Garje Elucidates Biomarker-Driven Approaches Generating Excitement in Metastatic Prostate Cancer

Although PARP inhibitors and radioligand therapies have shifted the treatment paradigm and allowed for more individualized treatment approaches in prostate cancer, challenges remain regarding their widespread implementation and accessibility in clinical practice, according to Rohan Garje, MD. As emerging biomarkers and other targeted therapies continue to reshape the precision oncology landscape, there is an increasing need to bridge the gap between their regulatory approval and real-world adoption to ensure patients experience optimal benefit.

In a presentation delivered at the ​​Second Annual Miami Cancer Institute Precision Oncology Symposium, Garje highlighted progress made in precision oncology for metastatic prostate cancer and predicted rapid advancements in the field of radiotheragnostics, as well as CAR T-cell therapies and androgen receptor degraders in the coming years.

“Prostate cancer is unique in the sense that we not only have precision therapies based on the genomics of the cancer, but also based on the novel receptors that we can use for theragnostics,” said Garje, who serves as the chief of genitourinary medical oncology at Baptist Health’s Miami Cancer Institute in Florida. “It’s exciting that we can target genomics by using PARP inhibitors and can also target [prostate cancer] using image-driven identification of novel receptors.”

In an interview with OncLive^® regarding his presentation, Garje discusses the transition from hormone therapies to genomically-targeted approaches in metastatic prostate cancer management, emphasized the role of genomic profiling and next-generation imaging in guiding treatment decisions, and expanded on the continued impact of and future directions for PARP inhibitors and radiotheragnostics in metastatic castration-resistant prostate cancer (mCRPC).

OncLive: How has the concept of precision medicine evolved in the management of metastatic prostate cancer?

Garje: Prostate cancer is one of the most common cancers in men, and patients [tend to] do well [with treatment]. A lot of treatments seem to be evolving and new [options] are [being developed]. In the past 5 to 6 years, we have seen a significant improvement in treatment approaches. For the most part, in prostate cancer care, we were relying on hormone therapies. Now, we are moving forward and targeting the genomics of prostate cancer. My talk was focused on the newer genomically-driven therapies, [such as] PARP inhibitors, as well as theragnostics.

What is the role of genomic profiling and next-generation imaging in guiding targeted therapy selection in metastatic prostate cancer? What are the challenges vs opportunities associated with incorporating these techniques and assays into the management of this disease?

Genomic testing in prostate cancer is rapidly evolving. About a decade ago, the use of genomic testing was very limited, and not many people underwent it. Around 2020, when we got PARP inhibitors approved, there was a huge need to do genomic testing, because those markers could be used to select treatments for patients. There are markers [that are indicative of] poorer prognosis that can help in risk stratification of patients to approach them differently.

However, there are several challenges regarding the implementation of genomic testing. Although we know there are biomarker-driven therapies, which are now the standard of care [SOC], their utility in the real world has not been that high. Unfortunately, there’s a lag between [the time] when combination therapies or various genomically-driven therapies are approved [and when we see] their widespread use in the community. The task is to implement them earlier so that our patients can benefit from them.

The unique aspect of prostate cancer is that we can use novel, prostate-specific membrane antigen–targeted imaging technologies. There are several imaging agents that can precisely identify where the cancer is, and we now know that we can also target those areas by using [radioligand] therapies. The most common one is lutetium Lu 177 vipivotide tetraxetan [Pluvicto; formerly 177Lu-PSMA-617], which is very well tolerated for most of our patients and shows meaningful disease control.

What research efforts have explored PARP inhibitor combinations in mCRPC, and how have these agents changed the treatment paradigm?

In the past year, we have seen all these new treatment modalities. For example, niraparib [Zejula] combined with abiraterone acetate [Zytiga] inthe [phase 3] MAGNITUDE study [NCT03748641]. We also saw [the phase 3 TALAPRO-2 study (NCT03395197)] of talazoparib [Talzenna] combined with enzalutamide [Xtandi], and in the [phase 3] PROpel study [NCT03732820], olaparib [Lynparza] was combined with abiraterone. The theme of all 3 studies was similar. They were all [examining] the efficacy of combining PARP inhibitors with androgen-receptor pathway inhibitors [ARPIs] in the first-line mCRPC setting. It is important to identify those patients so that they can benefit [from these approaches]. All the studies met with their primary end point of radiographic progression-free survival. The next important aspect was overall survival [OS]. Based on these analyses, patients who had BRCA1/2 mutations are the ones who benefit the most with these combination therapies regarding OS. Those 3 combinations are now FDA approved.

There are very subtle nuances [between these approvals], so it is very important to be aware of which specific group or homologous recombination repair [HRR] mutations they are approved for. For example, olaparib and abiraterone is approved for patients with BRCA1/2 mutations. Similarly, the niraparib combination is also approved [in this population], but the talazoparib [regimen] has broader approval for patients with HRR [gene] mutations. The adverse effect profile and drug interactions are other aspects that will help [us] pick and choose [between] these options. It’s exciting that there are 3 combination therapies approved, but it’s critical to test for these mutations so that patients can benefit from them.

With lutetium Lu 177 vipivotide tetraxetan being established as a SOC in mCRPC, what’s next for this agent’s investigation, and what do we still need to know about its use?

Currently, lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) is approved in later lines of therapy in metastatic prostate cancer after patients have been treated with ARPIs and chemotherapy. There are 2 different directions the field is [headed in. One is] trying to move this drug into earlier lines prior to chemotherapy. [The phase 3] PSMAfore trial [NCT04689828] looked into this, and it showed significant PFS benefit [with earlier use of the radioligand] when compared with an ARPI switch. At the same time, [the agent] has also been evaluated in the first-line setting in metastatic castration-sensitive prostate cancer. [This includes the] recent PSMAddition trial [NCT04720157,] which has just finished enrollment; we are waiting [to see the] results. These [kinds of] drugs are now moving earlier in the lines.

There are also studies looking at combining [radioligands] with various agents. Lutetium Lu 177 vipivotide tetraxetan has been combined with immunotherapy drugs, PARP inhibitors, chemotherapy, and also radiation therapy to try and enhance efficacy. As we saw inthe phase 3 VISION study [NCT03511664], patients benefit from lutetium Lu 177 vipivotide tetraxetan, but the responses are not durable. We’re trying to identify patients who are benefiting [from the agent] and make [responses] more durable by using different combination strategies.

What are some of the emerging biomarkers and the approaches that are being developed to target them?

Different types of biomarkers—such as [STK1] and DLL3, which are unique novel biomarkers present in prostate cancer—could also be targeted by using theragnostics. Another interesting aspect is that these biomarkers can also be targeted by using bispecific T-cell engagers and monoclonal antibodies, which can engage the tumor cells with cytotoxic T cells. This can lead to cytokine release and antitumor effects. A couple of studies that were recently published have shown exciting data [with these approaches] in a later-line setting, and where bispecific T-cell engagers are promising. A lot still needs to be done to improve their toxicity profiles, because this [drug class] is associated with cytokine release syndrome. Most elderly patients with prostate cancer may not be able to handle [this treatment], so we must fine tune these agents so that they become more tolerable and easier to administer.

Where is the field headed?

In terms of modalities of action, we are looking not only at the field of radiotheragnostics, where newer agents [such as] Actinium-225, Thorium-229, and Copper-64/65 are being developed. We are also looking at CAR T-cell [therapy] development, which is still in early phases but there is a lot of excitement around it. Bispecifics are rapidly being tested, and then there are also newer modalities called androgen receptor degraders. [We] are trying to evaluate whether patients who are resistant to ARPIs can benefit from agents that can degrade the androgen receptor and improve their outcomes. In the next 5 to 10 years, I think the field will advance rapidly in this direction.