Dr Lepor on Rise of Precision Strategies to Address Early Prostate Cancer

Prostate cancer’s often slow rate of progression has led to greater concern about overtreating patients and finding the ideal individualized treatment approach for each patient. With more advanced imaging and therapeutics playing a role in early disease management, genitourinary oncologists are appreciating the balance needed between patient quality of life and ensuring disease progression is carefully managed.

“Despite the fact that you often hear we're overtreating prostate cancer…it's still the second leading cause of cancer deaths for men. We've made a lot of progress, but too many [patients] are still dying of their disease,” said Herbert Lepor, MD, in an interview with Targeted Oncology^TM.

For Prostate Cancer Awareness Month, Lepor, who is the Martin Spatz Chairman of the Department of Urology and professor of urology and biochemistry and molecular pharmacology at NYU Grossman School of Medicine, discussed how the diagnosis and management of localized prostate cancer have evolved over the past decade.

Lepor addressed the growing role of MRI-guided biopsy in diagnosis, the evidence supporting active surveillance for low-risk disease, the judicious use of genetic testing and prostate-specific membrane antigen (PSMA) PET imaging, and outcomes from focal therapy, an organ-preserving alternative to radical prostatectomy and radiation therapy that he has helped pioneer at NYU Langone Health's Perlmutter Cancer Center.

Targeted Oncology: What do you see as the most important changes taking place right now in the diagnosis and treatment of prostate cancer?

Herbert Lepor, MD: The most impactful change over the last decade has been using MRI to guide prostate biopsy. Historically, we had ultrasound, which didn't give us a clue where the cancer was; I don't think that's done in any other organ system. We just did 12 random systematic biopsies and made the diagnosis that way. MRI has been very useful in identifying the potential sites of prostate cancer, so now when we do a biopsy, we use MRI guidance to target the biopsy where cancer is most likely to exist. Because co-registration between MRI and ultrasound isn't perfect, we still do a systematic biopsy alongside the targeted one, and we do it opposite the MRI target….

One of the other exciting developments is focal therapy. To apply focal therapy, you have to have focal disease, and the way we select candidates is by making sure the side we're not going to ablate doesn't have clinically significant cancer. We've shown that if you biopsy opposite the side of the target, and both the MRI and biopsy are negative on that side, patients remain good candidates for focal therapy.

There's also been a lot of advances in treating advanced prostate cancer: total androgen blockade, PARP inhibitors, radioactive labels we can target to the cancer, [and] chemotherapy. Twenty to 30 years ago, there was really nothing other than surgically removing the prostate, irradiating it, or hormonal therapy. Now the real challenge left to the medical oncologist, is how we order the various treatments we have. But despite all these advances, prostate cancer still is the second leading cause of cancer deaths for men. We've got a lot of work left to do.

How has the use of active surveillance contributed to individualizing treatment based on risk and patient goals?

At one time, we basically treated all prostate cancers. What we've since learned is that there are low-risk cancers we can very safely follow; that's termed active surveillance. There was a very important study out of the UK [with over] 1000 patients [ProtecT; NCT02044172] that [randomly assigned] one-third to active surveillance, one-third to immediate radical prostatectomy, and one-third to radiation therapy. Fifteen years later, there was no difference in prostate cancer mortality. There was a modest increase in metastases in those on active surveillance, but it was still a very low rate. What's important is that half of those patients [randomly assigned] to active surveillance ultimately underwent radical prostatectomy or radiation therapy.¹

Active surveillance is an effective strategy only if patients actually undergo surveillance. There isn't a standardized protocol for surveillance. In my patients, I always do an MRI and a targeted biopsy. Some patients with low-risk cancer will actually elect ablation despite being low risk, because the morbidity of focal therapy is quite low. If roughly half of these [patients] are going to end up getting treatment anyway, after multiple biopsies along the way, we can sometimes offer a treatment that doesn't carry the risks of radical prostatectomy or radiation therapy. For patients who elect to follow, I'll do a [prostate-specific antigen (PSA)] every 6 months, an MRI at 18 and 36 months, and a for-cause biopsy any time the PSA is concerning or the MRI shows a change in a lesion or a higher PI-RADS score. Even if PSA and MRI stay stable, I'll usually do a reflex biopsy around the 3-year mark. I believe for [patients] with low-risk disease, and even a select group of [patients] with intermediate favorable-risk disease, active surveillance is an appropriate strategy. The caveat is you've got to follow these patients actively. Many will go on to treatment, and delaying diagnosis doesn't seem to have significant consequences for prostate cancer mortality, though it may carry a higher risk of developing metastases.

What is your perspective on the rise of biomarkers and genetic testing in prostate cancer?

I think we underutilize genetic testing across the board. Who should undergo it? A [patient] with a more aggressive cancer very early in life, say a 50-year-old with a fairly aggressive but likely curable cancer, should undergo genetic testing. Anyone who presents with metastatic disease should undergo genetic testing. You should ask patients about a family history of prostate cancer specifically, since other cancers [such as] colon cancer [and] breast cancer can coexist in patients with a high penetrance of BRCA.

It's also important to use testing judiciously. Take PSMA-PET: it's indicated in high-risk patients, [patients] with intermediate unfavorable disease, or disease recurrence after radical prostatectomy or radiation therapy. But if you order it on a [patient] with intermediate favorable-risk cancer, the likelihood he has metastases at diagnosis is very low, and the likelihood a PET scan could even detect it is very low. If you get a positive finding in that setting, there's a greater chance it's a false positive than a true metastasis. I see many patients referred with low-risk or intermediate favorable-risk cancer who had a PET scan, and all it did was create anxiety without any real benefit.

The same caution applies to molecular signatures. I can't tell you the number of times a patient gets 2 different molecular assays and there's discordance between them. Radiation oncologists will use some of these signatures to decide whether to add neoadjuvant hormonal therapy to radiation, and I do think that's clinically useful information, though it's not binary; it's not that a higher-risk result means a 100% chance of benefit and a lower-risk result means 0%. There's some incremental benefit in selecting cases that way, but it isn't as definitive as you'd like it to be, and many men still end up getting hormonal therapy without a clear benefit.

Genetic testing can also influence treatment decisions more directly in specific cases. Take PARP inhibitors: they're extremely effective if you have a BRCA mutation, and of no clinical benefit if you don't. When those drugs were studied, patients were enrolled regardless of BRCA status, and the overall clinical benefit looked modest, but once you stratified by BRCA status, patients with the mutation had a robust response, and those without it had no clinical benefit at all.

How have advances in treatment strategies contributed to quality of life and other outcomes that matter to patients?

About 15 years ago, I was the highest-volume prostate cancer surgeon in the country, and I looked at the data and said: even with nerve sparing, sexual dysfunction is a real issue, and I don't believe [robotic surgery] is going to make a difference in improving outcomes. If you look at the randomized studies between open surgery, which I still do, and robotics, there's absolutely no difference²—even in recovery, even in pain control—yet probably 90% to 95% of cases are done robotically.

So…I pursued another strategy: focal therapy. Before starting, I went back and reviewed prostates we'd already removed to check how often a single MRI lesion really did correspond to truly focal, isolated disease. The results were favorable enough to move forward. Just like a lumpectomy has much less morbidity than removing the entire breast, we presumed that destroying just the affected area of the prostate would greatly reduce morbidity, but we had to show we weren't compromising cancer control. We biopsied everybody at 6 months, and 98% had no residual significant disease. At 2 years, upwards of 90% had no evidence of significant disease.³

Once imaging showed the original target ablated with no new targets and a stable PSA, we found that biopsying those patients added no real utility, so surveillance shifted to PSA every 6 months and MRI at 6 months, 2 years, 3.5 years, 5 years, 7.5 years, and 10 years. With 2 full-time data managers tracking this, our compliance with 7-year MRI follow-up is over 90%, which is unprecedented.³

Since 2017, we've enrolled over 600 patients in this prospective database. At 7 years, for [patients] with focal intermediate favorable-risk disease, 75% have required no additional treatment, 15% have required radical prostatectomy or salvage radiation, and 10% have undergone an additional focal treatment. Compare that with radical prostatectomy, where 20% of men with intermediate favorable-risk disease need salvage treatment by 10 years.

On the quality-of-life side, we don't use hormonal therapy the way radiation [oncology] does. We have zero adverse effect on rectal function, we've never had a patient with incontinence, and sexual function challenges are markedly less than with radiation or prostatectomy, and it's an outpatient procedure. Today, with almost 10 years of experience and 1000 patients, about 80% of patients elect focal treatment—[although] not 100%, because some patients aren't comfortable with anything that might compromise their cancer control, even slightly.

Our 1000th patient was Andre De Shields…he is an 80-year-old gentleman. He's won an Emmy and a Tony. Two days after his focal therapy, he was at rehearsal for the revival of Cats…

What unmet needs are remaining in prostate cancer?

Probably the biggest unmet need is a better screening tool. PSA [is] prostate specific, but not prostate cancer specific. A lot of men are subjected to unnecessary biopsies.

Despite the fact that you often hear we're overtreating prostate cancer…it's still the second leading cause of cancer deaths for men. We've made a lot of progress, but too many men are still dying of their disease.

Based on the evidence we have today, I think focal therapy is a very reasonable option in terms of both functional and oncologic outcomes. For men who ultimately have a radical prostatectomy or radiation therapy—or for whom focal therapy isn't an option—there's no way to guarantee an optimal outcome, but I strongly encourage patients to seek out experienced surgeons and radiation oncologists. That can't guarantee a perfect result, but it certainly increases the likelihood of achieving one.

How do you recommend counseling a patient to outline the path of their cancer journey?

When I counsel a patient, not only do I tell them what I think can happen, I tell them precisely their expectations, [in] terms of complications and outcomes, and help them guide their treatment. Everybody's concerned about complications, and everybody's concerned about surviving their cancer. But patients will have different priorities, and so my job is to make sure that they have realistic and honest expectations about treatment and then help them guide their decision process.

REFERENCES

1. Hamdy FC, Donovan JL, Lane JA, et al. Fifteen-year outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med. 2023;388(17):1547-1558. doi:10.1056/NEJMoa2214122. NCT02044172.

2. Nahas WC, Rodrigues GJ, Rodrigues Gonçalves FA, et al. Perioperative, Oncological, and Functional Outcomes Between Robot-Assisted Laparoscopic Prostatectomy and Open Radical Retropubic Prostatectomy: A Randomized Clinical Trial. J Urol. 2024;212(1):32-40. doi:10.1097/JU.0000000000003967

3. Lepor H, Rapoport E, Tafa M, Gogaj R, Wysock JS. Five-year oncologic outcomes following primary partial gland cryo-ablation prospective cohort study of men with intermediate-risk prostate cancer. Urology. 2025;196:189-195. doi:10.1016/j.urology.2024.10.039