Considering Optimal Treatment for Metastatic HSPC: Doublet vs Triplet Therapy

In a Medical Crossfire session at the 19th Annual New York GU Cancers Congress®, Tanya Dorff, MD, and Maha Hussain, MD, MBChB, took contrasting opinions regarding the addition of docetaxel chemotherapy to androgen receptor pathway inhibition (ARPI) and androgen deprivation therapy (ADT) among patients with metastatic hormone-sensitive prostate cancer (HSPC).¹ Dorff, division chief of the Genitourinary Disease Program and a professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, offered the perspective that, for most patients, doublet therapy excluding chemotherapy may often be the optimal choice. On the other hand, Hussain, Genevieve E. Teuton Professor of Medicine (Hematology and Oncology) at the Feinberg School of Medicine at Northwestern University, offered the perspective that a greater number of patients with HSPC may benefit from the addition of chemotherapy.

To better elucidate the rationale behind their claims, CancerNetwork® spoke with both oncologists at the conference. Initially, Dorff explained in greater detail the background behind her presentation before outlining considerations for using a doublet therapy and discussing whether there is a place for triplet therapy in treatment for patients with metastatic HSPC.

Doublet Therapy May Be Optimal for Most Patients with Metastatic Disease

First, Dorff outlined the background for her portion of the session, highlighting key data supporting the use of doublets among this patient group.

“I was asked to take the stance that doublet therapy, rather than triplet therapy, is appropriate for patients with newly diagnosed metastatic prostate cancer. There are a number of clinical trials that have reported on doublets with ARPIs, including abiraterone [Zytiga], apalutamide [Erleada], and darolutamide [Nubeqa],” she explained. “The triplet studies are primarily from a slightly older generation where the backbone is docetaxel added to ADT, and then the question was whether the ARPI was still beneficial, which it was.”

Data from the phase 3 LATITUDE (NCT01715285) and STAMPEDE trials (NCT00268476) revealed that the addition of abiraterone to ADT in metastatic prostate cancer was associated with a significant reduction in the risk of death, with HRs of 0.62 (95% CI, 0.51-0.76; P < .001) and 0.63 (95% CI, 0.52-0.76; P < .001).^2,3 Moreover, data from the phase 3 TITAN trial (NCT02489318) revealed similar findings with apalutamide (HR, 0.67; 95% CI, 0.51-0.89; P = .005).⁴ Additionally, darolutamide displayed a benefit over placebo in the phase 3 ARANOTE trial (NCT04736199), with an HR for overall survival (OS) of 0.81 (95% CI, 0.59-1.12).⁵

Furthermore, Dorff emphasized that there are no studies that directly examined the addition of chemotherapy to an ARPI doublet, but that patient selection may be an integral factor in determining patient benefit with or without docetaxel.

“Your typical [patient with] prostate cancer presenting with metastatic disease can have many years of good cancer control on an ADT and ARPI doublet. In fact, they can have quite good quality of life. There are certainly [adverse] effects [AEs] to ARPIs, but they have the advantage of not having long-lasting potential toxicity, such as peripheral neuropathy that you can see with docetaxel chemotherapy,” she stated.

Hussain conceded that, often, patients who are comorbid or who express characteristics of frailty might be among those whom she would consider for doublet therapy.

“Age is a big factor, but age should not be used to discriminate in terms of treatment choice; safety is the critical factor,” Hussain expressed. “As people get older, there are other comorbidities, and from my end, the safety trumps everything else. There are times where, [for] somebody who is much older…in their 80s and so on, or people who are in their late 70s but have other comorbidities and other factors, [it] is critical to look at their prognosis from non-cancer related [issues] to plan the merit of doing triplet therapy vs just adding ARPIs to the androgen deprivation.”

Triplet Therapy May Optimize Efficacy Without Sacrificing Safety in HSPC

Hussain, in outlining the background to her study, explained that she assumed a favorable position for triplet therapy among this patient population, particularly the addition of docetaxel to ARPI/ADT. Acknowledging the paucity of data, she expressed that prostate cancer in of itself is a complicated disease, with a non-zero chance that patients will respond to hormone therapy.

“The bottom line is this: prostate cancer is complicated, and not every prostate cancer cell is 100% guaranteed to be responsive, meaning [they] will die by starvation from the hormone treatment,” she stated in an interview with CancerNetwork. “The issue that comes up is, are there cells that are likely not to respond as well to hormone treatment? We know that happens because, ultimately, [a] significant percentage of patients progress to castration-resistant disease, which says there were cells hiding in there.”

Then, Hussain went into characteristics that might make a patient a preferred candidate for triplet therapy, guided by the mentality that treatment should not be given if there might be an implied harm with its use. Specific criteria include:

• Patients with de novo metastatic disease
• Patients who are younger and more fit
• Patients with high-volume, aggressive, or visceral disease

Moreover, she highlighted conditions for optimally escalating strategy to include docetaxel with the ARPI/ADT backbone. Hussain suggested that patients who experience sustained tolerability to treatment with the hormone backbone, for approximately 2 to 4 months, are among those considered for added docetaxel. After a discussion that includes patient self-reports and examining the relative risk/benefit ratio of chemotherapy, Hussain will suggest docetaxel if she believes a patient may benefit from its use.

“I always tell my patients that my job is to tell them what I think is their best chance, not what they want to necessarily hear,” Hussain said. “Chemotherapy can be scary for [patients], but the reality of it…in over 95% of times when I counsel a patient and recommend them triplet therapy, they go with it.”

Dorff conceded that triplets may have a role in treating patients with high-volume disease, those with visceral disease, and those with bone metastases. Specifically, she highlighted the potential utility of prostate-specific antigen (PSA) nadir as a means of selection for doublet or triplet therapy.

“We did also mention the clinical trial that's going on right now through the cooperative groups using PSA as a biomarker to select who needs the docetaxel,” Dorff expressed. “Even among those with more aggressive presentations, there are possibly patients who are going to respond well to doublet therapy. We know that at 7 months, a PSA nadir of less than 0.2 is predictive of patients who do well. Patients who don't have a PSA nadir of less than 0.2 at 7 months do poorly.”

Can Treatment Be Effectively De-Escalated in the Metastatic HSPC Setting?

Other considerations for treatment among patients with metastatic HSPC include treatment de-escalation, particularly examining the role of ARPI discontinuation with sustained ADT treatment to determine the potential impact on long-term disease control and testosterone recovery, in addition to a potential reduction in adverse effects (AEs).

“We don't know if stopping ADT and an ARPI or [having] some kind of de-escalation––sometimes removing the ARPI but maintaining the ADT, for instance—would be an intermediate intensification strategy. We don't know whether that impacts cancer control at 5 and 10 years. Those studies are being designed now, and the A-DREAM trial [NCT05241860] will provide some benchmark information for what percentage of patients remain progression-free at 18 months with testosterone recovery.^”6

Dorff further explained that a goal of treatment de-escalation is to achieve testosterone recovery while reversing ADT AEs and risks. Noting that a failure to achieve testosterone recovery is much like a patient still “on treatment,” she expressed that phase 2 data will help establish a benchmark and help power a phase 3 study exploring ADT deintensification.

Moreover, Dorff considered the relative benefit of continuous vs interrupted treatment for these patients, highlighting an increase in PSA as a primary concern.

“We have not gotten to a cure, unfortunately, with just systemic therapy, even when we add in the radiation intensification. Most of the time, you have to prepare patients [for] the cancer to show up again,” she explained. “I have not seen explosive progression, lack of control, or lack of sensitivity to reintroduction of treatment, and those are the things I use to reassure my patients when we're contemplating a treatment holiday. I have to tell them that we don't have enough data on how outcomes will be impacted for cancer control, but we do know quality of life certainly improves with an intermittent approach.”

She further cited the phase 3 JPR7 trial (NCT00003653), which compared outcomes between patients undergoing continuous vs intermittent androgen suppression.⁷ Although the study authors concluded that the intermittent regimen was noninferior, Dorff asserted that patients who are particularly struggling with toxicities impacting quality of life may be candidates for a drug holiday.

Final Takeaways

The contrasting perspectives offered by Dorff and Hussain underscore the increasing complexity of personalizing care for patients with metastatic HSPC. Although both experts agreed on the efficacy of the ADT plus ARPI doublet as a foundational standard, their debate highlighted a critical tension between maximizing efficacy and preserving quality of life for this group.

For Dorff, the doublet remains the optimal choice for the average patient, offering robust cancer control while avoiding the long-term AEs associated with chemotherapy, such as peripheral neuropathy. Conversely, Hussain advocated for a more aggressive triplet approach incorporating docetaxel for younger, fitter patients with high-volume or visceral disease, arguing that the heterogeneous nature of the disease requires intensive upfront intervention to target hormone-resistant cell populations. Ultimately, the decision between doublet and triplet therapy remains a patient-centric dialogue, weighing the promise of long-term survival against the reality of treatment-related toxicity. Moreover, emergent data will help to better identify biomarkers and patient characteristics that might be conducive to the addition of docetaxel.

References

1. Dorff T, Hussain M. MXF: treatment intensification in mHSPC: doublet vs triplet therapy. Presented at: 19th Annual New York GU Cancers Congress®; March 13-14, 2026; New York, NY.
2. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174
3. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351. doi:10.1056/NEJMoa1702900
4. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307
5. Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. 2024;42(36):4271-4281. doi:10.1200/JCO-24-01798
6. Testing Interruption of hormonal medications in patients responding exceptionally to therapy for metastatic prostate cancer, (A-DREAM) (A-DREAM). ClinicalTrials.gov. Updated December 22, 2025. Accessed March 17, 2026. https://clinicaltrials.gov/study/NCT05241860
7. Crook JM, O'Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012;367(10):895-903. doi:10.1056/NEJMoa1201546