Elucidating Treatment Selection for Metastatic HSPC at ASCO GU 2026

In an oral session at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, Christopher Sweeney, MBBS, DHS, FRACP, director of the South Australian Immunogenomics Cancer Institute (SAiGENCI) of Adelaide University, Australia, discussed optimal treatment selection for patients with metastatic hormone-sensitive prostate cancer (HSPC).¹ Specifically, he highlighted 4 major points when focusing on treatment for these patients:

• Harnessing investigator-generated data through industry and investigator-sponsored trials
• Acknowledging selective benefit with maximal dosing
• Leveraging companion diagnostics, despite difficulty, to minimize futile toxic therapy
• Realizing near-term benefit with personalized precision medicine through biomarker-directed treatment selection

“[This presentation] is timely and topical because we do need to make sense of some very complicated and overlapping data,” Sweeney explained.

Emphasizing Data From Investigator-Initiated Trials for HSPC Groups

In outlining his reasoning for the first point, Sweeney expressed that a focus on investigator-initiated studies may help provide the most exemplary data from HPSC trials. Additionally, they re-use existing data with broad patient groups and feature long-term data, less regulatory constraints, and higher value and accessible data, making these trials close to real-world studies. Additionally, Sweeney asserted that these trials would allow for biomarker work, development of companion diagnostics, and the optimization of personalized medical care.

Regarding treatment optimization, Sweeney explained that the current standard of care involves the addition of chemotherapy/docetaxel, androgen-signaling inhibition, and radiation to the prostate as well as stereotactic body radiation therapy (SBRT) to metastatic lesions to an androgen deprivation therapy (ADT) backbone. He added that discussions regarding care should also involve exercise, bone health, cardiovascular (CV) health, smoking and alcohol history/consumption, and psychosocial needs. Furthermore, he expressed that, since the 1990s, the transition from ADT alone with or without non-steroidal anti-androgens (NSAA) followed by docetaxel to docetaxel alone for metastatic castration-resistant prostate cancer (CRPC) and androgen pathway receptor inhibition (ARPI) for CRPC has resulted in an approximate doubling of 8-year overall survival (OS), from approximately 25% to approximately 50%.^2,3

“After a median follow-up of [more than] 8 years, OS remains statistically significant and clinically relevant for patients assigned enzalutamide [Xtandi] plus testosterone suppression compared [with] NSAA plus testosterone suppression,” Alison Y. Zhang, MD, of the NHMRC Clinical Trials Centre at the University of Sydney, wrote in a poster presentation of the ENZAMET study (NCT02446405) at ASCO GU 2025 with co-investigators.³ “Deaths due to prostate cancer were less frequent in those assigned to enzalutamide… enzalutamide was associated with a higher proportion of patients achieving PSA nadir of 0.2 or less at 7 months of therapy compared with NSAA.”

Moreover, he explained that achieving a PSA nadir of less than 0.2 at 6 or 7 months of treatment was associated with a 50% 8-year OS rate regardless of metastatic HSPC risk.⁴

“In the modern era, we’re still seeing a 50% OS [rate] for patients who achieve a PSA of less than 0.2 in both the CHAARTED and ENZAMET studies, but the other thing to point out…[is] the intensification that increases the number of patients to get to that good prognostic marker and get the OS,” Sweeney stated. “How do we increase the number of patients who [attain] a PSA value of less than 0.2 as an interim evaluation for the good prognosis?”

Outlining the Current State of Metastatic HSPC Therapy

Sweeney subsequently presented a chart outlining current standards of care for this metastatic MSPC population, stratified by tumor volume and presentation of metastases. Although ADT with ARPI is recommended for all patients, with ADT alone recommended for those with a shorter life expectancy, individualized treatment plans differed based on the presentation and volume of metastases:

• For metachronous, low-volume metastases, 68% of the Advanced Prostate Cancer Consensus Conference (APCCC) voters recommend the addition of SBRT;
• in metachronous, high-volume metastases, 84% recommend the addition of docetaxel among patients who are fit for chemotherapy;
• in synchronous, low-volume metastases, 82% of the APCCC recommends the use of prostate radiation and SBRT;
• and in synchronous, high-volume metastases, the APCCC recommends docetaxel among patients who are fit for chemotherapy based on a 94% vote.

Furthermore, Sweeney highlighted findings presented at the previous year’s conference, which revealed that abiraterone (Zytiga) conferred worse outcomes vs other ‘amides for the treatment of patients 75 years and older.⁵

Considerations For Future Treatment Options Across Modalities

Next, Sweeney outlined strategies that he suggested could be adopted for future use to better optimize the efficacy of ADT plus ARPI. Among those for consideration, he suggested that biomarker-directed therapies combined with docetaxel, treatment breaks, PARP inhibition, LuPSMA, and AKT inhibition are among those being considered to bolster treatment efficacy and patient outcomes among those with metastatic HSPC.

Initially, he presented data on the benefit of adding docetaxel to ADT, specifically by tumor volume and presentation of metastases. Overall, 2 studies found the greatest benefit was derived from patients with high-volume, synchronous metastases (HR, 0.63; 0.72), followed by those with high-volume, metachronous disease (HR, 0.72; 0.78).^{6, 7} Moreover, he presented data from samples from the STAMPEDE (NCT00268476) data set in which the 22-gene RNA DECIPHER test used in localized cancer displayed the ability to identify those who may not derive benefit from docetaxel (HR, 0.64; 95% CI, 0.48-0.86).

Additionally, he touched upon several ongoing studies assessing the impact of treatment breaks on patient outcomes for treatment. An EORTC study is examining a treatment break after 6 months on ADT plus ARPI vs continued therapy, the Libertas study (NCT05884398) is examining the intermittent use of testosterone suppression and continuation of ARPI following 6 months of treatment, and the A-DREAM trial (NCT05241860) is examining stopping therapy after an 18-month response to the ADT-based combination.^8-10

Next, he highlighted a couple of trials examining treatment optimization for docetaxel-based regimens. The first, the phase 3 ASPIRE trial (NCT06931340), is assessing ADT plus ARPI with or without docetaxel among all patients with high-volume or de novo low-volume metastatic CSPC.¹¹ The second, the phase 3 CCTG-PR26 TRIPLE-SWITCH trial (NCT06592924), is examining the standard combination with or without docetaxel among all metastatic CSPC of any volume or risk groups without any evidence of progression since the initiation of ADT.¹²

Then, Sweeney presented data from the phase 3 AMPLITUDE trial (NCT04497844) looking at PARP inhibition in patients with metastatic CSPC, in a population where 86% of disease was synchronous, 77% high-volume, 55% BRCA-mutant, and largely not previously treated with docetaxel (16%) or radiation to primary tumors (0%).¹³ The addition of niraparib (Zejula) was associated with a significant increase in median radiographic progression-free survival (PFS; HR, 0.52; 95% CI, 0.37-0.72; P <.0001) and OS (HR, 0.75; 95% CI, 0.51-1.11; P = .15). However, the benefit in non-BRCA homologous recombination repair (HRR) disease was unclear.

In the phase 3 PSMAddition trial (NCT04720157), ¹⁷⁷Lu-PSMA-617 (Pluvicto) exhibited a favorable median radiographic PFS advantage in a synchronous, high-volume, and older patient population (HR, 0.72; 95% CI, 0.58-0.90).¹⁴

“¹⁷⁷Lu-PSMA-617 [showed] a signal of benefit: a hazard ratio for radiographic PFS of 0.72 supported by a hazard ratio of less than 1 for OS. [Disease was] 52% synchronous, 68% high-volume, and 43% [of patients] were [70 years or older]. [There was] no prior docetaxel and no prior radiation,” Sweeney explained.

Sweeney then displayed findings from 2 additional studies, highlighting the use of mean standardized uptake value (SUVmean) to better select patients who may benefit from ¹⁷⁷Lu-PSMA-617. Therein, findings from the TheraP trial (NCT03392428) exhibited an approximate 8-month OS benefit among patients with an SUVmean of more than 10 vs less than 10.¹⁵ This was reinforced by findings from the VISION trial (NCT03511664), showing a similar approximate 7-month benefit in the SUVmean greater than 10 group.¹⁶ For patients with hormone-sensitive disease, finding a comparable biomarker to bolster treatment effect and reduce burden will be a challenge going forward, according to Sweeney.

Sweeney further highlighted data assessing capivasertib (Truqap) among patients with PTEN-deficient de novo metastatic HSPC in the phase 3 CAPItello-281 study (NCT04493853).¹⁷ Among patients with high-volume, synchronous disease and no prior prostate radiation or docetaxel (n = 6566), the HR for radiographic PFS was 0.81 (95% CI, 0.66-0.98), and for OS, it was 0.90 (95% CI, 0.71-1.15). Additional data from the IPATential150 study (NCT03072238) among patients treated with abiraterone with or without ipatasertib showed that the HR for radiographic PFS was 0.94 (HR, 0.76-1.17; P = .034), suggesting that PTEN immunohistochemistry may not be an optimal biomarker in metastatic HSPC.^{18, 19}

Although PTEN by next-generation-sequencing (NGS) was more reliable—with an HR for OS of 0.76 (95% CI, 0.54-1.07)—across the AKT activation pathway, a slightly more significant impact was observed (HR, 0.70; 95% CI, 0.51-0.96).

“This is… intelligence we’re leaving on the cutting room floor. There’s a signal here we need to continue to follow up on,” Sweeney expressed. “It’s interestingly supported by the other hormone-driven disease, breast cancer, with fulvestrant [Faslodex] plus or minus capivasertib, with an OS signal. This drug is approved for this setting.”

Next, Sweeney highlighted quality-of-life (QOL) impacts with PARP inhibition, particularly with fatigue and red blood cell (RBC) transfusion burden, as well as life threats from cardiac compromise and infections. For AKT inhibition, he noted diarrhea and rash as QOL impacts, while hyperglycemic complications were identified as life threats. Finally, he noted QOL impacts from gastrointestinal (GI) distress and lower enjoyment of food, as well as potential life threats from bone marrow and renal toxicities yet to be determined with LuPSMA.

Encouraging colleagues to look “beyond the headlines” with respect to QOL data for metastatic HSPC treatment, he touched upon data showing that the addition of docetaxel to ADT supports managing higher-volume tumors with respect to Functional Assessment of Cancer Therapy–Prostate (FACT-P) score.²⁰ Moreover, results from the same analysis found that enzalutamide-related fatigue and cognition QOL scores flatten out with dose reduction at a dose of 120 mg. Finally, he noted that the FACT-P score with LuPSMA was consistently below control after 6 months of treatment (HR, 1.14; 95% CI, 0.98-1.33).

In conclusion, he summarized the advances in data with AKT inhibition, PARP inhibition, and LuPSMA in the hormone-sensitive population, highlighting generally modest radiographic PFS benefit and clinically notable adverse effect (AE) profiles. Furthermore, he suggested that the clinical benefit for all 3 modalities was not significant enough for recommended routine use, but that next steps should include optimized dosing and biomarker selection for these patients.

Today’s Standards Are Still Standards

Returning to the chart outlining the current standards for metastatic HSPC therapy, he expressed that he still recommends their use today. However, Sweeney noted that an accrual to optimized biomarker-driven trials may help elucidate benefits with investigational therapies for this population.

“At the end of the day, I still think our current state of metastatic [HSPC] therapy is this table. This is how I make sense of the data,” he concluded. “I would aim to accrue patients to optimized biomarker-driven trials.”

References

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