Prostate Cancer Awareness Month: Advances and future directions

The prostate cancer landscape continues to evolve at a remarkable pace, with recent FDA approvals, innovative imaging modalities, and ongoing clinical trials reshaping the standard of care. As these advances move from research settings into everyday practice, they are providing clinicians with more opportunities to personalize therapy, delay disease progression, and improve quality of life for patients.

In recognition of Prostate Cancer Awareness Month, Urology Times® spoke with Jason M. Hafron, MD, CMO, to reflect on the most impactful recent developments in prostate cancer and offer insight into where the field is headed. From the expanded use of radioligand therapy with ¹⁷⁷Lu-PSMA-617 (Pluvicto; lutetium Lu 177 vipivotide tetraxetan) to the growing role of genomic testing and advanced imaging, Hafron highlights how the field is moving toward a more precise and patient-centered future.

Hafron is the Chief Medical Officer at Michigan Institute of Urology.

From your perspective, what have been the biggest advancements in the prostate cancer space over the past year?

We've had so many advancements over the past year, but I think [there have been] 2 big ones. One is that the FDA expanded the indication for Pluvicto in March of 2025. It's now approved for adults with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) [whose tumors have] failed an ARPI and who are appropriate candidates to delay taxane-based chemotherapy. This is great because it provides a new, earlier treatment option for patients before they need chemotherapy.

This approval was based on the PSMAfore trial (NCT04689828), which showed that Pluvicto significantly prolonged radiographic progression-free survival (rPFS) compared with standard change of an ARPI in taxane-naïve patients with mCRPC.¹ The data showed that Pluvicto more than doubled the rPFS to 11.6 months from 5.6 months compared with switching to another ARPI. Also, the PSMAfore trial showed that there was an improvement in health-related quality of life and delays in symptomatic skeletal events. This is important because with mCRPC, unfortunately, we can't cure the disease, but we can prolong progression-free survival and improve overall quality of life. Although the primary end point, overall survival (OS), wasn't met, this was done at a time when there was limited availability of Pluvicto, and there was a lot of crossover, so that's a limitation. Overall, we see a positive study that led to FDA approval for Pluvicto pre-chemotherapy, which will help a lot of patients in our practices.

The other big news was that in June, the FDA approved darolutamide (Nubeqa) for metastatic castration-sensitive prostate cancer (mCSPC) in combination with ADT. This was based on the phase 3 ARANOTE trial (NCT04736199). The ARANOTE trial found that darolutamide plus ADT significantly improved rPFS by 46%,² so a strong signal there. It also delayed the time to castration-resistant prostate cancer, pain progression, and PSA progression. So, a very positive trial that made the guidelines as another option for doublet therapy for patients with mCSPC.

What is your perspective on the role for genomic testing in guiding treatment decisions?

Over the past decade, we've seen a significant transformation on how prostate cancer is managed. Genetic and genomic testing has rapidly matured from a research tool to a standard practice across multiple clinical settings. Genomic testing plays an increasingly critical role in guiding treatment decisions. But even if there isn't an opportunity to change treatment decisions based on their genetic testing, it does provide additional information on the patient's prognosis and overall journey. It's very helpful to have that information in front of you when you're counseling a patient, even if that information is not going to change management.

As we're moving from this one-size-fits-all type of treatment, we need to move to a model that's a more personalized approach specific to patients’ tumor or their genes. Genomic testing will continue to become more important as we see further approvals of drugs in the future.

Could you discuss some of the current trends surrounding imaging for prostate cancer? How have advancements like multi-parametric MRI (mpMRI) and PSMA-PET transformed the landscape?

Both mpMRI and PSMA-PET have changed the landscape of prostate cancer for the better. What I'm looking forward to in the coming years, and we're starting to see some literature on this, is the standardization of using PSMA-PET for localized disease, particularly clinically significant prostate cancer. The goal would be to standardize imaging interpretation across various tracers, specifically evaluating the accuracy of SUVmax, miPSMA scores, and PSMA-RADS system. I'm really looking for the societies to develop guidelines and templates so that we can apply those in our radiology centers to standardize and improve the quality of these reads as they become more important using PSMA-PET for localized prostate cancer.

I'm also excited about PSMA-PET imaging as a biomarker in metastatic prostate cancer beyond its current use to determine suitability for radioligand therapy (RLT) or lutetium-based therapy. But truly, is it a biomarker? Can it give us more information and guide therapy? We're starting to see a sprinkling of that data come out, specifically in the TheraP trial (NCT03392428) that demonstrated that a higher baseline PSMA-PET SUVmean was strongly predictive of improved PSA response.³ So [we may be able to use] PET imaging to identify patients who would better respond to lutetium-based therapies.

We also saw in the ENZA-p trial (NCT04419402), which was a phase 2 trial in Australia and New Zealand, that the SUVmean was not a predictor of overall survival, but baseline PSMA-TTV, or total tumor volume, was predictive of improved survival.⁴ I think what is exciting is using the data [beyond determining if the] patient is PSMA-positive or PSMA-negative and using some of the characteristics of the tumors within these studies to a better identify who will respond to RLT therapy.

What are some of the ongoing clinical trials in prostate cancer that you're most excited about, and how do you see these influencing clinical practice?

There are so many trials going on right now, it's hard to keep up, which is great for us and it's great for our patients. I think the most exciting trials that catch my eye when I see them presented are the trials combining radioligands with other therapies.

We should start with the PEACE-3 trial (NCT02194842), which showed that combining enzalutamide plus radium-223 improved overall survival and progression-free survival by about 30% in mCRPC patients.⁵ It's important for clinicians to realize that this was newly diagnosed mCRPC patients, as well as that bone resorptive agents were mandatory to reduce skeletal fractures. PEACE-3 was a very exciting trial.

Another trial that's very interesting is the PSMAddition trial (NCT04720157). This was a phase 3 trial comparing Pluvicto vs standard of care in mCSPC. It's what I refer to as the new triplet therapy, adding lutetium plus ADT and an ARPI in mCSPC. At interim analysis, PSMAddition met its primary end point, showing statistically significant and clinically meaningful benefit [in rPFS] for those patients that received ADT, ARPI, and lutetium.⁶ There was also a positive trend in overall survival, so very exciting.

The other trial that I really like to read about is the ENZA-p trial. This was a phase 2 trial investigating the combination of enzalutamide and lutetium for patients with mCRPC. The study demonstrated that the combination significantly improved OS and quality of life for patients.⁷ But what I thought was interesting about the trial was that they introduce this concept of adaptive dosing, where you could treat patients with 2 cycles of lutetium, evaluate them with a PSMA-PET, and if they showed response, you could discontinue or follow the patients. I think that's a concept that will continue to develop over the coming years. In ENZA-p, 80% went on to complete the complete course, and about 20% of patients were stopped after 2 doses [because they] had such a great response. What's also interesting about ENZA-p is the inclusion criteria. In our trials previously, patients just had to be PSMA-PET positive. But in ENZA-p, they had specific criteria where they required an SUVmax greater than or equal to 15 at 1 site, and then at least greater than or equal to 10 SUV at all measurable sites. Why this is important is that [it gets at the] goal of determining who is the ideal candidate for radioligand therapy. [It looks at if we can] get past who's positive or negative by identifying PSMA characteristics or PSMA phenotype that will help us improve responses.

Another exciting trial that I've been watching is the LuPARP trial (NCT03874884). This is a phase 1 trial of lutetium plus a PARP inhibitor, olaparib [Lynparza]. I haven't seen any data on it yet, but I think conceptually the mechanism of action is very exciting. We know that lutetium causes single strand breaks in the DNA, and if we add a PARP, we'll increase our double strand break. In theory, that should improve cell death, and hopefully that will improve responses.

A very exciting trial that I'm a part of is the phase 2a LEGION-100 trial (NCT06533644). It's a novel mechanism of action that uses SYNC-T. What we do is we freeze a small part of the of the prostate if they have a prostate intact, or we freeze a metastatic lesion in patients who have failed an ARPI in mCRPC patients. After we infuse them for a quick freeze, then we instill at the tumor site a cocktail of antibodies. So, we create this personalized, localized immune response that, in turn, after multiple treatments, could create a systemic response. The phase 1 trial showed great response rates. Hopefully, we'll be able to duplicate that for our patients in this phase 2 trial.

Another exciting trial, which will hopefully read out shortly, is CAPItello-281 (NCT04493853). This was a phase 3 trial of Truqap [capivasertib] and abiraterone acetate [Zytiga] vs placebo and abiraterone in patients with de novo metastatic hormone-sensitive prostate cancer. The novel part of CAPItello-281 is that they need to have a PTEN deficiency. PTEN deficiency is not new to oncology, but it’s new to urology. It's an aberrant activation of the AKT pathway. Again, as urologists, we're not really familiar with this, but it's common in many other solid tumors. If you find patients with a PTEN loss, and it can be determined by IHC, we think that these patients will benefit from this therapy. The data are still pending, but hopefully adding Truqap to abiraterone in patients with PTEN deficiency will improve outcomes in mCSPC.

What gives you hope about the future for prostate cancer?

Like many of us, we hope for a cure for prostate cancer, which would be amazing to see in our lifetime. However, nearly every 6 months, we notice incremental improvements in therapy through precision medicine, innovative treatments like RLT, immunotherapy, and early combination therapies. I am eager to see if we can apply radioligand therapy in a way that offers ADT-free treatment options.

In the future, we will hopefully better understand when to escalate or de-escalate therapy based on the biology of the patient's cancer or their response to current treatment. No patient wants to be on treatment forever. I am hopeful that AI and machine learning will give us better tools to personalize patients’ treatment plans. Hope is essential for those of us who treat this disease, but it’s even more important to share this hope with our patients and their families who are affected by prostate cancer.

REFERENCES

1. Morris MJ, Castellano D, Herrmann K, et al. ¹⁷⁷Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404(10459):1227-1239. doi:10.1016/S0140-6736(24)01653-2

2. Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. 2024 Sep 16:JCO2401798. doi:10.1200/JCO-24-01798

3. Buteau JP, Martin AJ, Emmett L, et al. PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [177Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial. Lancet Oncol. 2022;23(11):1389-1397.doi:10.1016/S1470-2045(22)00605-2

4. Emmett L, Papa N, Subramaniam S, et al. Prognostic and predictive value of baseline PSMA-PET total tumour volume and SUVmean in metastatic castration-resistant prostate cancer in ENZA-p (ANZUP1901): a substudy from a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2025;26(9):1168-1177. doi:10.1016/S1470-2045(25)00339-0

5. Tombal B, Choudhury A, Saad F, et al. Enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer: Results of the EORTC 1333/PEACE-3 trial. Ann Oncol. doi:10.1016/j.annonc.2025.05.011

6. Novartis Pluvicto demonstrates statistically significant and clinically meaningful rPFS benefit in patients with PSMA-positive metastatic hormone-sensitive prostate cancer. News release. Novartis. June 2, 2025. Accessed September 30, 2025. https://www.novartis.com/us-en/news/media-releases/novartis-pluvicto-demonstrates-statistically-significant-and-clinically-meaningful-rpfs-benefit-patients-psma-positive-metastatic-hormone-sensitive-prostate-cancer

7. Emmett L, Subramaniam S, Crumbaker M, et al. Overall survival and quality of life with [177Lu]Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (ENZA-p): secondary outcomes from a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2025 Mar;26(3):291-299. doi:10.1016/S1470-2045(25)00009-9