Dr Sartor on Efficacy and Safety of Lutetium Lu 177 Vipivotide Tetraxetan in Taxane-Naive mCRPC

Oliver Sartor, MD, director, radiopharmaceutical trials, Mayo Clinic, discusses updated efficacy findings from the phase 3 PSMAfore trial (NCT04689828) of lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) in patients with previously treated, taxane-naive metastatic castration-resistant prostate cancer (mCRPC).

The open-label, multicenter randomized study compared the efficacy of lutetium Lu 177 vipivotide tetraxetan with standard-of-care treatment with an androgen receptor pathway inhibitior (ARPI), Sartor begins. All patients on the study were required to confirmed mCRPC, have progressed on a prior second-generation ARPI, and be eligible for treatment with a second-line ARPI. Other eligibility criteria included the presence of metastatic disease, and confirmed PSMA PET positivity. Patients were randomly assigned to receive either lutetium Lu 177 vipivotide tetraxetan or an ARPI that they did not receive in the first-line setting.

Data from the second interim analysis of PSMAfore showed that patients treated with lutetium Lu 177 vipivotide tetraxetan experienced prolonged radiographic progression-free survival (rPFS) vs treatment with an an ARPI, with a hazard ratio of 0.43 (95% CI, 0.33-0.54), Sartor reports. The median rPFS with lutetium Lu 177 vipivotide tetraxetan was 12.02 months (95% CI, 9.30-14.42) vs 5.59 months (95% CI, 4.17-5.95) with an ARPI, he adds. Moreover, patients on the lu 177 vipivotide tetraxetan arm experienced an objective response rate of 50.7% (95% CI, 38.6%-62.8%) vs 14.9% (95% CI, 7.7%-25.0%) in the ARPI arm.

An analysis of the trial’s secondary end points showed that the hazard ratio for the crossover-adjusted overall survival (OS) was 0.80 (95% CI, 0.48-1.33), Sartor continues. As the range between confidence intervals surpassed 1, this result was not deemed statistically significant, he explains. Additional assessments of health-related quality of life, time to prostate-specific antigen (PSA) progression, time to pain progression, PSA decline rate, and objective response, all favored lutetium Lu 177 vipivotide tetraxetan, Sartor details.

The incidence of grade 3/4 adverse events (AEs) and dose adjustments were notably lower with lutetium Lu 177 vipivotide tetraxetan compared with secondary hormonal therapy, Sartor states, adding that this was an unexpected finding. Discontinuation rates were low, at 5% in both treatment arms, he adds. These findings underscore the favorable safety and efficacy profile of lutetium Lu 177 vipivotide tetraxetan across a spectrum of clinical end points, Sartor concludes.

Videos

Oliver Sartor, MD, discusses updated efficacy findings from the phase 3 PSMAfore trial of lutetium Lu 177 vipivotide tetraxetan in patients with previously treated, taxane-naive metastatic castration-resistant prostate cancer.

 The main factors that I look at when I’m assessing a patient with mCRPC [metastatic castration-resistant prostate cancer] are their prior therapy exposures, genetic profile, and phenotype: basically, the pattern of spread and the clinical prognostic factors that help you make a decision. Generally, the NCCN [National Comprehensive Cancer Network] guidelines, which we recently updated, can provide a lot of this information. Genetic profiling could be helpful even in the frontline setting. For example, the PROpel and MAGNITUDE studies suggest that if a patient has a 

 mutation, there may be a substantial benefit to the combination of abiraterone plus olaparib or niraparib, pending FDA authorization. But in most patients who are HRD [homologous recombination deficiency] negative, using an AR [androgen receptor] inhibitor as a frontline therapy is the most common practice.

We’re increasingly seeing these therapies move into earlier settings. When a second AR inhibitor isn’t the standard of care and you’re picking a non–cross-resistant drug or something else that may benefit the patients, radium, [lutetium-] PSMA [prostate-specific membrane antigen], docetaxel, and cabazitaxel are good weapons. Molecular profiling can also help. If a patient has had an AR inhibitor and has an HRD mutation, olaparib and rucaparib are available. For a patient who has MSI [microsatellite instability]–high [disease], I’ve seen some of the greatest remissions that I’ve ever seen with pembrolizumab. It would certainly be worth testing for the 3% to 5% of patients who can have an extraordinary response.

 Thankfully for me and the patients I see every day, we have more options today than we did before. That being said, for the average practitioner who sees many types of cancers, it can be complicated. One [clinical pearl] I’d offer is don’t be afraid to ask for help, whether that’s reaching out to a consultant or sending the patient for a second opinion. That’s quite important.

It’s important to recognize that multiple drugs are better than a single drug in the first-line [noncastration] setting. That’s one of the biggest travesties that I see. Our data are a little behind, but there are still too many patients receiving only ADT [androgen deprivation therapy] or ADT plus a nonsteroidal or old-fashioned antiandrogen, such as bicalutamide, in the first-line setting. But at least 2 drugs, and potentially 3, are indicated for most patients.

[It’s also important to] remember clinical trials. As I mentioned, clinical trials are available for every single line of therapy. If you’re in private practice and running out of options, it’s a no-brainer to find out what clinical trials [exist]. But they also exist for earlier lines of therapy, including frontline therapy. Patients as well as physicians can benefit from participation in clinical trials.

 I’ve mentioned a few clinical trials and I’d like to emphasize them again. One is the PSMAfore trial, which is looking at patients with metastatic CRPC who have failed a novel hormone, such as apalutamide, darolutamide, enzalutamide, or abiraterone. We also have the SPLASH trial that’s in a similar space. Both of these use PSMA-lutetium. But [another] important trial is PSMAddition, where [we have a] hormone-sensitive patient who’s PSMA-positive and give them novel hormones—ADT-apalutamide, ADT-abiraterone, whatever—[including or excluding] PSMA-lutetium.

Moving forward, we’re going to explore other isotopes. We have isotopes right now with thorium-227 and another trial with actinium-225 that we’re exploring. We have a variety of radiopharmaceutical trials, targeted trials with AR mutations, and some bispecific [antibody] trials, including targeting STEAP1. All of these are of potential interest for those with advanced prostate cancer.

Highlighting ongoing clinical trials in prostate cancer, experts share practical advice on optimal treatment strategies for community physicians.

Metastatic CRPC: Clinical Pearls and Practical Advice

A. Oliver Sartor, MD, a professor of medicine and the medical director of the Tulane Cancer Center and the Bernadine Laborde Professor of Cancer Research in the Department of Urology at Tulane University, discusses the significance of the REASSURE trial in patients with metastatic castration-resistant prostate cancer.

In the global observational trial, investigators are examining the safety of radium-223 dichloride (Xofigo) in routine clinical practice over 7 years of follow up in this patient population. A second prespecified interim analysis of the trial focused on outcomes of patients who received lutetium-177 PSMA-617 (177Lu-PSMA) following radium-223. What was understood from the study of this registry is that a series of patients did receive sequential radiopharmaceuticals—alpha and beta particles, which were given in sequence, says Sartor. This is important because no prior data are available on this. Although it is difficult to discern whether there was activity with the approach, no safety signals were identified, adds Sartor.

The results from the trial presented during the 

 are not particularly exciting, Sartor explains, they are still important in that they indicate that 177Lu-PSMA and radium-223 can be used sequentially without undo harm. Prospective trials will need to be conducted to properly determine which patients might or might not benefit from this approach and whether any toxicities that were not recognized do exist, says Sartor. This research is very preliminary, but it is the first step, that is what makes it important, concludes Sartor.

Oliver Sartor, MD, discusses the significance of the REASSURE trial in patients with metastatic castration-resistant prostate cancer.

Dr. Sartor on the Significance of the REASSURE Trial in mCRPC

A. Oliver Sartor, MD, a professor of medicine and medical director of the Tulane Cancer Center, and C. E. and Bernadine Laborde Professor of Cancer Research in the Department of Medicine and the Department of Urology at Tulane University, discusses the design of the REASSURE trial (NCT02141438) in patients with metastatic castration-resistant prostate cancer (mCRPC).

In the global, observational trial, investigators examined the long-term follow-up results of patients with mCRPC who received lutetium-177 PSMA-617 therapy after radium-223 dichloride (Xofigo), says Sartor. Graciously, investigators have a very extensive database that can be utilized to fully understand what the ultimate outcomes might be for this patient population, adds Sartor.

In addition to the information compiled on secondary cancers and survival rates, investigators also collected data with regard to various subsequent therapies, explains Sartor. To date, investigators are still trying to determine how effective these subsequent therapies were. However, factors such as the duration of time a patient received these therapies are being closely analyzed, adds Sartor.

Ultimately, the substrate of the study was to closely observe the outcomes of patients who were treated with radium-223 at selective practices as part of a prospective registry, and reporting on the subsequent use of 177Lu-PSMA therapy in these patients, concludes Sartor.

A. Oliver Sartor, MD, discusses the design of the REASSURE trial (NCT02141438) in patients with metastatic castration-resistant prostate cancer.

Dr. Sartor on Outcomes With 177Lu-PSMA-617 After Radium-223 in mCRPC

A. Oliver Sartor, MD, professor of medicine, medical director, Tulane Cancer Center, and C. E. and Bernadine Laborde Professor of Cancer Research, Departments of Medicine and Urology, Tulane University, discusses the rationale for investigating the sequential use of beta emitters and alpha emitters in metastatic castration-resistant prostate cancer (mCRPC).

Beta emitters such as samarium-153 and strontium-89 have been used in mCRPC for years, says Sartor.

Novel beta emitters including lutetium-177 PSMA-617 (

Lu-PSMA-617) have demonstrated promising efficacy in this setting, explains Sartor. Additionally, the phase 3 VISION trial, which is evaluating 

Lu-PSMA-617 plus standard of care compared with standard of care alone in mCRPC, recently completed accrual.

Notably, the majority of trials investigating 

Lu-PSMA-617 have excluded patients who received a prior radiopharmaceutical, says Sartor.

As such, evaluating the sequential use of the beta emitter 

Lu-PSMA-617 and the alpha emitter radium-223 dichloride (Xofigo) may have utility in mCRPC, concludes Sartor.

A. Oliver Sartor, MD, discusses the rationale for investigating the sequential use of beta emitters and alpha emitters in metastatic castration-resistant prostate cancer.



Dr. Sartor on Sequential Use of Beta and Alpha Emitters in mCRPC

A. Oliver Sartor, MD, professor of medicine, medical director, Tulane Cancer Center, and C. E. and Bernadine Laborde Professor of Cancer Research, Departments of Medicine and Urology, Tulane University, discusses the implications of prostate-specific membrane antigen (PSMA)-PET positivity in prostate cancer.

Antiandrogen agents such as enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) have shown improved metastasis-free survival in patients with nonmetastatic castration-resistant prostate cancer (CRPC).

However, a retrospective analysis of 200 patients with nonmetastatic CRPC showed that 98% of men were PSMA-PET positive. Moreover, 55% of men who had negative conventional imaging had M1 disease according to PSMA-PET.

PSMA-PET positivity may inform other potential treatment options for patients, explains Sartor. For example, patients with metastatic disease could receive radiotherapy while patients with localized disease could receive radiotherapy and potentially surgery.

Additional data regarding PSMA-PET is necessary in this space; however, new imaging modalities are expected to influence the treatment of patients with prostate cancer, concludes Sartor.

A. Oliver Sartor, MD, discusses the implications of prostate-specific membrane antigen-PET positivity in prostate cancer.



Dr. Sartor on Implications of PSMA-PET Positivity in Prostate Cancer

A. Oliver Sartor, MD, professor of medicine, medical director, Tulane Cancer Center, and C. E. and Bernadine Laborde Professor of Cancer Research, Departments of Medicine and Urology, Tulane University, discusses emerging agents in prostate cancer.

A variety of prostate-specific membrane antigen (PSMA)-targeted agents are being evaluated in prostate cancer. For example, one trial is testing an anti-PSMA agent conjugated to thorium-227, which is an alpha-emitting radionuclide, says Sartor. Another trial is evaluating a bispecific antibody T-cell engager that targets PSMA and CD3. Additional small molecules that bind to PSMA and are conjugated to radioactive iodine are also under investigation, adds Sartor.

Studies with actinium-225 are also in development. Preliminary evidence suggests that lutetium-177 PSMA-617 (Lu-PSMA-617) conjugated to actinium-225 is effective in prostate cancer. Moreover, research with an alpha emitter is yielding provocative results. Although alpha emitters, beta emitters, and small and large molecules are being evaluated in the space, Lu-PSMA-617 appears to be the furthest along in development, concludes Sartor.

Dr. Sartor on Emerging Agents in Prostate Cancer

A. Oliver Sartor, MD, professor of medicine, medical director, Tulane Cancer Center, C. E. and Bernadine Laborde Professor of Cancer Research, Departments of Medicine and Urology, Tulane University, discusses research on immunotherapy, radiopharmaceuticals, and combinations in prostate cancer.

Prostate cancer is not curable for most patients once it becomes metastatic. Some subsets of patients respond to immunotherapy; pembrolizumab (Keytruda) was approved for patients with microsatellite instability—high or mismatch repair deficiency without regard to underlying tumor source. Responses have been positive in this patient population, according to Sartor.

Research is also investigating the use of the radiopharmaceutical lutetium-177 PSMA-617 (LuPSMA) with positive responses, says Sartor. In the future, prostate cancer will be divided into smaller subsets with some receiving molecularly targeted therapy. However, Sartor prefers the radiopharmaceuticals because, according to him, they will ablate the cancer regardless of the underlying genotype.

The exploration of combination therapies in prostate cancer are examining LuPSMA with a PARP inhibitor or immunotherapy. Alpha and beta particles can also be combined, as well as alpha or beta particles with radiation sensitizers, modulating the way the drugs are excreted, concludes Sartor.

A. Oliver Sartor, MD, discusses research on immunotherapy, radiopharmaceuticals, and combinations in prostate cancer.

Dr. Sartor on Promising Treatment Approaches in Prostate Cancer

A. Oliver Sartor, MD, professor of medicine, medical director, Tulane Cancer Center, C. E. and Bernadine Laborde Professor of Cancer Research, Departments of Medicine and Urology, Tulane University, discusses the phase III VISION trial in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC).

The VISION trial recently completed its accrual of 815 patients, says Sartor. Patients will be randomized 2:1 to receive standard of care with or without the radiopharmaceutical, lutetium-177 PSMA-617 (LuPSMA). Overall survival and radiographic progression-free survival will serve as primary and secondary endpoints of the trial, respectively.

Positive results from the VISION trial could introduce an option for patients previously treated with androgen receptor inhibitors such as abiraterone acetate (Zytiga) or enzalutamide (Xtandi), and taxane chemotherapy. Currently, there is no approved treatment or standard of care in this space, concludes Sartor. 

A. Oliver Sartor, MD, discusses the phase III VISION trial in patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer.
 

A. Oliver Sartor, MD

Articles