Radiopharmaceuticals Show Signs of Progress in Prostate Cancer

A. Oliver Sartor, MD

Radiopharmaceuticals could be part of the next wave of progress in prostate cancer treatment, pending a phase III trial evaluating efficacy with lutetium-177 PSMA-617 (Lu-PSMA-617) in patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC), explained A. Oliver Sartor, MD.

In the study (NCT03511664), researchers will explore treatment with Lu-PSMA-617 plus best supportive care (BSC) or standard care compared with BSC/standard care alone in patients with progressive PSMA-positive mCRPC; the primary endpoint is overall survival (OS).¹

Prior data showed activity with Lu-PSMA-617 in this patient population in a single-center phase II trial.² Among 50 heavily pretreated patients with PSMA-positive mCRPC who were treated with Lu-PSMA-617, 32 (64%; 95% CI, 50%-77%) had a prostate-specific antigen (PSA) decline ≥50%, with 22 (44%; 95% CI, 30%-59%) having a decline ≥80%. Additionally, the median OS was 13.3 months.

“Radiopharmaceuticals could be remarkably impactful in prostate cancer,” said Sartor. “As we look toward the future, we're going to [see more of] these PSMA-binding agents.”

In an interview with OncLive, Sartor, medical director at Tulane Cancer Center and Bernadine Laborde Professor of Cancer Research at Tulane University School of Medicine, discussed the development of radiopharmaceuticals in prostate cancer.

OncLive: First, in nonmetastatic castration-resistant prostate cancer, what are the currently available treatments for patients?

Sartor: There are 3 drugs approved in the nonmetastatic castration-resistant prostate cancer space: apalutamide (Erleada), enzalutamide (Xtandi), and darolutamide (Nubeqa). All 3 of the trials were positive, which led to their FDA approvals.

There are some differences in toxicity between the drugs, but there are no head-to-head trials. When choosing between these drugs, the cost of therapy must be considered, as well as the implications for subsequent therapies. We know virtually nothing about [how to treat] patients who have been previously treated with those agents.

How has PSMA-PET positivity influenced the prostate cancer paradigm?

In the trial of enzalutamide [in this setting], even though these patients had nonmetastatic CRPC, 98% of them had PSMA-PET positivity and 55% were metastatic—even though they were classified by conventional imaging as having nonmetastatic disease. However, these results don't change the outcomes of the study. The apalutamide, enzalutamide, darolutamide studies are conducted in a particular space using conventional imaging with PSA doubling times of less than 10 months. There is an unequivocal improvement in metastasis-free survival [with these agents].

Now, PSMA-PET positivity opens up a whole panoply of other possibilities for treatment. For patients with metastatic disease, [receiving a PSMA-PET scan] can be a tactic prior to receiving radiotherapy. Patients with localized disease can receive radiotherapy and potentially even surgery. We have a lot more to learn, given the new imaging results that are consequential for patients in this space.

What studies are you most excited about?

The phase III VISION trial recently completed accrual in October 2019 with a total of 815 patients. The study compares standard of care against plus or minus the radiopharmaceutical Lu-PSMA-617. The trial has 2 endpoints—radiographic progression-free survival and OS—for patients previously treated with androgen receptor inhibitors, such as abiraterone acetate (Zytiga) or enzalutamide, and taxane chemotherapy. This is a patient population without a good standard of care.

The CARD trial showed that cabazitaxel (Jevtana) is better than a second antiandrogen. If [the VISION study] is positive, then Lu-PSMA-617 could have a considerable impact on care for that space.

What other agents are emerging in prostate cancer?

There are a variety of agents that are targeting PSMA. One trial is using an anti-PSMA agent conjugated to thorium-227, which is an alpha-emitting radionuclide.

Another trial is using a bispecific antibody T-cell engager (BiTE) combined with CD3. The PSMA-binding BiTE plus CD3 combination can lead to real responses in patients with prostate cancer.

There are other small molecules that are binding to PSMA that are conjugated to radioactive iodine. When we begin to look at the various trials, there are both large and small molecules, lutetium, and iodine.

Actinium-225 studies are also moving forward. There are also some studies indicating Lu-PSMA-617 conjugated to actinium-225 [is effective]. An alpha emitter is yielding some very provocative results. Alpha emitters, beta emitters, small and large molecules are all moving rapidly [through the pipeline], but Lu-PSMA-617 in the VISION trial is leading the pack.

Are there any emerging non-PSMA targeting agents in this paradigm?

The binding agent STEAP1 is expressed preferentially on prostate cancer cells. When you move beyond prostate cancer, there are a whole variety of surface antigens involved. There are a variety of targets that have been identified. Right now, the work is so preliminary that I'm not going to say which ones are going to make it into the clinic. Simply said, PSMA is not the only target being examined at this time.

What does the future of prostate cancer treatment hold?

There are other surface molecule—binding agents under investigation. When you bind them to a radiopharmaceutical, either an alpha or beta particle, the degree of toxicity is pretty low as a whole. I see these being incorporated earlier in the treatment paradigm.

We have a trial that is being planned between the [cooperative groups] looking at upfront therapy in metastatic castration-sensitive disease. In 5 years, we're going to know a lot more than we do now.

What are some challenges in prostate cancer?

It's completely evident that once metastatic, prostate cancer is not curable for the vast majority of patients. We tout our triumphs and we promote the drugs that are going to challenge the current paradigm, but we don't have curative agents. There are some patients who can respond to the new immunotherapies. Pembrolizumab (Keytruda) was approved for patients with microsatellite instability-high or mismatch repair deficiency without regard to underlying tumor source. We have some astounding responses in some of those patients and we're very excited.

We saw some great responses with Lu-PSMA-617. As we begin to move forward, we're going to be dividing this disease into smaller subsets. Some of [the subsets] will receive molecularly targeted therapy, but I personally like the targeted radiopharmaceuticals because they will ablate the cancer regardless of its underlying genotype.

We have much more to learn, but we are also looking into combination therapies, such as Lu-PSMA-617 combined with a PARP inhibitor or in combination with immunotherapy. There's some rationale for that. You can also put together alpha and beta particles or combine alpha or beta particles with radiation sensitizers, modulating the way the drugs are excreted.

References

1. Sartor AO, Morris MJ, Krause BJ. VISION: an international, prospective, open-label, multicenter, randomized phase 3 study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(suppl; abstr TPS5099). doi: 10.1200/JCO.2019.37.15_suppl.TPS5099.
2. Hofman M, Violet JA, Hicks RJ, et al. Results of a 50 patient single-centre phase II prospective trial of Lutetium-177 PSMA-617 theranostics in metastatic castrate-resistant prostate cancer. J Clin Oncol. 2019;37(suppl; abstr 228). doi: 10.1200/JCO.2019.37.7_suppl.228.