Expert Says Talazoparib Plus Enzalutamide May Change the Standard of Care for Prostate Cancer

Neeraj Agarwal, MD

Neeraj Agarwal, MD

Researchers are recruiting patients with metastatic castration-resistant prostate cancer (mCRPC) for part 2 of the randomized phase III TALAPRO-2 trial study of talazoparib (Talzenna) in combination with enzalutamide (Xtandi) after part 1 of the study showed promising findings.

In part 1 of the study, the researchers first sought the correct starting dosage of talazoparib and enzalutamide. After dividing the patients into 2 cohorts and examining patient reaction to the combinations, it was determined that patients in the study should receive talazoparib (0.5 mg) and enzalutamide (160 mg).

Data from part 1 of the study showed that talazoparib plus enzalutamide was safe and effective in patients with mCRPC. Patients did experience treatment-emergent adverse events (TEAEs), including anemia, low white blood cell count, and low platelet count. However, the researchers concluded that these TEAEs were manageable.

“I have no doubt that the study will come out with [great] results very soon and will change the standard of care for our patients,” said Neeraj Agarwal, MD. Part 2 of the study is looking at overall survival and radiographic progression-free survival as primary endpoints with the doses defined in part 1. Additionally, because the trial is recruiting both patients with and without DNA repair defects, experts believe that this combination may benefit all subsets of patients with prostate cancer in the future.

In an interview withTargeted Oncology, Agarwal, professor of medicine at the Huntsman Cancer Institute, University of Utah, gave an overview of the TALAPRO-2 trial and discussed its potential for changing the standard of care for patients with mCRPC.

TARGETED ONCOLOGY: Can you discuss the background of TALAPRO-2?

Agarwal: TALAPRO-2 is a phase III trial that is evaluating enzalutamide plus/minus talazoparib, a poly (ADP ribose) polymerase (PARP) inhibitor, in patients with mCRPC. 

This study has 2 parts. Part one, which has already been completed and was presented at the ASCO 2019 Annual Meeting, showed that the combination of talazoparib with enzalutamide was safe and we got the right dose. The next step is a global phase III registration trial which is randomizing patient to enzalutamide versus enzalutamide plus talazoparib. 

Why this combination? As we know, talazoparib is a PARP inhibitor. Like other PARP inhibitors, it stops the prostate cancer cells from repairing the DNA, especially where there is already deficiency in the DNA repair proteins. But, talazoparib goes one step beyond other PARP inhibitors. It traps PARP on the DNA, and because of this advantage, which is unique to talazoparib, it may not have to rely on underlying DNA repair deficiency inside the cancer cells. So, when enzalutamide is given to the patients who have progressive CRPC, they increasingly rely on PARP to survive. PARP becomes essential for the survival of prostate cancer cells when they are being killed by enzalutamide. At this point, we use talazoparib to deactivate and trap PARP. This is what we think will be the ultimate weapon against these prostate cancer cells. 

The ultimate goal of the study was to improve survival in these patients. [We wanted to improve] not only radiographic progression-free survival, which was the co-primary endpoint, but overall survival as well.

This study is randomizing more than 800 patients worldwide and is already open in 27 countries. The study is in full steam already and we are hoping to see exciting results which will change the standard of care for these patients.

TARGETED ONCOLOGY: What are the findings so far?

Agarwal: What we have seen so far [occurred in] TALAPRO-2 part 1, which was a non-randomized study of the safety and efficacy of this combination. We wanted to [find] the right dose of talazoparib with enzalutamide. What we found was that talazoparib is very safe and associated with efficacy when enzalutamide [is given] at full dose and talazoparib [is given] at 0.5 mg daily.

The pill is pretty easy to take and doesn't burden patients with too many pills a day. I think that's a great advantage. So far, we've not seen any signal of concern from a safety perspective. It's a very well-tolerated combination. 

TARGETED ONCOLOGY: Were there any TEAEs associated with this combination?

Agarwal: Enzalutamide is a very well-tolerated drug. It causes fatigue, but these patients in the CRPC setting have already been on testosterone suppression therapy. On top of enzalutamide, when we add talazoparib, we are not seeing an increase in fatigue. Now, there are some TEAEs which are unique to PARP inhibitors, such as lower white counts, anemia, and lower platelet counts. Surprisingly, with the doses we are using in this trial, we are not seeing any unusual incidents of these TEAEs. 

TARGETED ONCOLOGY: What other prostate can care subgroups do you see this combination having activity in?

Agarwal: [Here] is the beauty of this combination. We are not only looking for patients with prostate cancer who have tumors harboring DNA repair defects. We are looking for all patients, regardless of whether they have a DNA repair defect or not. That's the biggest novelty or innovation with this trial. Hopefully, all patients with prostate cancer will benefit from this combination.

There's going to be a subset of patients who have tumors harboring DNA repair defects and we will be looking at them separately, but we are not ruling out any patients with prostate cancer.

TARGETED ONCOLOGY: What is unique about the patient experience in this trial?

Agarwal: As I mentioned, TALAPRO-2 part 2 is a phase III trial, randomizing patients to enzalutamide standard of care versus enzalutamide plus talazoparib. Both drugs are supplied through the study, which is a major advantage. In my view, I'm very attracted by the fact that my patients are not burdened with the co-pay of enzalutamide, which can vary a lot depending on the insurance background. Having said that, I'm also attracted by the tolerability of the combination so far. 

In my view, talazoparib is the most potent PARP inhibitor we have experienced so far because of the unique mechanism of action which includes trapping of PARP on the DNA. Based on these data, which includes safety, tolerability, and the unique action beyond usual PARP inhibition, I think enzalutamide with talazoparib is the most promising combination among all the similar combinations being used right now. 

TARGETED ONCOLOGY: What message would you give to community oncologists about this study?

Agarwal: As we know, many of these drugs have deeper androgen blockade but our front intensification of therapy has moved to the hormone-sensitive setting. So, now when we see patients who are developing CRPC, there's a big challenge with how to treat them. As a general message, if you have a patient who is progressing to a CRPC setting, [physicians should] think about this trial. We are dealing with the best drugs in its class, but [the other advantages] are that they are very well tolerated and both drugs are available through the study, so patients don't have to worry about the affordability of these agents.

Reference:

Agarwal N, Shore ND, Dunshee C, et al. Clinical and safety outcomes of TALAPRO-2: A two-part phase III study of talazoparib (TALA) in combination with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC).J Clin Oncol. 2019;37(suppl; abstr 5076).