 177 vipivotide tetraxetan is that patients will have a dry mouth, and we noticed that here as well; that is a unique AE. There are some gastrointestinal AEs. Interestingly, there is a little bit more diarrhea, and a little more constipation, nausea, and anemia, but overall, it is very well tolerated. If you look at the [safety] profile [of the agent] in the VISION trial, you pretty much have a recapitulation here [in PSMAfore].

What next steps or considerations will be evaluated based on the results of this study?

There are a couple things that are important following this study. We want to have a better handle on the longer-term AEs. We want to have a better handle on the longer-term effects of OS, we want to be able to understand the context and the post-protocol therapies in a little more detail. All that information is going to come with longer follow-up.

Of course, we have new trials that seem to be bringing this [agent] into the hormone-sensitive space. There is a big phase 3 trial called PSMAddition [NCT04720157] that is already fully accrued. That’s the next one up.

How might this study influence clinical practice and guidelines for patients with mCRPC?

In order to change the guidelines, I think it’s very helpful to have the regulatory enforcement. At this point, there will be regulatory assessment and those aspects are going to be related to people I do not influence and agencies that I do not influence.

I believe that they should act in the interest that they believe is best for our patients. When we look at the totality of data, we certainly have some very strong data in support of this [approach]. It’ll be practice changing when the regulators say that it’s practice changing.

References

1. Sartor O, Castellano Gauna DE, Herrmann K, et al. Phase III trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). Ann Oncol. 2023;34(suppl 2):S1324-S1325. doi:10.1016/j.annonc.2023.10.085
2. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA. March 23, 2022. Accessed December 7, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer