Personalization Drives Next Wave of Metastatic Castration-Sensitive Prostate Cancer Treatment

As treatment options for patients with metastatic castration-sensitive prostate cancer (mCSPC) have expanded to include doublet and triplet regimens featuring androgen receptor (AR) inhibitors such as darolutamide (Nubeqa) and enzalutamide (Xtandi), patient quality of life (QOL), prostate-specific antigen (PSA) thresholds, and tolerability have gained even more importance in treatment decision-making.

“There are a lot [of factors such as] prognosis, clinical variables, volume of disease, genomic variables, and PSA response that we can pull from to help inform our patients,” Rana R. McKay, MD, explained. “One of the biggest things that patients struggle with is the unknown of what the future holds, and whatever we can use to help guide what that may look like for a given patient in a personalized [fashion] can go a long [way]. In this setting, QOL is of the utmost importance because there are many patients who can go on for years doing well. It’s exciting to see the field continue to evolve, [with] multiple treatments entering the landscape that are making patients live longer and feel better.”

In an OncLive Peer Exchange filmed during the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, expert panelists in the field of mCSPC discussed considerations for the use of triplet vs doublet regimens, emerging prognostic indicators, and the use of QOL data to guide treatment selection.

Combination Regimens Solidify Their Place, Underscoring Treatment Considerations

The panelists began their discussion by highlighting considerations for personalizing doublet and triplet regimens for patients with mCSPC. “In my clinical practice, I’m using a multitude of variables, first looking at disease characteristics [such as] Gleason score, volume and extent of disease, and [the presence of metastases]. I’m also looking at patient characteristics such as performance status, underlying comorbidities, [and potential] drug-to-drug interactions. Something that’s also beginning to play a role is genomics and potential biomarkers, although these are still in the early [stages].”

In August 2022, the FDA approved darolutamide plus docetaxel for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC).1 The regulatory decision was supported by data from the phase 3 ARASENS trial (NCT02799602).

At the time of the approval, findings from ARASENS demonstrated that patients who received darolutamide in combination with docetaxel and androgen deprivation therapy (ADT) achieved a significant overall survival (OS) benefit compared with those who received docetaxel plus ADT and placebo (HR, 0.68; 95% CI, 0.57-0.80; P < .0001). Additionally, patients in the darolutamide arm achieved a significant delay in time to pain progression vs the placebo arm (HR, 0.79; 95% CI, 0.66-0.95; 1-sided P = .006).

Furthermore, the phase 3 PEACE1 study (NCT01957436) examined the addition of abiraterone acetate (Zytiga) to ADT and docetaxel for the treatment of patients with de novo mCSPC.2 The European study randomly assigned patients 1:1:1:1 to receive standard-of-care (SOC) ADT with or without docetaxel (n = 296), SOC therapy plus radiotherapy (n = 293), SOC plus abiraterone (n = 292), or SOC plus abiraterone and radiotherapy (n = 291).

At a median follow-up of 6 years (IQR, 5.1-7.0), data from PEACE1 published in The Lancet revealed that patients who received SOC plus abiraterone and radiotherapy experienced a significant radiographic progression-free survival (rPFS) benefit vs SOC alone (HR, 0.52; 99.9% CI, 0.37-0.72; P < .0001). However, an OS benefit was not reported when comparing SOC with or without abiraterone and SOC plus radiotherapy with or without abiraterone (HR, 0.98; 95.1% CI, 0.83-1.14; P = .75).

“The data from ARASENS and PEACE1 tried to [elucidate] if the addition of an AR inhibitor improved outcomes, but we don’t know [the answer of] the reverse question,” Petros Grivas, MD, PhD, said. “If you give an AR inhibitor with ADT, does the addition of docetaxel help?”

“PEACE1 was the first trial to demonstrate that triplet therapy with abiraterone plus ADT and docetaxel bested docetaxel,” Neal Shore, MD, FACS, added. “When we think about triplet therapy, I realize that most urologists are not comfortable with it. I believe it speaks to the importance of a multidisciplinary team. Urologists have to incorporate their medical oncology colleagues to at least have this important discussion with patients [regarding] the shared decision-making, [with the] notion that we have level 1 evidence for triplet therapy. [However], there’s the trade-off of more toxicities.”

During the 2025 ASCO Annual Meeting, investigators presented data from the 5-year update of the phase 3 ARCHES trial (NCT02677896).3 ARCHES examined enzalutamide in combination with ADT vs ADT plus placebo in patients with mHSPC who had an ECOG performance status of 0 or 1. Prior data from ARCHES trial supported the December 2019 FDA approval of enzalutamide for the treatment of patients with mCSPC.4

Findings from the updated analysis showed that at a median follow-up of 61.4 months (range, 0.03- 89.33), patients who received enzalutamide plus ADT (n = 574) had a median OS that was not eval- uable (NE; 95% CI, 83.06-NE) compared with 59.50 months (95% CI, 49.74-NE) in the placebo plus ADT group (n = 576) after adjustment for crossover (adjusted HR, 0.64; 95% CI, 0.51-0.75).3 A significant benefit in favor of the enzalutamide arm was also reported without a crossover adjustment (HR, 0.70; 95% CI, 0.58-0.85; P < .001).

Additionally, the 5-year OS rates in the investigational (n = 109) and control (n = 59) arms among patients with low-volume disease were 76.7% (95% CI, 70.0%-82.0%) and 67.5% (95% CI, 59.8%- 74.0%), respectively. Patients with high-volume disease in the investigational (n = 134) and control (n = 56) arms experienced 5-year OS rates of 58.4% (95% CI, 52.6%-63.5%) and 45.0% (95% CI, 38.9%- 50.9%), respectively. Notably, the addition of enzalutamide to ADT also produced higher 5-year OS rates vs placebo plus ADT across other key subgroups (Table).3

“We saw in this analysis that among the patients with high-volume disease, the median OS was prolonged by [approximately] 3 years [in the investigational arm] compared with placebo plus ADT,” Alicia Morgans, MD, MPH, said. “That’s a powerful number to share with our patients. We have to use these doublets in order to get that benefit, but the benefit is real when we do use them. There was also a clear benefit in patients with low-volume disease, but the median OS wasn’t reached in both arms, and that’s why this particular number wasn’t reported. [However], in all the subgroups, [there was] a benefit to intensification of ADT [with] enzalutamide.”

Grivas noted that Black patients with mCSPC may present with more aggressive disease and a worse prognosis. Findings from an analysis of the phase 3 ARANOTE trial (NCT04736199), which examined darolutamide plus ADT in patients with mHSPC, were presented during the 2025 American Urological Association (AUA) Annual Meeting in Las Vegas, Nevada, and showed that Black patients in the darolutamide arm (n = 41) achieved a significant rPFS benefit vs placebo plus ADT (n = 24; HR, 0.51; 95% CI, 0.21-1.23). The 24-month rPFS rates were 70.9% and 58.1%, respectively.4

“We have to keep in mind that ARANOTE basically enrolled patients from outside of the US; this was largely a [cohort] from Brazil,” McKay noted. “Overall, the effect with darolutamide was consistent in Black patients [compared with the overall population]. [However], we need to try to bridge the disparities. At the end of the day, our underrepresented populations experience the greatest divergence with regard to use of SOC therapies, treatment escalation, and various biases that may exist.”

Examining Early Prognostic Indicators and Strategies to Preserve QOL

The panelists transitioned their conversation to discussing early prognostic indicators and approaches to maximize the QOL of patients with mCSPC, beginning with the role of PSA in assessing response to therapy. “Taking into account clinical status, patient symptoms, and toxicities, PSA can be synthesized to customize the cadence and frequency of scans,” Grivas commented.

During the 2025 ASCO Annual Meeting, investigators presented data from a real-world, international analysis of the IRONMAN registry (NCT03151629).5 The analysis examined the prognostic significance of a PSA level greater than 0.2 ng/mL among patients with mHSPC who received ADT plus an AR inhibitor with or without docetaxel.

Findings from the analysis revealed that patients with a PSA level of less than 0.1 ng/mL (n = 509), 0.10 ng/mL to 0.19 ng/mL (n = 182), and at least 0.2 ng/mL (n = 271) had 3-year OS rates of 84%, 79%, and 45%, respectively (Figure).5 The respective 3-year PFS rates were 80%, 62%, and 41%. Notably, PSA levels were found to be prognostic of outcomes irrespective of AR inhibitor selection or the receipt of a doublet vs a triplet regimen.

Similarly, data from an analysis of ARANOTE presented during the 2025 AUA Annual Meeting demonstrated that patients who received darolut- amide plus ADT with a baseline PSA level of at least 0.02 ng/mL (n = 143), 0.02 ng/mL to less than 0.2 ng/mL (n = 90), and less than 0.02 ng/mL (n = 185) experienced respective median rPFS values of 17 months (95% CI, 14-23), not reached (NR; 95% CI, 27 months-NR), and NR (95% CI, NR-NR).6 The HRs when comparing the less than 0.02 ng/mL group vs the 0.2 ng/ mL or more group and the 0.02 ng/mL to at least 0.2 ng/mL group were 0.09 (95% CI, 0.05-0.16) and 0.41 (95% CI, 0.27-0.63), respectively.

“The predictive and prognostic implications of getting an ultralow PSA are clearly very valuable,” Shore said. “We’re seeing in ARANOTE and other studies such as IRONMAN and the importance of that initial nadir of PSA and the rapidity of how quickly patients get there. When patients have PSA [levels] in the thousands or hundreds and they drop down to 4 or 5 [ng/mL], we need to potentially be thinking about adding docetaxel at that point.”

The panelists concluded their conversation by discussing health-related QOL data from ARANOTE. Patients in the darolutamide plus ADT arm (n = 446) experienced a median time to PSA progression that was NR (95% CI, NR-NR) vs 16.8 months (95% CI, 13.9-20.1) in the placebo plus ADT arm (n = 223; HR, 0.31; 95% CI, 0.23- 0.41).7 Moreover, patients in the investigational arm experienced significant benefits in terms of time to mCSPC (HR, 0.40; 95% CI, 0.32-0.51) and time to pain progression (HR, 0.72; 95% CI, 0.54-0.96) vs the placebo arm. The study authors noted that these data suggest that the addition of darolutamide has a positive impact on patients’ QOL.

“When we can control cancer, we can often do better in terms of preventing progression of symptoms,” Morgans said. “One of the interesting things about darolutamide in this doublet was that it seemed to prolong the time that patients felt well and had superior QOL in terms of deterioration vs ADT alone.”

References

1. FDA approves darolutamide tablets for metastatic hormone-sensitive prostate cancer. FDA. August 5, 2022. Accessed July 22, 2025. bit.ly/45fZYMe
2. Bossi A, Foulon S, Maldonado X, et al; PEACE-1 Investigators. Efficacy and safety of prostate radiotherapy 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. 2024;404(10467):2065-2076. doi:10.1016/S0140-6736(24)01865-8
3. Armstrong AJ, Petrylak DP, Shore ND, et al. ARCHES: five-year follow-up overall survival (OS) analysis of enzalutamide (ENZA) plus androgen-deprivation therapy (ADT) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2025;43(suppl 16):5005. doi:10.1200/JCO.2025.43.16_suppl.5005
4. Trinh QD, George DJ, Shore N, et al. Efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) in Black patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase 3 ARANOTE trial. J Urol. Published online May 1, 2025. doi:10.1097/01. JU.0001109908.15997.76.01
5. Ong M, Roy S, Chi KN, et al. Prognostic significance of PSA>0.2 after 6-12 months treatment for metastatic hormone-sensitive prostate cancer (mHSPC) intensified by androgen-receptor pathway inhibitors (ARPI): a multinational real-world analysis of the IRONMAN registry. J Clin Oncol. 2025;43(suppl 16):5002. doi:10.1200/JCO.2025.43.16_suppl.5002
6. Shore N, Haresh KP, Vjaters E, et al. Ultra-low PSA response (<0.02 ng/ml) with darolutamide plus ADT in ARANOTE correlates with greatly improved clinical outcomes. J Urol. Published online May 1, 2025. doi:10.1097/01. JU.0001110200.18879.65.07
7. Saad F, Vjaters E, Shore N, et al; ARANOTE Study Investigators. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. 2025;42(36):4271-4281. doi:10.1200/JCO-24-01798