177Lu-PSMA-617 vs. ARDT for Prostate Cancer

(PSMAfore Trial)

Not currently recruiting at 117 trial locations

Overseen By Robert Zlotecki

Age: 18+

Sex: Male

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must be taking: Second generation ARDT

Must not be taking: Cytotoxic chemotherapy, Immunotherapy

Disqualifiers: CNS metastases, Cardiac arrhythmias, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 15

Duration: 36 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates whether a new treatment, 177Lu-PSMA-617, can improve outcomes for people with metastatic castrate-resistant prostate cancer (mCRPC) compared to the current standard therapy, Androgen Receptor-Directed Therapy (ARDT). The researchers aim to determine if the new treatment helps people live longer or slows cancer progression as seen on scans. Participants should have prostate cancer that has spread and continued to grow despite previous hormone therapy, but they should not have received certain chemotherapy treatments for their cancer. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking advancements in prostate cancer treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on certain treatments like chemotherapy, immunotherapy, or investigational agents during the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that 177Lu-PSMA-617 is generally well-tolerated by patients. In studies, some patients experienced side effects, but these were often manageable. For example, mild to moderate tiredness and dry mouth were reported. Serious side effects occurred less frequently.

For those considering joining a trial, it's important to know that 177Lu-PSMA-617 has been extensively studied in other trials, providing doctors with a clear understanding of its safety.

Androgen receptor-directed therapy (ARDT), including drugs like abiraterone and enzalutamide, is already approved for treating prostate cancer. These treatments are generally safe but can cause side effects such as high blood pressure and liver problems.

Both treatments have been tested in people before, providing solid information about their effects on patients. Discuss any concerns with your doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for prostate cancer?

Researchers are excited about 177Lu-PSMA-617 because it offers a unique approach to treating prostate cancer by directly targeting prostate-specific membrane antigen (PSMA). This is different from standard treatments like androgen receptor-directed therapies (ARDTs), which focus on blocking hormones that fuel prostate cancer growth. By using a radioactive compound, 177Lu-PSMA-617 delivers radiation directly to cancer cells, potentially sparing healthy tissue and improving precision. This targeted approach could offer new hope for patients, especially those who may not respond well to traditional hormone therapies.

What evidence suggests that this trial's treatments could be effective for prostate cancer?

Research has shown that 177Lu-PSMA-617, a treatment under study in this trial, holds promise for treating advanced prostate cancer that no longer responds to hormone therapy. One study found that this treatment extended the time patients lived without their cancer worsening, averaging 8.7 months compared to 3.4 months for those receiving standard care. Additionally, about half of the patients experienced a significant drop in their PSA levels, often indicating a positive response to the treatment. Overall, patients receiving 177Lu-PSMA-617 lived longer, with some studies noting an average increase in survival of about four months. These findings suggest that 177Lu-PSMA-617 could be an effective option for managing this type of prostate cancer. Meanwhile, another arm of this trial will evaluate the effectiveness of Androgen receptor-directed therapy (ARDT), including treatments like abiraterone or enzalutamide, as a comparator. ^{1 2 5 6 7}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

Adults over 18 with advanced prostate cancer that's resistant to castration and has spread, who've only had one type of hormone therapy (like abiraterone or enzalutamide) but not chemo for this stage. They must have a low testosterone level, be in good physical shape (ECOG 0-1), and show positive signs on a specific PET scan. Major organs need to function well, they can't have severe allergies to trial drugs or certain heart conditions, and should agree to use contraception.

Inclusion Criteria

My prostate cancer is worsening despite treatment.

My cancer has worsened only once after treatment with a specific prostate cancer medication.

My organs are functioning well, including my bone marrow, liver, kidneys, and I have a good level of albumin.

Exclusion Criteria

Concurrent serious medical conditions that may impair study participation or cooperation.

I have had chemotherapy, immunotherapy, or biological therapy for prostate cancer.

I have brain metastases but am not stable, have symptoms, or need steroids for brain function.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Randomization

Participants are randomized to receive either 177Lu-PSMA-617 or a change in ARDT treatment

1 week

Treatment

Participants receive 177Lu-PSMA-617 every 6 weeks for 6 cycles or a change in ARDT treatment

36 weeks

6 visits (in-person)

End of Treatment

End of Treatment visit conducted ≤ 7 days after the last day of study treatment period

1 week

Post-treatment Follow-up

Participants are monitored for safety and effectiveness after treatment, including a 30-day safety follow-up and long-term follow-up

43 months

Visits every 8 weeks initially, then every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 177Lu-PSMA-617
• ARDT

Trial Overview The study is testing if the drug 177Lu-PSMA-617 improves survival without cancer progression compared to changing the current hormone therapy in men whose prostate cancer has worsened despite treatment. About 450 participants will be randomly assigned equally into two groups: one receiving the new drug and supportive care; the other getting an alternative hormone therapy plus supportive care.

How Is the Trial Designed?

Group I: 177Lu-PSMA-617 Experimental Treatment 2 Interventions

Participants received 7.4 GBq (200 mCi) +/- 10% 177Lu-PSMA-617 once every 6 weeks for 6 cycles. Best supportive care, including ADT could be used.

Group II: Androgen receptor-directed therapy (ARDT) Active Control 2 Interventions

For participants randomized to the ARDT arm, abiraterone or enzalutamide was administered per the physician's orders. Best supportive care, including Androgen deprivation therapy (ADT) could be used.

177Lu-PSMA-617 is already approved in United States, European Union for the following indications:

Approved in United States as Pluvicto for:

• Metastatic castration-resistant prostate cancer

Approved in European Union as Pluvicto for:

• Metastatic castration-resistant prostate cancer

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

[177Lu]Lu-PSMA-617 (PluvictoTM) is an FDA-approved treatment for prostate cancer specifically for patients with PSMA-positive metastatic castration-resistant prostate cancer who have already undergone other therapies.

This treatment uses a targeted radioligand therapy that delivers radiation directly to tumor cells, effectively killing them while minimizing damage to healthy tissue, as shown in multiple clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[177Lu]Lu-PSMA-617 (PluvictoTM): The First FDA-Approved Radiotherapeutical for Treatment of Prostate Cancer. Hennrich, U., Eder, M.[2022]

In a study involving 145 patients with metastatic castration-resistant prostate cancer (mCRPC), treatment with 177Lu-PSMA-617 showed a biochemical response rate of 45%, indicating high efficacy, especially with 40% of patients responding after just one treatment cycle.

The therapy demonstrated a favorable safety profile, with only 10% of patients experiencing severe hematotoxicity and 8% reporting dry mouth, suggesting it may be a safer option compared to other third-line treatments for mCRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients. Rahbar, K., Ahmadzadehfar, H., Kratochwil, C., et al.[2022]

Treatment with lutetium-177 (177Lu)-prostate-specific membrane antigen (PSMA) significantly reduces prostate-specific antigen (PSA) levels in patients with advanced metastatic prostate cancer, especially after the first treatment cycle.

The therapy shows a beneficial effect on reducing lymph node metastasis, while also indicating potential negative impacts on visceral metastasis, highlighting its efficacy in managing certain aspects of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Advanced Metastatic Prostate Cancer Using Molecular-Targeted Therapy: Radioligand Lutetium-177 Prostate-Specific Membrane Antigen. Rathore, R., Rangrej, SB., Kieme, I., et al.[2023]

[177Lu]Lu-PSMA-617 is effective in targeting prostate cancer, but some patients do not respond well; ongoing research is exploring combination therapies to improve outcomes for both treatment-naïve and resistant patients.

Combining [177Lu]Lu-PSMA-617 with other treatments, such as alpha radiation emitters and immune checkpoint inhibitors, shows promise in enhancing therapeutic responses, particularly for patients who have developed resistance to initial therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards Improving the Efficacy of PSMA-Targeting Radionuclide Therapy for Late-Stage Prostate Cancer-Combination Strategies. Arbuznikova, D., Eder, M., Grosu, AL., et al.[2023]

The VISION trial demonstrated that Lutetium-177[177Lu]Lu-PSMA-617 significantly improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy, marking a breakthrough in treatment options.

Both the VISION and TheraP trials showed that [177Lu]Lu-PSMA-617 has a favorable safety profile, with common side effects including fatigue and nausea, suggesting it could be beneficial even for patients who have undergone extensive prior treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lutetium-177-PSMA-617: A Vision of the Future. Chandran, E., Figg, WD., Madan, R.[2022]

177Lu-PSMA-617 therapy has shown promising efficacy in treating metastatic prostate cancer, with a majority of patients experiencing a decline in prostate-specific antigen (PSA) levels, which is associated with longer survival rates.

The analysis of 17 studies indicated that while significant toxicities were infrequent, cytopenias were noted, and factors like performance status and tumor grade were important predictors of treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of 177Lu-PSMA-617 in Patients With Metastatic Castration-Resistant Prostate Cancer. Sun, M., Niaz, MO., Nelson, A., et al.[2020]

In a phase 3 trial involving 831 patients with metastatic castration-resistant prostate cancer, the addition of 177Lu-PSMA-617 to standard care significantly improved both imaging-based progression-free survival (8.7 months vs. 3.4 months) and overall survival (15.3 months vs. 11.3 months).

While 177Lu-PSMA-617 was associated with a higher incidence of grade 3 or above adverse events (52.7% vs. 38.0%), it did not negatively impact the patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. Sartor, O., de Bono, J., Chi, KN., et al.[2023]

In a study of 84 Asian patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Lutetium-177 PSMA radioligand therapy, the median overall survival was 12.2 months and the median PSA progression-free survival was 5.2 months, indicating promising efficacy.

A significant 51.8% of patients experienced a PSA decline of 50% or more, which was linked to longer overall survival and PSA progression-free survival, while the treatment showed a manageable safety profile with grade 3 hematotoxicity occurring in 13 out of 78 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes and prognostic predictors of Lu-177 PSMA radioligand therapy in metastatic castration-resistant prostate cancer (Asian Population Study). Chua, WM., Lam, WW., Tong, AK., et al.[2023]

In a phase 2 trial involving 30 men with metastatic castration-resistant prostate cancer, 57% achieved a significant PSA decline of 50% or more after treatment with Lutetium-177 [177Lu]-PSMA-617, indicating its efficacy in this patient population.

The treatment was associated with low toxicity, with the most common side effects being mild dry mouth and transient nausea, and it also led to clinically meaningful improvements in pain and quality of life for many patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Hofman, MS., Violet, J., Hicks, RJ., et al.[2021]

The UpFrontPSMA trial is evaluating the effectiveness and safety of combining lutetium-177 (177 Lu)-PSMA-617 with docetaxel in 140 men with newly diagnosed metastatic hormone-naïve prostate cancer, aiming to determine the proportion of patients achieving undetectable PSA levels after 12 months.

This study is significant as it compares the experimental treatment to standard docetaxel therapy while all patients receive continuous androgen deprivation therapy, potentially providing insights into improved treatment strategies for this aggressive cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

UpFrontPSMA: a randomized phase 2 study of sequential 177 Lu-PSMA-617 and docetaxel vs docetaxel in metastatic hormone-naïve prostate cancer (clinical trial protocol). Dhiantravan, N., Emmett, L., Joshua, AM., et al.[2021]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2107322

Lutetium-177–PSMA-617 for Metastatic Castration ... Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40752988/

Outcomes for [ 177 Lu]Lu-PSMA-617 with and Without ... Key findings and limitations: Among 256 patients, 106 (41.4%) received an ARPI with [177Lu]Lu-PSMA-617. Those receiving an ARPI had lower ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.97

Real world outcomes of 177 Lu-PSMA-617 ... The cohort completed a median number of 4 cycles of 177Lu-PSMA-617; 35.7% completed six cycles. The overall cohort had a 12-month survival of ...

4. jnm.snmjournals.org jnm.snmjournals.org/content/66/supplement_1/251559

Overall survival of prostate cancer patients treated with Lu-177 ... Median overall survival was found to be approximately 4 months higher than OS reported in VISION trial and equal to that in TheraP trial.

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37818966/

The real-world outcomes of Lutetium-177 PSMA-617 ... The Lu-177 PSMA-617 RLT led to a significant PSA response, with 50.6% of patients achieving a >50% decrease in PSA levels. Median overall ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.TPS294

Long-term safety outcomes of 177Lu-PSMA-617 in patients ... It is important to further characterize long-term safety outcomes in 177 Lu-PSMA-617–treated patients, with particular regard to potential treatment-related ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)00852-X/fulltext

Final overall survival and safety analyses of the phase III ... At the time of the final OS analysis, 299 deaths were reported in 142/234 participants (60.7%) in the 177Lu-PSMA-617 arm and 157/234 (67.1%) in ...