Talazoparib/Enzalutamide Combo, Radioligand Therapy Expand Options in mCRPC

Marc R. Matrana, MD

In the second part of an interview with OncLive®, Marc R. Matrana, MD, discussed the evolving role of molecular profiling in treatment selection for patients with prostate cancer; the clinical implications of the phase 3 TALAPRO-2 trial (NCT03395197) evaluating talazoparib (Talzenna) plus enzalutamide (Xtandi) in the first-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC); and key considerations for optimizing frontline treatment based on patient- and disease-specific factors.

He also addressed the growing utility of radioligand therapies, such as lutetium Lu 177 vipivotide tetraxetan (Pluvicto), and the ongoing questions surrounding their sequencing and retreatment strategies.

In the first part of the interview, Matrana outlined frontline treatment considerations for patients with advanced renal cell carcinoma.

Matrana is the medical director of the Ochsner Precision Cancer Therapies Program and a staff physician at Ochsner Medical Center in New Orleans, Louisiana.

OncLive: What patient- and disease-related clinical characteristics do you typically evaluate when determining the most appropriate initial therapy for a patient with metastatic prostate cancer?

Matrana: The first consideration when we think about metastatic advanced prostate cancer is: have you done appropriate molecular testing for the patient? Even though [this testing] that won't [always] influence our first-line therapy, sometimes it will, but it may also influence our second-line therapy. We now know that every patient with advanced or metastatic prostate cancer should have both somatic, tumor-based, next-generation sequencing, as well as hereditary [germline] testing, even if they don't have a family history, because that's going to inform our use of PARP inhibitors for these patients.

The National Comprehensive Cancer Network Guidelines recommend comprehensive molecular profiling for all patients with metastatic prostate cancer, and systematizing that is important at my institution. That testing happens automatically when the pathologist looks under the microscope and sees cancer; that testing is automatically sent, just like we would test estrogen receptor or HER2 for [a patient with] breast cancer.

We do comprehensive molecular profiling for all [patients with] advanced cancers. Specifically [with] prostate cancer as well, it has to become ingrained and systematized. Based on that molecular testing, we're going to select our first-line [treatment] for prostate cancer [and determine potential subsequent therapies].

When I think about, selecting the best first-line option for [patients with metastatic] prostate cancer, I'm automatically thinking combinations of androgen deprivation therapy [ADT] and novel hormonal therapies, combinations of ADT and chemotherapies for some patients in some cases, or combinations of ADT, novel hormonal therapies ,and PARP inhibitors. We have a lot of combinations to choose from, [and] it's getting complicated. At the end of the day, you have to look at the patient and [pay attention] to things like age, comorbidities, and performance status, and then look at the disease.

If I have a very young patient with very aggressive disease and widely metastatic disease who has a good performance status, we need to get to control the disease very quickly. That's a patient in whom I'm going to be thinking about a chemotherapy approach up-front. If I have, on the other hand, a very elderly patient with a borderline performance status, comorbidities, and a life expectancy maybe more in the 5-year range, I'm going to approach that patient very differently. ADT [is an option], but now I think about a single next-generation hormonal-based therapy for that patient, rather than a more aggressive approach. They probably don't need the more aggressive approach, and they probably wouldn't tolerate it well.

In my practice, we see a lot of the second scenario I described: the more frail, older [patients with] more indolent disease, but also patients who just doesn't have the strength and stamina that some others do. We have to personalize our treatment recommendations based on [those considerations], as well.

Where does talazoparib fit within the current treatment paradigm, and how do findings from TALAPRO-2 inform its role in clinical practice?

PARP inhibitors have given us new options for patients, and in many ways, we had to get our brain around testing. Like I said, systematizing testing is the most important thing we can do. By just testing an individual on a patient-by-patient basis, you're just never going to get to 100% testing rates doing that because there are always [obstacles] in the way. People forget and things fall through the cracks.

Systematizing the testing for homologous recombination repair [HRR] gene mutations is key. PARP inhibitors [are] extremely useful tools, and the data pan out well for that. That said, they also have some safety profiles [to keep in mind]. The TALAPRO-2 study was a randomized, double-blind, placebo-controlled study that randomly assigned patients to the oral PARP inhibitor with enzalutamide compared with just enzalutamide alone for first-line therapy for mCRPC.

This is a patient population that already [progressed on] first-line therapy for castration-sensitive disease, so they had either prior abiraterone acetate [Zytiga] or docetaxel in the castration-sensitive setting. [Investigators] enrolled patients both that had HRR mutations, as well as those who didn't, and they looked at radiographic progression-free survival as the primary end point, and then overall survival as a key secondary end point. Within that study, they saw improvement in both cohorts; however, the maximum improvement was in patients who were HRR-deficient, as you might suspect. There was a nice separation of [survival] curves there.

We have to think about the comorbidities of the patient and also the [adverse] effects [AEs] of the drug. In terms of the PARP inhibitors, anemias, thrombocytopenias, leukopenias, and neutropenias [can occur] across the board. The other thing we have to look for with these PARP inhibitors is that there is a slight risk of developing a serious bone marrow issues up to acute myeloid leukemia, due to the mechanism of action of these drugs in inhibiting DNA repair.

PARP inhibitors have their place. They are powerful antineoplastic drugs, particularly when used in combination with other with hormonal-based therapies in prostate cancer, like ADT and second-generation, novel hormonal therapies like enzalutamide.

The flip side is that we do have to be realistic about some of the AEs which we which we may see, including those rare leukemias. Is the combination of PARP inhibition and hormonal therapy right for everybody? No, but for the right patient who can tolerate it, it provides a nice new tool in our armamentarium.

How is radioligand therapy currently being integrated into the treatment landscape for prostate cancer?

Radioligand therapies, particularly in metastatic prostate cancer, have truly been a game-changer clinically. We didn’t have a lot of great options for after [patients had] progressed in the castration-sensitive setting with some of the novel hormonal therapies, or even beyond that into the castration-resistant setting. Particularly for patients where we want to avoid palliative chemotherapy, [radioligand therapies] give us a great option.

They don’t have a lot of AEs compared with some of the alternatives, like chemotherapy, and they are effective for the large majority of patients who [receive] them. The challenge here is that the way [lutetium Lu 177 vipivotide tetraxetan ] is currently approved, [given as] only 6 doses.

[Lutetium Lu 177 vipivotide tetraxetan] offers [a] very effective therapy that is well tolerated, but also a therapy that is finite in terms of [only being] 6 doses. The big question is, what do you do after? What do you do with the patient who responds well? Those studies are ongoing in that space, but those answers are kind of needed clinically as soon as possible. Do you retreat?

As somebody who prescribes these a lot, another big question—and biggest challenge for the patient—is how do I manage the precautions with [lutetium Lu 177 vipivotide tetraxetan]? How do I manage the precautions of [the patient needing to] sleep in a different bed than [their] spouse [for 7 days], and [not being] able to be around pregnant women, and having to be careful about sharing food and utensils with people for a few days after therapy? A lot of those precautionary things are the biggest kind of hassles that patients [have to] overcome. However, compared with the AEs of chemotherapy or some of the other toxicities, most of my patients would gladly [follow] those precautions over anything else.

How we pair the radioligand therapies like [lutetium Lu 177 vipivotide tetraxetan] with some of the other therapies we already have still eludes us. [The] jury is still out. Research is still yet to be completed on that, and we’ll see. As we mentioned before, the biggest question is, what do you do afterward with the patient who responds and completes therapy? What is the next best line for them? The jury is still out, but [lutetium Lu 177 vipivotide tetraxetan is an] intriguing and efficacious therapy with not a lot of toxicities. Still, there are a lot of questions remaining: how do we pair it, and what do we do next?