Data Continue to Support Triplet Therapy With ADT, AR-Targeted Therapy, and Chemotherapy in mHSPC

Kevin Kayvan Zarrabi, MD, MS, FACP

Findings from the phase 3 PEACE1 (NCT01957436) and ARASENS (NCT02799602) trials have supported the use of triplet therapy consisting of androgen deprivation therapy (ADT), androgen receptor (AR)-directed therapy, and docetaxel as the new standard of care for select patients with metastatic hormone-sensitive prostate cancer (mHSPC), particularly for those with high-volume disease and those who are fit for docetaxel or cytotoxic chemotherapy, according to Kevin Kayvan Zarrabi, MD, MS, FACP.

“There is still consideration for doublet therapy in the form of ADT and AR-directed therapy. Until we have more data, it will be difficult to say that for the all-comers population that triplet therapy is necessarily superior to doublet therapy. However, in the meantime, we do know that for a subset of the population, primarily patients the high-volume tumor burden, triplet therapy is effective in prolonging overall survival [OS],” Zarrabi said following a presentation on prostate cancer at an OncLive^® State of the Science Summit^™ on genitourinary cancers.

In an interview with OncLive, Zarrabi, an assistant professor at Sidney Kimmel Cancer Center at Jefferson Health, in Philadelphia, Pennsylvania, discussed the emergence of triplet therapy of ADT, AR-targeted therapy, and cytotoxic chemotherapy for patients with mHSPC; highlighted key trials that have explored and supported the use of these triplets; and expanded on the unanswered questions that remain regarding patient selection and chemotherapy eligibility.

OncLive: Could you provide an overview of your presentation on treatment intensification in patients with mHSPC?

Zarrabi: We had an excellent discussion regarding the treatment of patients with mHSPC with a focus on treatment intensification over the years. Most recently, [there has been an] emergence of triplet therapy in the form of ADT, AR-targeted therapy, and cytotoxic chemotherapy together for patients with both de novo mHSPC and those who have localized disease with disease progression or recurrence in the metachronous setting.

The emergence of triplet therapy has provided more data that treatment intensification can be beneficial for some patients and prolong OS with an overall tolerable adverse effect [AE] profile; again, this is in select patients.

Could you elaborate on some of the key trials that have examined doublet or triplet therapy in mHSPC?

Over the past few decades, we started off intensifying treatment with ADT in addition to radiation therapy, and later on we had the addition of AR-targeted therapy. We had some landmark trials, such as the phase 2/3 STAMPEDE [NCT00268476], phase 3 LATITUDE [NCT01715285], and the phase 3 ENZAMET [NCT02446405] trials, to name a few. Later we had the additional cytotoxic chemotherapy in the phase 3 CHAARTED trial [NCT00309985], as well as in arm C of STAMPEDE.

Those were all doublet regimens. However, most recently, we've seen the presentation of both progression-free survival [PFS] and OS [data] from the PEACE1 trial looking at ADT and abiraterone acetate [Zytiga] with prednisone and docetaxel, as well as the phase 3 ARASENS study, which looked at the same treatment paradigm, with some caveats in terms of differences, [including the use of] darolutamide [Nubeqa] as the AR-targeted therapy.

How do you select between triplets and doublets for certain patients? Are there any characteristics or biomarkers that help with this choice?

Unfortunately, we are still working on finding the ideal biomarker to identify which patient may benefit from treatment intensification, either in the form of the addition of AR-targeted therapy or cytotoxic chemotherapy. However, we currently have several tools to risk stratify our patients. Both the CHAARTED and LATITUDE criteria, which accounted for tumor burden and tumor biology, help us determine whether intensification is appropriate.

How I like to frame it: If a patient is already going to be getting ADT plus cytotoxic chemotherapy, then the addition of an AR-targeted therapy—whether that be abiraterone acetate or darolutamide—makes a lot of sense for most of our patients. The ideal patient where the benefit is most clear is in those with high tumor volume, high tumor burden, more aggressive disease, and those who are fit for chemotherapy.

What unanswered questions remain regarding the use of triplet approaches?

The data from both PEACE1 and ARASENS are very convincing toward the benefit of treatment intensification with triplet therapy. I believe the OS benefits are also equally convincing. It was nice to see a separation of the curves in the Kaplan-Meier analyses [in both studies].

A few questions remain unanswered. A minority of the patients in these studies had metachronous metastases diagnosed earlier in their disease course, with a natural progression to distant metastases in the future. That tumor biology may be different from the patients represented in this trial. Moreso, in the patients with low-volume disease, although we see a signal favoring triplet intensification, it's not abundantly clear on most analyses that are available to us. The confidence intervals remain wide for some of the OS data. As the data mature, it will become clearer in terms of whether there's truly an [OS] benefit and whether that benefit is for a subset of patients or the majority of patients.

We are also left without a great understanding of what it truly means to be fit for chemotherapy. Which patients will benefit from docetaxel? Which patients may have morbidity associated with it and possibly early mortality? As I like to think of it, we have the eye test in terms of clinicians assessing where patients are in terms of performance status and tolerability to the toxicities that come with chemotherapy. However, we do not have a standardized way of measuring chemotherapy eligibility. Therefore, we don't have a way of studying outcomes in patients who are borderline chemotherapy eligible. As time goes on and we develop further studies, these answers will hopefully be more evident.

Lastly, both the PEACE1 and ARASENS trial provided data toward the utility and the benefit of adding an AR-directed therapy on top of an ADT and docetaxel backbone. We don't have a trial investigating the benefit of the docetaxel in that triplet combination therapy. In other words, [we do not have] a trial in which the control arm, rather than being [the combination of] ADT and docetaxel, it may be ADT and an AR-directed therapy, and the addition of cytotoxic chemotherapy would be the experimental component for that study.

With time, we may see that study or studies similar to that design emerge. That will only be helpful in terms of clarifying this picture of the utility of treatment intensification and finding the ideal patient.

Are there any planned or ongoing investigations of treatment intensification that you're looking forward to?

There are quite a few trials ongoing, both in the phase 2 and phase 3 settings, looking at triplets. These triplets [do not all necessarily include] ADT, AR-directed therapy, and chemotherapy; there are other therapeutic modalities, including radioligand therapy. I am hopeful the phase 3 PSMAddition trial [NCT04720157] will read out soon. [This trial] investigated triplet therapy with the addition of Lu 177 vipivotide tetraxetan [Pluvicto; formerly 177Lu-PSMA-617] to [AR-targeted therapy and ADT].

There are also trials looking at triplets with PARP inhibitors in the hormone-sensitive setting, as well as with novel targeted therapies, including CDK4/6 inhibitors and AKT inhibitors.

The future is bright. We have a lot of agents that are active in the prostate cancer space. It will be interesting to see which agents are moved up in the treatment paradigm and which agents show the most benefit in patients with mHSPC.

With different emerging data for prostate radiotherapy, how do you evaluate the potential benefits and risks of incorporating local therapies to a treatment plan?

The PEACE1 trial was a unique trial that had a 2 x 2 factorial design in which it not only looked at the benefit of adding abiraterone acetate to treatment, but [it also looked at the addition] of radiotherapy. Data presented by Maha Hussain, MD, [of the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine] at the 2023 Genitourinary Cancers Symposium highlighted the benefit of the addition of radiotherapy in the low-volume patient population in that trial. Notably, the Kaplan-Meier curve [for OS] was impressive. There was an early separation of the curves and it seemed sustained.

Even more convincing than that is the secondary end point of time to serious genital urinary events. Many of our patients do well on therapy, but down the line may develop an obstructive uropathy or complications from their prostate or pelvic disease that may lead to morbidity, early mortality, or treatment interruptions.

[Data from] PEACE1 nicely demonstrated that introduction of radiotherapy to the prostate in the all comers, in both patients with low-volume disease and the overall population, delayed time to serious genital urinary events. After patients completed their course of docetaxel, they then underwent radiotherapy to the prostate.

This trial demonstrates the beneficial impact of thinking of radiotherapy earlier on in our disease course. We do not necessarily need to be reactive in terms of introduction of radiotherapy; rather, we can be proactive.