Pluvicto for mHSPC?

[FaithOverFear104]

Good morning - Just looking for clarification/insight on the announcement pasted below. If I am understanding correctly, it looks like it means that Pluvicto is now an option for newly diagnosed mHSPC -- as a possible alternative to Triplet Therapy with chemo, etc. Is that correct? If so, that's great news.

But, I am wondering if it could mean that all mHSPC patients could possibly be eligible for Pluvicto now?

The treatment options for men who continue to be hormone sensitive after first-line treatment seem to be pretty limited from what we can tell.

My husband was successfully treated with Triplet Therapy not long after diagnosis in January 2022 and has continued to be hormone sensitive. Currently on Intermittent Enzalutamide monotherapy.

We are looking for what options could be available to him beyond just full, continuous ADT and wonder if this is something to ask his MO about, or is he still not eligible because he is three plus years in, has already had chemo, etc.

Anyone know of any other treatment options on the horizon for men with mHSPC?

Thanks in advance.

FDA approves Novartis radioligand therapy Pluvicto® for earlier use before chemotherapy in PSMA-positive metastatic castration-resistant prostate cancer

Mar 28, 2025

New indication approximately triples eligible patient population, allowing Pluvicto® to be used after one androgen receptor pathway inhibitor (ARPI) and now before chemotherapy

Basel, March 28, 2025 – Novartis announced today that the US Food and Drug Administration (FDA) approved Pluvicto® (lutetium Lu 177 vipivotide tetraxetan) for patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with an androgen receptor pathway inhibitor (ARPI) therapy and are considered appropriate to delay chemotherapy.

The expanded indication, which approximately triples the number of patients eligible to receive Pluvicto, is based on results of the Phase III PSMAfore trial. In the study, Pluvicto reduced the risk of radiographic progression or death by 59% (HR=0.41; 95% CI: 0.29, 0.56; p<0.0001) compared to a change in ARPI in patients with PSMA-positive mCRPC after treatment with ARPI therapy. At an updated exploratory analysis, Pluvicto more than doubled median radiographic progression-free survival (11.6 months vs. 5.6 months)*.

“The earlier indication for Pluvicto could really change our treatment paradigms for patients with mCRPC. It offers a targeted therapy that better delays disease progression compared to a second ARPI,” said Michael Morris, MD, Prostate Cancer Section Head, GU Oncology, Memorial Sloan Kettering Cancer Center, and the Principal Investigator of the study in the US. “This approval is a significant step forward and should open the doorway to a therapy that has clear clinical advantages for the patient with mCRPC who has progressed on one ARPI and has not received chemotherapy.”

In PSMAfore, the final overall survival (OS) analysis numerically favored Pluvicto, with a hazard ratio of 0.91 (95% CI: 0.72, 1.14), but was not statistically significant. The OS analysis was confounded by the high rate of patients who crossed over from the control arm to Pluvicto (60.3%). When adjusted for crossover, the OS hazard ratio was 0.59 (95% CI: 0.38, 0.91) with the inverse probability of censoring weighting (IPCW) method**.

Additional findings from the PSMAfore study showed Pluvicto demonstrated a consistent and favorable safety profile. The most frequently reported all-grade adverse events for Pluvicto were primarily Grade 1-2 and included dry mouth (61%), fatigue (53%), nausea (32%), and constipation (22%). Pluvicto did not impair the ability of patients to be treated with subsequent chemotherapy.

“The clinical development of PSMA-targeting radioligand therapy has provided important insights into the treatment of metastatic castration-resistant prostate cancer,” said Oliver Sartor, MD, Chair of Genitourinary Cancer Disease Group and Director of Radiopharmaceutical Clinical Trials, Mayo Clinic. “The trial data demonstrated a clear clinical benefit in delaying disease progression in eligible patients, offering an additional therapeutic approach in this setting.”

More than 35,000 men die from prostate cancer each year, and the incidence of the disease is rising.2 Half of patients with mCRPC will not live long enough to receive a second treatment.1 While hormone therapy and chemotherapy are essential treatments for mCRPC, they may not be appropriate for all patients.3 Many patients and their healthcare providers prefer to avoid or delay chemotherapy due to side effects, and treatment guidelines recommend avoiding the use of multiple ARPIs.4-7

“With worsening outcomes after each successive line of treatment, patients with this type of metastatic prostate cancer and their families have long faced limited options and uncertain outcomes,” said Gina Carithers, CEO and President of the Prostate Cancer Foundation.8 “The now expanded approval of Pluvicto is an empowering development for the prostate cancer community. We now have more choices earlier in the treatment journey, enabling patients to advocate for their preferences and work with their oncologist or urologist to determine the treatment option that best suits their needs.”

“Today’s approval for an expanded indication for Pluvicto brings more choice to nearly three times as many patients, enabling us to further establish radioligand therapies as a pillar in cancer care,” said Victor Bultó, President US, Novartis. “As pioneers in the RLT space, Novartis is committed to providing education, resources, and practical solutions to healthcare providers to help ensure access for all patients navigating this challenging disease.”

About Pluvicto® (lutetium Lu 177 vipivotide tetraxetan)

Pluvicto is an intravenous radioligand therapy (RLT) combining a targeting compound (a ligand) with a therapeutic radionuclide (a radioactive particle, in this case lutetium-177). After administration into the bloodstream, Pluvicto binds to target cells, including prostate cancer cells that express PSMA, a transmembrane protein. Once bound, energy emissions from the radioisotope damage the target cells and nearby cells, disrupting their ability to replicate and/or triggering cell death.

Based on two Phase III studies, Pluvicto is the only PSMA-targeted agent proven to significantly improve rPFS and demonstrate a safety profile with proven tolerability in both pre- and post-taxane settings for patients with ARPI-treated, PSMA-positive mCRPC. Pluvicto is the first and only targeted radioligand therapy for patients with PSMA-positive mCRPC before the need for chemotherapy.

Novartis is investigating Pluvicto in earlier stages of disease, including metastatic hormone-sensitive prostate cancer (PSMAddition, NCT04720157) and oligometastatic prostate cancer (PSMA-DC, NCT05939414).

*Results observed at third interim analysis of PSMAfore (NCT04689828) with a data cutoff of February 2024. Pluvicto met its primary endpoint of rPFS at the primary analysis based on centrally confirmed rPFS events with an October 2022 data cut off.

**IPCW is an established statistical method that includes a number of assumptions

[Tall_Allen]

No. It has only been approved before chemo for mCRPC.

healthunlocked.com/advanced...

[FaithOverFear104 in reply to Tall_Allen]

Oh thank you. So sorry. I should have searched the forum first.

[FaithOverFear104 in reply to Tall_Allen]

But still wondering what treatment options might be (currently or on the horizon), if any, other than full, continuous ADT for men who are still hormone sensitive after chemo, etc.

Can't quite understand why so many treatments require men to be castrate resistant.

[Tall_Allen in reply to FaithOverFear104]

Almost all clinical trials for new drugs are tested in men who are mCRPC first. This assures the quickest path to new drug approval (new drug trials usually have to continue until half the control group has died or surrogate endpoint), and provides the new drug for those patients who are most likely to survive because of it.

After a new drug gets approved for a more serious indications, trials for less serious indications (like mHSPC) can begin. Because men with mHSPC live much longer, the FDA often does not require proof of survival extension and the trial can be shortened.

There are trials to use Pluvicto for mHSPC. The first, the PSMAddition trial began in 2021 (even before Pluvicto was first approved) and is expected to have first results later this year. It also uses rPFS as its primary endpoint.

So far, Zytiga, Xtandi, Erleada, docetaxel, Nubeqa+docetaxel, Zytiga+docetaxel, and Orgovyx have been approved in newly diagnosed metastatic men.

[FaithOverFear104 in reply to Tall_Allen]

Thank you so much for explaining all of that. Three years in and still trying to understand how it all works. I appreciate you taking the time.

[GP24]

You can take part in a clinical trial which tests Pluvicto in mHSPC. Here is an overview of all the trials: urotoday.com/conference-hig... You can look up the details of these trials at clinicaltrials.gov.

This overview mentions the PSMA fore trial. This has completed and was the reason for the FDA to change the current indication for Pluvicto.

[FaithOverFear104 in reply to GP24]

Thank you. We will look into trials.

[Chewiemo]

I participated in the pSMAaddition trial Tall Allen referenced. In addition to SOC of Lupron and zytiga I had 6 pluvicto treatments in January 2023. Over two years later psa still undetected and scans show no progression. I’m interested to learn they will publish results of study this year.

[FaithOverFear104 in reply to Chewiemo]

So glad to hear that you had good outcome and that you are doing well. Looking forward to seeing the results of the study as well.

[Chewiemo]

some predict pluvicto will become soc for HSPC in next year or so.

[Yzinger in reply to Chewiemo]

And what would that mean? Dropping hormone therapy?

[Chewiemo in reply to Yzinger]

No it would be part of triplet therapy instead of chemo.

[j-o-h-n]

With a wife like you, who needs a girlfriend. Lucky, Lucky man.

Good Luck, Good Health and Good Humor.

j-o-h-n

[FaithOverFear104 in reply to j-o-h-n]

Awe - that's nice of you to say. Thank you. I'm pretty lucky too.

[PELHA]

At our appointment with MO this week (Dr. Bryce at City of Hope) perhaps this is why he said if husband needs to go beyond his doublet therapy he would likely have him do Pluvicto (even though he said husband could tolerate chemo very well given his physical condition.). But he expects this will not be needed for several years. Hope so!!

[FaithOverFear104 in reply to PELHA]

Yes - hope that's the case for your husband.