Novel Drugs May Introduce ‘New Era’ of Metastatic Prostate Cancer Treatment

The “exciting” development of novel agents, ranging from androgen receptor (AR) inhibitors to bispecific T cells may lead to a new “era of treatment” for patients with metastatic prostate cancer, according to Neeraj Agarwal, MD.

Neeraj Agarwal, MD, a professor of medicine, presidential endowed chair of cancer research, and director of both the Genitourinary Oncology (GU) Program and the Center of Investigational Therapeutics at the Huntsman Cancer Institute (HCI) of the University of Utah

In a conversation with CancerNetwork® during Prostate Cancer Awareness Month 2023, Agarwal, a professor of medicine, presidential endowed chair of cancer research, and director of both the Genitourinary Oncology (GU) Program and the Center of Investigational Therapeutics at the Huntsman Cancer Institute (HCI) of the University of Utah, discussed several novel therapeutics that are under investigation and ongoing clinical trials in the prostate cancer space.

In light of the FDA approval of enzalutamide (Xtandi) plus talazoparib (Talzenna)in homologous recombination repair (HRR)–mutated metastatic castration-resistant prostate cancer (CRPC) in June 2023,1 Agarwal discussed how he sequences these agents when treating patients in his clinic. Additionally, he emphasized the importance of genomic testing when it comes to selecting therapies for patients and shared his thoughts on the role that artificial intelligence (AI) may play in prognostication and drug development.

“With all these [new] drugs—assuming they are approved and all these trials are positive—there will be a new era in the treatment of metastatic prostate cancer or metastatic hormone-sensitive prostate cancer [HSPC],” Agarwal explained. “We will be obtaining tumor genomic sequencing with next-generation sequencing and see what mutations these patients are carrying in their tumors before offering them treatment according to the underlying mutations.

CancerNetwork®: Talazoparib plus enzalutamide was approved for HRR–mutated metastatic CRPC. How have approached treatment sequencing in light of this?

Agarwal: I would like to bring attention to the fact that the label expands beyond BRCA1/2 mutations and includes many other HRR mutations, which were included as eligibility criteria in the registration phase 3 TALAPRO-2 trial [NCT03395197]. The FDA label includes all those mutations.

Now, how do I use this combination? The most important thing is patients who are eligible for enzalutamide treatment and harbor HRR mutations are basically eligible in my clinic. If I see a patient with newly diagnosed metastatic CRPC who is a candidate for treatment with enzalutamide, I offer them treatment with enzalutamide plus talazoparib if they also harbor DNA repair or HRR mutations.

What factors do you take into consideration when determining which patients should receive genetic testing?

All patients with metastatic prostate cancer should undergo 2 types of testing as far as genomic testing is concerned. Number one is germline testing, where patients undergo testing to look for one of the mutations present in their germline DNA, which means they have inherited this mutation from their parents and may share these mutations with their siblings and their children. If they have germline mutations in HRR pathways, they are a candidate for treatment with PARP inhibitors.

The second type of testing is tumor genomic testing or somatic testing. There are multiple reasons why we should be doing the tumor testing for those genomic mutations. This tumor testing can be solid tumor testing, meaning you obtain the biopsy or the tumor tissue and order a comprehensive genomic profiling, or you can even do with circulating tumor DNA.

The reason we need to do that is because we have PARP inhibitors either as monotherapy or in combination with AR pathway inhibitors approved for patients who have HRR mutations. But this testing has implications beyond HRR mutation testing. We know there are several trials going on right now that are recruiting patients based specifically on certain types of mutations. We also know that many of these mutations—especially if you have RB, PTEN, or p53 loss—cause these patients to have a more aggressive clinical phenotype of prostate cancer, and they may require more close monitoring as far as how often we see them in the clinic.

We also know that if patients have all 3 of these mutations, they may have an even more aggressive type of prostate cancer, and they are more likely to have what we call de-differentiated prostate cancer, where [the disease], after a certain time of being treated with conventional therapies, develop phenotypes which comprise a non-secretory [subtype]. In this case, there is not a sufficient level of prostate-specific antigen [PSA] to reflect the tumor burden. In those patients, we cannot rely on PSA monitoring. These patients will require more frequent imaging studies. These patients are also more likely to not respond to standard AR pathway inhibitor therapies. If you look at the first-line, metastatic CRPC setting, enzalutamide is usually able to control the disease progression for 20 months if you look at median progression-free survival [PFS]. In patients who have many of these mutations, enzalutamide or novel hormonal therapies may not be as effective. They may be failed by these treatment options earlier. That may provide the rationale for offering clinical trials to these patients or offering combination therapies such as enzalutamide plus talazoparib if they have HRR mutations.

As I said, tumor genomic testing and germline testing do not just have implications on their family members and how we select therapies for these patients. These testing results have other implications on how we monitor these patients, how often we should do scans, and how we counsel these patients about their survival? These tests, germline and tumor somatic testing, are extremely important and can no longer be ignored in the clinic when we see these patients.

What are your thoughts about the current use and potential future applications of AI in prostate cancer?

AI is becoming more and more important. With each passing month, we see new papers in different cancer settings, including in prostate cancer, which continue to highlight the importance of utilizing AI in improving our diagnosis of these patients and improving prognostication. In the near future, we will also be using AI in frequent selection of these patients.

I don’t think AI-based tools are going to replace clinicians. However, clinicians who do not use AI-based tools are going to be replaced by clinicians who are using AI-based tools. That’s how important AI will be in our clinics in the very near future. We have already seen some wonderful studies being done in the localized prostate cancer setting in the context of radiation therapy.Multiple teams have reported that AI-based tools, which read the pathology slides, were able to provide a better prognostication than the conventional algorithms that used tumor and patient characteristics as far as recurrence is concerned. I think this is just the beginning, and we will see AI playing a much bigger role in treatment selection, diagnosis, prognostication, and drug development.

What treatments are on the horizon that clinicians should be aware of?

I remain optimistic about many options that are going to be approved for patients with prostate cancer in the very near future. The drug development in prostate cancer has been unprecedented. We have never seen so much momentum in drug development in prostate cancer in the recent past as we’re seeing now.

I don’t think we are far away from a day when we will be able to assure our patients that they will not die of their prostate cancer; they will die with their prostate cancer. Some of the therapies I would like to highlight, which I think are close to being approved, include AR-targeted therapies—novel ways to target AR. I remain optimistic about the product technology, the AR degraders, and the antibody-drug conjugates that are using novel ways to deliver chemotherapy in prostate cancer. I also remain optimistic about immunotherapy beyond immune checkpoint inhibitors such as CAR T cells and bispecific T cells that are being developed by different companies. B7-H3 targeting is another novel tool that I hope will see some more momentum in the phase 3 trials.

We also know that the 177Lu-PSMA-617 [Pluvicto] approval2 was just the start of delivering radionuclide therapy in precise fashion in the prostate cancer cells. We are going to see an antibody, rosopatamab [J591] that will deliver 177Lu-PSMA-617 by utilizing an antibody to deliver the beta particles into the prostate cancer cells. Antibodies can carry a bigger payload of radiation particles, so hopefully we’ll use fewer doses to achieve the same results.

Are there any ongoing clinical trials that have the potential to move the needle forward in prostate cancer?

We also saw the press release from the phase 3 CONTACT-02 trial [NCT04446117] utilizing the combination of the tyrosine kinase inhibitor cabozantinib [Cabometyx] with the immune checkpoint inhibitor atezolizumab [Tecentriq].3 We are looking forward to seeing the data in one of the future meetings, and I hope that the data are encouraging. Another strategy is moving 177Lu-PSMA-617 therapy to the up-front setting. Currently, it is approved in patients after failure of chemotherapy in metastatic CRPC.2 With the PSMAfore trial [NCT04689828], we are hoping to move 177Lu-PSMA-617 to the first-line metastatic CRPC setting, and with the PSMAddition trial [NCT04720157], hopefully 177Lu-PSMA-617 will move to the first-line metastatic HSPC setting.

We are also waiting for the results from the phase 3 TALAPRO-3 trial [NCT04821622] and the phase 3 AMPLITUDE trial [NCT04497844], which are using the combination of AR-targeting with PARP inhibitors. Talazoparib plus enzalutamide [is being assessed] in the TALAPRO-3 trial, and [investigators are assessing] abiraterone acetate [Zytiga] plus niraparib [Zejula] in the AMPLITUDE trial. These trials are for patients who have HRR mutations in the metastatic HSPC setting. We are also eagerly waiting for the results of the phase 3 CAPItello-280 trial [NCT05348577], which is using the AKP inhibitor capivasertib in combination with standard-of-care therapy for metastatic HSPC cancer.

With so many novel treatments emerging, how do you anticipate this impacting clinical practice?

It is great to see these phase 3 trials leading to the approval of new drugs and combinations for our patients. But it is also very demoralizing to see these drugs, which are backed by level 1 evidence, not being utilized in the real world. I’m sure it has something to do with access—whether our patients can afford this treatment. But considering this whole issue where most patients not being treated with standard-of-care FDA-approved drugs, a lot of it is because of financial constraints, lack of knowledge [among patients], lack of advocacy, and lack of knowledge among even clinicians, which sometimes makes it impossible to keep up with recent advancements. When I say recent advancements, I’m talking about drugs that have been approved in last 2 or 3 years; it’s not only about the last 6 months.

How do we tackle this lack of use of evidence-based therapy in our patients in the clinic, in the real world? Several parties must come together to solve this problem for our patients. It will require advocacy at the highest level to allow better access to our patients, to better handle copay issues, and to improve knowledge among patients and the providers as far as newer drugs, newer technology, and newer data are concerned. How do we make sure that when we are prescribing a treatment for our patients who have newly diagnosed metastatic prostate cancer, the AI-based tools embedded in any electronic medical record will show us if you’re not using the most appropriate treatment for that patient? The solution will encompass a variety of measures, including financial constraints, lack of education, busy clinicians in the clinic, and so on. That is one of the most important issues in my mind.

References

1. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. FDA. June 20, 2023. Accessed September 27, 2023. https://bit.ly/3pcuSTH
2. Novartis Pluvicto approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. News release. Novartis. March 23, 2022. Accessed September 27, 2023. https://bit.ly/36lu4Ct
3. Exelixis and Ipsen announce positive results from phase 3 CONTACT-02 pivotal trial evaluating cabozantinib in combination with atezolizumab in metastatic castration-resistant prostate cancer. News release. Exelixis, Inc. August 21, 2023. Accessed September 27, 2023. https://shorturl.at/hlpq1