Prostate Cancer Living Guidelines Establish Frontline Combinations

Several trials in metastatic castration-resistant prostate cancer (mCRPC) focusing on systemic therapy have prompted the American Society of Clinical Oncology (ASCO) to issue updated living guidelines for the disease.¹ The updated guidelines, which detail significant shifts in the management of advanced prostate cancer, are centered on new data from clinical trials, practical recommendations for community oncologists, and a robust pipeline of emerging therapies.

Rahul A. Parikh, MD, PhD, coauthor of the guidelines and professor of medical oncology at the University of Kansas in Kansas City, discussed key updates on first-line therapies, bone protection, and the growing role of genetic testing in an interview with Targeted Oncology.

A New Frontline Standard?

A major focus on the guidelines highlighted results from the phase 3 PEACE-3 trial (NCT02194842),² which evaluated the combination of radium-223 dichloride (Xofigo) and enzalutamide (Xtandi) in patients with mCRPC with bony metastases. Parikh noted that the trial results may establish a new default first-line option for this group.

“The primary end point was radiographic progression-free survival [rPFS], which improved from about 16.4 months with enzalutamide alone to about 19.4 months with the combination,” Parikh said. He further noted an overall survival (OS) benefit, from approximately 35 months to 42.3 months with the combination, and highlighted that “nearly 43% [of patients] had not progressed at the end of 2 years.”²

However, this benefit comes with a trade-off in toxicity. “There is about a 9% to 10% higher risk of severe adverse events [AEs] with the combination,” Parikh said, “specifically increased incidence of high blood pressure, fatigue, and fractures.”

Making Bone Protection a Clinical Priority?

The heightened fracture risk observed in PEACE-3 led to a critical guideline adjustment: the mandated use of bone-protecting agents. After enrolling 115 patients, the study protocol was amended to require zoledronic acid or denosumab (Xgeva) for all participants.² Parikh emphasized that this should be a clinical priority beyond trials.

“I feel it’s important to identify these patients and treat them accordingly…even before the start of treatment for castrate-resistant disease,” he said. Parikh recommended using the Fracture Risk Assessment Tool (FRAX), which estimates the probability of a major fracture, or baseline dual-energy x-ray absorptiometry (DEXA) scans to assess risk.

Chemotherapy or ARPI for Quicker Symptom Relief?

On choosing between chemotherapy (docetaxel) and an androgen receptor pathway inhibitor (ARPI) such as enzalutamide, Parikh offered a clear clinical perspective. “Personally, I have preferred using chemotherapy in patients who are symptomatic,” he said, citing its potential for quicker symptom relief.

He highlighted visceral metastases (eg, in the liver or lungs) as a pivotal moment for additional investigation, not just treatment selection. “I would also try to get a biopsy…to confirm that, yes, this is prostate adenocarcinoma,” Parikh said, noting the need to rule out treatment-emergent neuroendocrine prostate carcinoma. Furthermore, a biopsy provides tissue for essential genetic testing to identify targetable alterations, a step he integrates into the decision-making process.

Critical Push for Early Genetic Testing

Parikh emphasized the need to expedite genetic testing to guide therapy. When asked about starting an ARPI alone while awaiting genetic results for a patient with rapid progression, Parikh acknowledged the treating physician’s discretion to act before clinical decline. However, he highlighted a shifting landscape that makes this dilemma less common.

“Genetic testing is fairly prevalent currently…. We get the results within a couple of weeks,” he noted. Furthermore, citing the phase 3 AMPLITUDE trial (NCT04497844), he pointed to approvals in the castration-sensitive setting that combine ARPIs with PARP inhibitors, reinforcing the need for early genetic data.³ “We are trying to move that testing up as soon as possible, as soon as the development of metastatic disease,” he said.

AMPLITUDE evaluated the efficacy and safety of niraparib (Zejula) and abiraterone acetate (Zytiga) plus prednisone in patients with metastatic castration-sensitive prostate cancer whose tumors harbor germline or somatic homologous recombination repair gene alterations, including BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, and RAD54L.³

The primary end point was met, with rPFS not reached (NR) in the combination arm vs abiraterone acetate plus prednisone (median, 29.5 months; 95% CI, 25.8-NR). Findings were similar for the prespecified BRCA1/2 subgroup (HR, 0.52; 95% CI, 0.37-0.72; P < .0001).

Navigating a Negative Trial: The CONTACT-02 Conundrum

The conversation also addressed the phase 3 CONTACT-02 trial (NCT04446117), which combined cabozantinib (Cabometyx) with atezolizumab (Tecentriq).⁴

Parikh cited the trial’s mixed results: a 2-month progression-free survival (PFS) benefit but no OS advantage (14.8 vs 15.0 months) compared with switching ARPIs, alongside a much higher severe toxicity risk (56% vs 26%, respectively).

Any-cause grade 3 or 4 AEs occurred in 158 of 284 (56%) patients given cabozantinib plus atezolizumab and 74 of 284 (26%) patients who switched the ARPI; the most common in the cabozantinib plus atezolizumab group were hypertension in 24 of 284 (8%) patients and anemia in 23 (8%), and the most common in the ARPI switch group was anemia in 18 of 284 patients (6%).

Serious AEs deemed related to treatment occurred in 45 of 284 (16%) patients in the cabozantinib plus atezolizumab group and in 11 of 284 (4%) patients in the ARPI switch group; the most common with cabozantinib plus atezolizumab was diarrhea in 5 of 284 patients (2%) and the most common with ARPI switch was increase in alanine aminotransferase in 2 of 284 patients (1%).

Given this and newer effective agents, Parikh indicated the combination would be reserved for a “very specific, smaller population,” such as those with rare biomarker-driven diseases like mismatch repair deficiency or PD-L1 positivity. He stressed the importance of counseling patients on the lack of survival benefit and increased toxicity.

Looking Ahead

Parikh expressed enthusiasm for the rapid pace of progress, noting the latest guideline iteration had incorporated 21 new or updated trials. To keep up, he suggested “reviewing the guidelines twice a year, at the least.”

He outlined a promising future pipeline, including the following

• Bispecific T-cell engagers targeting antigens such as prostate-specific maturation antigen and STEAP1
• Antibody-drug conjugates
• Novel androgen receptor degraders such as proteolysis targeting chimeras
• Advancements in radiopharmaceuticals, such as the alpha emitter actinium-225, building on the success of lutetium-177 (¹⁷⁷Lu) vipivotide tetraxetan (¹⁷⁷Lu PSMA-617; Pluvicto).

His takeaway message for community oncologists was one of collaboration: “They are kind of the feet on the ground…. I think we really would like to engage them,” he said, emphasizing that their feedback is vital for keeping guidelines practical and current.

REFERENCES

1. Taplin ME, Riaz IB, Rumble RB, et al. Systemic therapy in patients with metastatic castration-resistant prostate cancer: ASCO Living Guideline, version 2026.1. J Clin Oncol. Published online January 20, 2026. doi:10.1200/JCO-25-02693

2. Tombal B, Choudhury A, Saad F, et al. Enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer: results of the EORTC 1333/PEACE-3 trial. Ann Oncol. 2025;36(9):1058-1067. doi:10.1016/j.annonc.2025.05.011

3. Attard G, Agarwal N, Graff JN, et al; AMPLITUDE Investigators. Phase 3 AMPLITUDE trial: niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. J Clin Oncol. 2025;43(suppl 17):LBA5006. doi:10.1200/JCO.2025.43.17_suppl.LBA5006

4. Agarwal N, Azad AA, Carles J, et al. Cabozantinib plus atezolizumab in metastatic prostate cancer (CONTACT-02): final analyses from a phase 3, open-label, randomised trial. Lancet Oncol. 2025;26(7):860-876. doi:10.1016/S1470-2045(25)00209-8