Treating Biochemical Recurrence in Oligometastatic Prostate Cancer

In a conversation with CancerNetwork® at the 19th Annual New York GU Cancers Congress® (NY GU), Oliver Sartor, MD, director of the Transformational Prostate Cancer Research Center at LCMC Health and adjunct faculty at Tulane University School of Health, highlighted the clinical complexities of treating biochemical recurrence, particularly when PSMA-PET imaging reveals oligometastatic disease that conventional CT or bone scans fail to detect. Contextualized by a session he gave at the conference, this scenario, increasingly common in clinical practice, requires a patient-centric approach that often involves stereotactic body radiation therapy (SBRT) and a nuanced decision on whether to integrate hormonal therapy.¹

Sartor emphasized the importance of the PSMA-DC trial (NCT05939414), a phase 3 study evaluating the addition of lutetium Lu 177 vipivotide tetraxetan (lutetium-177; Pluvicto) to SBRT in patients with a prostate-specific antigen (PSA) doubling time of 10 months or less.² Beyond eligibility, certain PSMA-PET parameters serve as critical prognostic indicators; for instance, a low SUV mean, high-volume disease, and the presence of liver metastases are often predictive of a poorer response to beta-emitting therapies.

The conversation also touched upon the evolving sequencing of treatments. While PARP inhibitors remain a priority for patients with BRCA mutations, emerging data from the phase 1 LuPARP study (NCT03874884) suggest provocative potential for combining olaparib with lutetium-177.³ Looking ahead, the role of alpha-emitting isotopes like actinium-225 is gaining traction, particularly for patients who progress after beta-emitting therapy, marking a new chapter in precision oncology.

CancerNetwork: Are you able to provide background on your portion of the session from NY GU?

Sartor: My presentation today [involved] some fun things. [I talked about] about some of the novel imaging agents, some of the novel therapeutic agents, and some novel combinations. My job [was] to give an overview of some of the new things.

How should clinical teams resolve discrepancies when a patient presents with a rising PSA but a negative conventional bone scan/CT while PSMA-PET imaging shows oligometastatic disease?

The patient with biochemical recurrence with PSMA-PET–positive disease is seen every day in the clinic. It’s an extremely common scenario; [there are] probably 750,000 patients like this across the US. We manage oligometastatic disease by consideration of SBRT to all available lesions. Maybe we will consider the possibility of adding in hormonal therapy. Maybe we will consider the possibility of a protocol…and maybe we will consider the possibility of using some type of alternative to hormonal therapy. It depends on the patients, their circumstances, and the location of the lesions and the number of lesions.

There’s a bit of complexity here. I mentioned the protocol called PSMA-DC. For those with oligometastatic disease for whom all the lesions can be radiated with SBRT, we have a randomization between SBRT alone and the SBRT plus/minus the lutetium-177. That's a nice protocol for these patients. It does require PSA doubling time that is of a certain type. That can be important when PSA doubling time is 10 months or less.

Whether or not we add in hormonal therapy depends, in part, on patient preferences. Whether or not we add a little more radiation beyond SBRT is dependent on what nodal group might be involved. With nodal groups, we try to encompass the entire nodal group with a boost to PSMA-PET–positive lesions. There's a lot of complexity in making that decision. The bottom line is we see these patients every day and we try to [treat] them in a [patient-centric] fashion.

Beyond standard eligibility criteria, what specific PSMA-PET parameters, such as standard uptake value (SUV) mean thresholds or the presence of PSMA-negative lesions, are most predictive of a poor response to lutetium-177?

When it comes to lutetium-177 treatment, we have a couple of FDA-approved indications, and want to be the phase 3 VISION trial [NCT03511664] trial setting, which is post-taxane and post-ARPI [androgen receptor pathway inhibitor], as opposed to the phase 3 PSMAfore trial [NCT04689828] setting, which is going to be in the taxane-naive space, but it’s going to be a post-ADT [androgen deprivation therapy] and ARPI.^4,5 What are poor predictors? We have a lower SUV mean as being a poor predictor in general; high-volume disease is a poor predictor in general. Liver metastasis is a poor predictor in general. If we end up having any discrepancies where the areas on the PSMA-PET are relatively poorly visualized, and we know that there’s conventional imaging positive, that’s also a poor prognostic finding. We assess the patient, the SUV, the conventional imaging PSMA-PET parameters, location of the lesions, and volume of the lesions, and then decide.

Given the evolving landscape, what is the current rationale for sequencing PSMA-targeted therapies relative to PARP inhibitors or second-generation ARPIs in patients with metastatic CRPC?

When it comes to sequencing issues we don’t. We use concomitant therapies with ARPIs. PARP inhibitors are a bit complex. The PARP inhibitors, if we have a [BRCA-mutated] lesion, are typically going to be used before the PSMA–lutetium-177. If there is no evidence of a DNA repair defect, then the use of PARP inhibitors would be considered experimental.

There is a phase 1 study called the LuPARP study that looked at combination of the PARP inhibitor olaparib [Lynparza] in combination with lutetium-177, had provocative results presented by Shahneen Sandhu, MBBS, FRACP, at [the European Society of Medical Oncology (ESMO) Congress 2025]. There's a bit of discussion–– experimental––about combining the PARP inhibitor with lutetium-177. [There’s] a bit of complexity about sequencing and combination.

As we move toward new strategies, what role will alpha-emitting isotopes, such as Actinium-225, play for patients who have progressed after beta-emitting PSMA therapy?

The use of alphas post-betas is a very evolving topic. We don't have good prospective data, but we will collect good prospective data, and there are trials now examining the use of actinium containing PSMA-targeted radionuclides, post-beta progression. A lot of it depends on when the progression occurs. Did somebody blow right through the initial beta, or do they respond and then progress later. Two different categories of patients. Patients who respond and then relapse later are typically going to respond quite well to both an alpha and a beta. We need to do this in a prospective, randomized way, and those trials are now getting underway.

References

1. Sartor O. PSMA in focus imaging, therapy, and new strategy. Presented at: 19th Annual New York GU Cancers Congress. March 13-14, 2026. New York, NY.
2. Sartor AO, Kiess AP, Feng FY, et al. PSMA-delay castration (DC): an open-label, multicenter, randomized phase 3 study of [177Lu]Lu-PSMA-617 versus observation in patients with metachronous PSMA-positive oligometastatic prostate cancer (OMPC). J Clin Oncol. 2025;43(suppl 16):TPS5127. doi:10.1200/JCO.2025.43.16_suppl.TPS5127
3. Sandhu S, Joshua AM, Emmett L, et al. LuPARP: phase I trial of [177Lu]Lu-PSMA-617 (LuPSMA) and olaparib in patients (pts) with metastatic castration resistant prostate cancer (mCRPC). Ann Oncol. 2025;36(suppl 2):1216-1217. doi:10.1016/j.annonc.2025.08.3007
4. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103.
5. Sartor AO, Morris MJ, de Bono JS, et al. PSMAfore: a phase 3 study to compare 177Lu-PSMA-617 treatment with a change in androgen receptor pathway inhibitor in taxane-naïve patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2022;40(suppl 6):TPS211. doi:10.1200/JCO.2022.40.6_suppl.TPS211