Pluvicto, Chemo or a Targeted Triplet? Decision Points in Newly Diagnosed Metastatic Prostate Cancer

  • Physicians boil this crowded treatment landscape down to three decisive checkpoints: confirm the hormonal doublet, test for actionable biomarkers, and determine whether the disease biology favors chemotherapy or radioligand therapy.
  • Confirm the foundational doublet and decide what the “third drug” should be. As Dr. Morris puts it, “The core therapy…should be a two‑drug hormonal regimen. That’s the very minimum.” The clinical decision is whether the add‑on should be a biomarker‑selected agent (BRCA2 → niraparib/abiraterone; PTEN loss → capivasertib/abiraterone) or a non‑genomic intensification strategy.
  • Use tumor profiling to sort patients into targeted triplets vs. non‑actionable biology. Physicians must check both NGS and PTEN IHC to identify candidates for the two FDA‑approved biomarker‑defined triplets.
  • Match treatment to disease biology: High PSMA expression and bone‑only/bone‑nodal disease support Pluvicto; low‑burden oligometastatic disease may warrant SBRT first; high‑volume or neuroendocrine‑leaning disease pushes toward chemotherapy.

The question in newly diagnosed metastatic prostate cancer is no longer whether to intensify treatment; instead, it is what to add.

As of October 2026, the FDA has approved three biomarker-selected options in this setting: niraparib plus abiraterone (Akeega) for BRCA2-mutated disease, capivasertib plus abiraterone for PTEN-deficient disease, and Pluvicto (lutetium Lu 177 vipivotide tetraxetan) plus an ARPI for PSMA-positive disease.

Dr. Michael Morris, Prostate Cancer Section Head in the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center, tells SurvivorNet how he sequences those decisions.

Dr. Morris was a U.S. principal investigator of PSMAddition, the phase 3 trial behind the Pluvicto approval, according to Novartis.

The Doublet Is the Floor

“The core therapy for nearly everybody who has a newly diagnosed metastatic prostate cancer should be a two-drug hormonal regimen. That’s the very minimum,” Dr. Morris says.

That means Androgen Deprivation Therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI). Everything else in his framework is layered on top.

Step Two Comes First In Practice: Test the Tumor

“Everybody who has metastatic prostate cancer should get a genomic profiling of their disease in order to determine whether they are candidates for one of several genomically defined therapeutics, which should be given as a third drug on top of the two-drug regimen,” he said.

The National Comprehensive Cancer Network (NCCN), which recommends germline and somatic tumor testing for HRR gene alterations in all patients with metastatic prostate cancer.

Two targeted triplets now have labels.

In AMPLITUDE (n=696, HRR-altered mCSPC), niraparib plus abiraterone produced an rPFS HR of 0.46 (95% CI 0.32–0.66) in the BRCA2 subgroup.

The non-BRCA2 HR was 0.88 (95% CI 0.63–1.24), which is why the label is restricted to BRCA2.

CAPItello-281 (n=1,012) selected patients with PTEN deficiency, defined as PTEN loss in at least 90% of tumor cells by immunohistochemistry. That is a protein-based assay, not a sequencing result, so “profiling” in practice means NGS plus PTEN IHC.

The Third Option

“For those who aren’t candidates for a genomically defined therapy, consideration should be given to a third drug with either chemotherapy or with Pluvicto,” Dr. Morris says.

His chemotherapy profile: “Those with the least differentiated disease and high disease volumes, and perhaps there is a neuroendocrine feature to their disease, those are the patients that we tend to think of as chemotherapy appropriate.”

Neuroendocrine-differentiated prostate cancer tends to lose PSMA expression, because PSMA (FOLH1) is AR-regulated according to a study published in “Frontiers in Oncology.” Aggressive-variant and neuroendocrine disease is platinum-sensitive, though responses tend to have “short-lived clinical benefit,” according to research published in “Cancers.”

Patients Most Suitable for Pluvicto

“For patients who are candidates for triplet therapy but don’t have those features and do have avidly expressing, that is PSMA-avid disease, and bone-only disease or bone and nodal disease, they do not have a genomic mutation that is actionable; those are the patients that I think are really quite appropriate for Pluvicto,” Dr. Morris explains.

PSMAddition randomized 1,144 patients to Pluvicto plus ADT and an ARPI versus ADT and an ARPI alone. The primary rPFS HR was 0.72 (95% CI 0.58–0.90).

An updated analysis showed an rPFS HR of 0.67 (95% CI 0.55–0.82) and an OS HR of 0.80 (95% CI 0.63–1.01), with OS still immature.

Grade ≥3 adverse events occurred in 50.7% of patients on the Pluvicto triplet vs 43.0% on ADT plus an ARPI.

Low Burden: Radiate First, Save the Radioligand

“Let’s say you have just one bone lesion or two bone lesions; give that patient SBRT, focal external beam radiation therapy, to those lesions and save the Pluvicto for a rainier day when there may be more disease,” Dr. Morris says.

The randomized phase 2 ORIOLE trial supports metastasis-directed SBRT in recurrent oligometastatic hormone-sensitive disease. Progression at 6 months was 19% with SABR vs 61% with observation.

ORIOLE enrolled recurrent rather than de novo disease, and phase 3 survival data for SBRT on top of a systemic triplet are not yet available. Novartis is testing Pluvicto in oligometastatic disease in the PSMA-DC trial (NCT05939414).

Three Big Questions 

Dr. Morris reduces it to a sequence:

“Step one is what’s their volume of disease? Step two is what’s the histology and the genomics of the disease? And step three is what’s the PSMA avidity of the disease?”

What Comes Next

Several questions remain open. These include final PSMAddition OS, whether radioligand therapy should be combined with or replace docetaxel in high-volume disease, and whether PSMA-PET-defined oligometastatic disease warrants SBRT, Pluvicto, or both.