During a recent OncLive Peer Exchange, prostate cancer experts discussed the evolving role of treatment intensification in mCSPC.
Although androgen deprivation therapy (ADT) remains a crucial part of the metastatic castration-sensitive prostate cancer (mCSPC) treatment paradigm, the rationale for treatment intensification to continue to improve long-term survivorship for patients who are good fits for the approach is gaining significant momentum in the field, according to experts.
“If we say, ‘Why not just do ADT alone with nothing else?’ The answer is, if we do that, your life would be shorter by 40% or 50%,” Alan H. Bryce, MD, said during a recent OncLive Peer Exchange. “The primary driver of loss of quality of life [QOL] in a patient with cancer is uncontrolled cancer. Better cancer control leads to better QOL.”
During the conversation, experts in the field of prostate cancer discussed how patient complexity, long-term survivorship, and emerging evidence are shaping treatment intensification strategies in mCSPC.
The panelists began their discussion by explaining how patient presentation in the modern age of mCSPC treatment contributes to treatment intensification decisions. Bryce noted that he has observed a shift in the number of patients who are presenting with metastatic disease at first diagnosis, partially due to a decline in screening. He underscored that if the disease is metastatic from the time of diagnosis, it is likely more aggressive compared with cancers that become metastatic several years after prostatectomy.
“We have 2 issues in confluence right now in this clinical state,” Charles J. Ryan, MD, said. “One is the difference in outcome [and] presentation of a [patient] for whom his first diagnosis of prostate cancer includes a diagnosis of metastasis vs metachronous [disease]; he was treated with curative intent some time ago, then developed a recurrence or a progression to metastatic disease. Issue number 2 is our definition of metastasis has changed because our ability to image the disease has [changed] so much.”
Bryce went on to add that imaging advances such as PSMA/PET scans have changed the number of lesions that are being found and allow for the discovery of smaller lesions. These advances have changed the thinking in terms of which patients may have curable disease, due to the significant number of patients who now receive radiation therapy and metastasis-directed therapy because they have been diagnosed with a small volume of metastatic disease.
Although more patients are now presenting in the clinic with metastatic disease, these patients are now living longer than ever before thanks to recent treatment advances, the panelists explained. Thus, oncologists must now think beyond short-term disease control and consider the long-term effects of therapy on patients’ daily functioning and overall wellbeing. Preservation of physical function, independence, and QOL are all essential components of present-day clinical decision-making, they argued.
“We have data now that the median patient in this space is living 8 or 9 years after diagnosis, so it becomes important to think about not just how long they're going to live, but how they're going to live during this time period,” Gautam Jayram, MD, said. “Something that we see all the time in the urology clinic is men who potentially have urinary issues or potency issues after definitive treatment. This has got us thinking about [mCSPC] as a chronic disease state more so than an acute disease, and the way I talk to my patients about it is more along those lines. There's a pretty high likelihood that even after definitive treatment, [many patients’ disease is] going to recur, based on the data that we have.”
Bryce explained that in the frontline setting in mCSPC, there is now ample evidence that points to increased long-term QOL with initial treatment intensification. “The conversation is that chemotherapy leads to a decrement in QOL. We have seen that during the 4 months of chemotherapy, QOL takes a dip and is worse than hormone therapy alone. But, by [approximately] month 8 or 9, the QOL of a patient treated with chemotherapy is higher than the QOL of a patient who didn’t get chemotherapy. This is consistent across a lot of clinical trials,” Bryce explained.
Beyond the addition of chemotherapy to ADT, there are now several treatment options that can be used as combination components to intensify upfront treatment for patients with mCSPC. Androgen pathway receptor inhibitors (ARPIs), such as darolutamide (Nubeqa) and enzalutamide (Xtandi), have emerged as valuable additions to standard ADT that have been shown to improve outcomes for patients with mCSPC.
Additionally, data from the 5-year follow-up of the phase 3 ARCHES trial (NCT02677896) presented during the 2025 ASCO Annual Meeting demonstrated that patients who received enzalutamide plus ADT (n = 574) experienced a significant benefit in terms of overall survival compared with those who received ADT plus placebo (n = 576; HR, 0.70; 95% CI, 0.58-0.85; log-rank P < .001).3 In patients with high-volume disease, the median OS was 83.06 months (95% CI, 69.59-not estimable [NE]) in the enzalutamide arm (n = 354) compared with 47.57 months (95% CI, 40.11-75.66) in the placebo arm (n = 373; HR, 0.70; 95% CI, 0.56-0.88). The investigational regimen also displayed a significant OS benefit in both patients with high- and low-volume synchronous disease, reducing the risk of death by 29% (HR, 0.71; 95% CI, 0.56-0.91) and 30% (HR, 0.70; 95% CI, 0.45-1.07) vs placebo plus ADT in the respective subgroups.
Another ARPI, abiraterone acetate (Akeega), gained FDA approval in combination with the PARP inhibitor niraparib (Zejula) and prednisone for the treatment of adult patients with deleterious or suspected deleterious BRCA2-mutated mCSPC as determined by an FDA-approved test
Findings from the phase 3 AMPLITUDE trial (NCT04497844), which supported the approval, showed that patients with homologous recombination repair gene–mutated mCSPC who received the triplet experienced a significant benefit in terms of rPFS compared with those who received placebo plus abiraterone acetate and prednisone (HR, 0.46; 95% CI, 0.32-0.66). Moreover, findings from an exploratory analysis demonstrated that the rPFS benefit did not translate to those without BRCA2 mutations (n = 373; HR, 0.88; 95% CI, 0.63-1.24).
“It’s hard to talk [with patients] about every detail, every single dose, and every single drug that we have available, and we don't have head-to-head comparisons to really tell our patients that [one drug] is better than this [other one],” Murilo De Almeida Luz, MD, said. “We know these drugs are effective and that they have adverse effects [AEs] despite ADT [use]. In the old days, we used to put the blame on ADT [and say] ‘this is because of testosterone suppression,’ but now we know these [other] drugs are effective and have AEs.”
The panelists explained that cognitive changes, fatigue, and fall risk are particularly relevant for older patients receiving long-term systemic therapy. Bryce noted that maintaining patient independence and preserving QOL are important goals when selecting therapy for patients who are expected to remain on treatment for extended periods. Additionally, cardiovascular risk, metabolic complications, and steroid exposure can affect both treatment choice and long-term patient monitoring strategies, underscoring the importance of a thorough evaluation of patient comorbidities before the initiation of combination therapy.
Bryce pointed out key distinctions between the available ARPI-based regimens. Abiraterone acetate is often associated with worse OS outcomes among patients who are at least 75 years old and requires rigorous liver functioning and electrolyte monitoring, he noted. Meanwhile, enzalutamide possesses improved central nervous system (CNS) penetration but carries a higher fall risk and often leads to more cognitive AEs, he added. Darolutamide has a favorable CNS toxicity profile and has displayed better OS outcomes vs abiraterone acetate in patients who are 75 years or older, he said.
The panelists concluded their conversation by discussing how real-world data can best be used to inform the treatment intensification processes. "The majority of treatment that I'm giving is not based upon actual clinical trial data, because [the patient] wouldn't have been eligible for that trial," Bryce commented.
Jayram emphasized the point that, as someone who practices in the community, patients who fit all the clinical trial inclusion [criteria] are not the patients who are being seen every day. However, Luz noted that real-world data does have limitations, such as selection biases that often make it difficult to compare with statistical tests. On the other hand, clinical trial populations often do not match real-world populations in terms of factors such as patient race and age, which can be better represented in real-world samples.
“[We want to use real-world data] to try to narrow the variables down,” Bryce said. “Age is a great example, [but] ethnic and cultural background also matters. Socioeconomic status is a big one. We know there are massive variations in health outcomes based on social determinants of health, and we're not getting [those data] out of clinical trials right now. In the United States, one of the primary drivers of cancer outcomes is distance to the cancer center; rural outcomes are far worse than urban outcomes. So, access to medicine [is something we can evaluate with real-world data].”
Alan H. Bryce, MD, is a medical oncologist and the chief clinical officer at City of Hope Cancer Center in Phoenix, Arizona.
Charles J. Ryan, MD, is an attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.
Murilo De Almeida Luz, MD, is an assistant professor of urology at Mount Sinai in New York, New York.
Gautam Jayram, MD, is the co-director of the Advanced Therapeutics Center at Urology Associates in Nashville, Tennessee.
