Bimodal Vs Trimodal Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer

Ashley Evan Ross, MD, PhD

Targeted OncologyTM: What therapeutic options would you consider for this patient with high-volume, hormone-naive metastatic prostate cancer?

ROSS: Based on the NCCN [National Comprehensive Cancer Network] guidelines for prostate cancer, combination therapy for M1 disease is the preferred approach.¹ So, ADT [androgen deprivation therapy], plus abiraterone [Zytiga], ADT plus apalutamide [Erleada], ADT plus enzalutamide [Xtandi], or ADT plus chemotherapy, which are all category 1 recommendations.

Now, ADT alone is not supported by category 1 evidence. It’s a [worse] therapy than doing ADT plus an androgen axis inhibitor or plus chemotherapy, and so it’s a category 2A recommendation. Recent published results not included in the guidelines were from the PEACE1 trial [NCT01957436] and the ARASENS trial [NCT02799602], which both had ADT plus chemotherapy plus either darolutamide [Nubeqa], an androgen receptor [AR] blocker, or abiraterone.

Why do the NCCN guidelines have a category 1 recommendation for these options?

Both ADT plus 6 cycles of chemotherapy and ADT alone were in the CHAARTED trial [NCT00309985] and STAMPEDE trial [NCT00268476] that tested the strategy. There is an overall survival [OS] benefit if it’s newly diagnosed hormone-sensitive prostate cancer and you offer the gentleman 6 cycles of docetaxel [Taxotere] plus ADT or ADT alone, and they extend their survival by about 1 year or so.

How about if we can avoid chemotherapy and do bimodal therapy with ADT plus an oral agent like abiraterone, which shuts down the enzyme CYP17A1 and in doing so shut off exogenous androgens from the adrenals or from the tumor itself? That was done in the LATITUDE [NCT01715285] and the STAMPEDE trials that again show an OS benefit of over 1 year compared with ADT alone.

There were trials that looked at adding in an AR blocker with trimodal mechanisms of action like apalutamide or enzalutamide. These block binding to the receptor, translocation to the nucleus, and transcription of the androgen responsive genes. When these are added, what we see is an OS benefit in those groups as well, again extending the survival compared with ADT alone.

The newest data are from the PEACE1 and ARASENS data, which use trimodal mechanisms of action with an AR blocker, ADT, and chemotherapy. There was, in the higher-volume disease particularly, an OS benefit with trimodal therapy.² The PEACE1 trial data came out in the Lancet in April 2022.³ The ARASENS trial data were published in the New England Journal of Medicine in March 2022.⁴

What data support the use of bimodal therapy vs ADT alone?

The TITAN study [NCT02489318] had a bimodal therapeutic selection of apalutamide and ADT vs ADT alone. [The data were] published in the New England Journal of Medicine a couple of years ago,⁵ and there was an update that was published after that as well.⁶ The TITAN trial is an example of [the type of therapy] we’re saying most of your patients should be on. It was an all-comers phase 3 trial with 1052 patients. They were [randomly assigned] to receive an oral apalutamide, which is an AR blocker plus ADT vs ADT alone.

The median follow-up was about 40 months [at last reporting]. If the patient had a combination therapy of apalutamide plus ADT, they had a better OS. This trial was first reported at about 2 years. After they reported it, because apalutamide made people live longer by about 30%, they allowed crossover, and a lot of the people crossed over to receive bimodal therapy with apalutamide if they were on placebo alone. So, they adjusted the placebo group for people who crossed over. [The reduction in risk of death with the bimodal therapy] was 30% or 35%. After adjusting for crossover, the reduction in risk of death was 48% [HR, 0.52; 95% CI, 0.42-0.64; P < .0001]. So bimodal therapy is significantly better than just ADT alone if you adjust for crossover.

When they looked carefully at the quality of life of these patients, the quality of life was similar by FACT-P [Functional Assessment of Cancer Therapy–Prostate], which is a patient-reported outcome, among the groups that got placebo or bimodal therapy. In fact, as you get toward a longer time of survival, it favors the bimodal therapy. All the secondary end points were also met beyond just the primary end point of OS. There was low toxicity, particularly when adjusted for how long they were on therapy. The fractures and falls were very similar. The people who got apalutamide had [a higher rate of] rash than people with ADT alone.^5,6

What if the baseline ECOG [status] was a little bit higher, 1 instead of 0? What if the age was higher and they were over 75 years? Would they benefit? Forest plots are subset analyses, and they’re limited because they’re subset analyses. Still, the bimodal-type therapy is greatly favored over ADT plus placebo in basically every single subgroup analysis with the exception of patients who had received prior docetaxel, which is by itself a bimodal therapy, kind of, and we don’t see that OS benefit. They saw some progression-free survival [PFS] benefit, but not an OS benefit, for that subset of patients. But bimodal therapy had a benefit across all other subgroups; therefore, it’s preferred. It increased OS, and the hazard ratio after adjustments was around 0.5—a 2-fold improvement, which was across categories, even for patients over 75 years.⁶ [In summary], ADT plus apalutamide has an OS benefit across subgroups and it’s very well tolerated.

What data support the use of trimodal therapy vs bimodal therapy in such a patient?

It’s important to talk about the PEACE1 and ARASENS trials. What do the data look like for this trimodal therapy? PEACE1 was trying to answer a lot of things in an international trial. It had a trial design where they were trying to get about 1000 patients [on] combinations for de novo metastatic hormone-sensitive prostate cancer.

They were trying to say what’s better: ADT alone, ADT plus radiation to the primary tumor, ADT plus abiraterone, ADT plus abiraterone plus radiation, all with or without docetaxel. The Lancet article focused on the ADT plus docetaxel alone arm vs the trimodal therapy arm [ADT, docetaxel, abiraterone]. They found that the OS with [ADT, abiraterone, docetaxel] was better than just standard-of-care ADT alone or with docetaxel. So it was trimodal therapy vs bimodal therapy.³

They saw some improvements in people on standard of care with docetaxel. Improvement with trimodal therapy with the abiraterone was only in the high-volume patients. So if there is high-volume disease, like the patient we presented with liver metastases, and you give them the trimodal therapy, there is an improvement in their OS [HR, 0.72; 95.1% CI, 0.55-0.95; P = .019], which is clinically and statistically significant. It’s extending their life by about 1.5 years.³

Now, if they had low-volume disease at presentation—so less than, say, 5 metastases—if you compare them getting docetaxel plus ADT vs docetaxel, ADT, plus abiraterone, there is no benefit [HR, 0.83; 95.1% CI, 0.50-1.39; P = .66]. What the PEACE1 data show is that the trimodal therapy is probably best reserved for your high-volume de novo presenting metastatic disease.³ Bimodal therapy from the TITAN trial is for your all-comer disease that is metastatic, low volume, or high volume, as there is benefit.

Is the response in low-volume disease because of toxicity?

What I saw in the data is that more is not always better. I don’t think that the toxicities were much worse. When we added abiraterone to docetaxel plus ADT, we did not see a lot more toxicities. It was mostly [grade 3 to 5] hypertension, which was 21% in the trimodal group vs 13% in the docetaxel plus ADT alone group, and maybe a little bit more liver toxicity at 6% vs 1%. Most of the other AEs were lower grade and manageable.3 So I think like in the TITAN results, you’re getting such a big response with bimodal therapy that it’s just doing so much better than ADT alone. The question is how much more you get when you add the chemotherapy. I know it’s not exactly how the trials were designed, but how much better [efficacy] are you getting with chemotherapy or how much do you need a trimodal?

[In the TITAN study], the forest plots favor the apalutamide plus ADT bimodal combination for low-volume disease [more than high-volume disease]. So more is usually better but not always better. The bimodal therapy did such a good job with low-volume disease that I think you might be getting marginal benefit from trimodal therapy. So the question is, are you going to see an OS benefit by adding abiraterone? That’s where it fell short. My interpretation of these data and the TITAN and other data altogether is that for low-volume disease, we’re having discussions with our patients about bimodal therapy. But what is that bimodal therapy going to be? Is it an AR inhibitor like apalutamide? Is it abiraterone, an [androgen] synthesis inhibitor, or do we do 6 cycles of docetaxel and watch?

Does low-volume disease with a high Gleason score make a difference with trimodal therapy?

There’s going to be nuances at the periphery. So if you go to the ARASENS trial, what that brought up is that we should never look at the definitions of high- and low-volume disease as rigid definitions. There was the CHAARTED definition for high- or low-volume disease and there was the LATITUDE definition of high-risk and low-risk disease in the metastatic setting. How are we accounting for grade? If I see a patient who technically has low-volume disease because they have 10 metastases all in the pelvis but their Gleason grade is 5 + 4 = 9, I’m worried about that patient. If I add in that the patient is 55 years, should I be hamstrung by the idea that technically, by the CHAARTED definition, they have low-volume disease?

I think that there’s patients [for whom], even though they’re “CHAARTED” low volume, we know that they have aggressive disease; we know that the person has good performance status, but their life-limiting situation is certainly going to be the prostate cancer. So could trimodal therapy be appropriate for them? When the ARASENS trial [data were] published, which was a trimodal therapy using darolutamide, ADT, and docetaxel, they were not using that restriction of high- or low-volume disease.⁴ They basically said, “We want patients with metastatic hormone-sensitive prostate cancer who are candidates for chemotherapy.”

The medical oncologists and others then selectively recruited patients.

So most of these patients had either high-volume disease or they were high-grade patients with low-volume disease who were healthy. One knew that they’re going to have a problem. These are patients who you would usually think about throwing the kitchen sink at. They were [randomly assigned] to “the kitchen sink” trimodal therapy vs bimodal therapy.

In this case, the bimodal therapy was docetaxel plus ADT vs a trimodal therapy that added darolutamide. There was a benefit for the trimodal approach both in the time to castration-resistant disease and OS. There are some patients with high-grade but lower-volume disease. One knows that the disease is aggressive and going to be a bad actor, so you may want to do trimodal therapy. The quality of life seems OK even with trimodal therapy and the toxicities are tolerable.

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 4.2022. Accessed September 6, 2022. https://bit.ly/3qcTto2}

_{2. Ong S, O’Brien J, Medhurst E, Lawrentschuk N, Murphy D, Azad A. Current treatment options for newly diagnosed metastatic hormone-sensitive prostate cancer– a narrative review. Transl Androl Urol. 2021;10(10):3918-3930. doi:10.21037/ tau-20-1118}

_{3. Fizazi K, Foulon S, Carles J, et al; PEACE-1 Investigators. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707. doi:10.1016/S0140-6736(22)00367-1}

_{4. Smith MR, Hussain M, Saad F, et al; ARASENS Trial Investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115}

_{5. Chi KN, Agarwal N, Bjartell A, et al; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307}

_{6. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488}