Isaac Y. Kim, MD, PhD, MBA, and Anthony V. D'Amico, MD, PhD, discuss radiotherapy, surgery, and emerging strategies in mHSPC.
The roles of radiation therapy and surgery for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC) are evolving with emerging agents such as lutetium Lu 177 vipivotide tetraxetan (Pluvicto) and notable ongoing clinical trials, including the phase 2.5 SIMCAP study (NCT03456843), poised to potentially add additional therapeutic avenues for patients, according to Isaac Y. Kim, MD, PhD, MBA; and Anthony V. D’Amico, MD, PhD.
In a joint presentation at the 19th Annual New York GU Cancers Congress®, an event hosted by Physician’s Education Resource (PER®) in New York, New York, Kim and D’Amico discussed the current and future landscapes of radiation therapy and surgical treatment approaches in mHSPC.1,2
Kim is the chair and chief of urology, the coleader of the Cancer Signaling Networks, and a professor of urology at Yale Cancer Center in New Haven, Connecticut. D’Amico is the chief of the Division of Genitourinary Radiation Oncology and an institute physician at Dana-Farber Cancer Institute, as well as a professor of radiation oncology at Harvard Medical School, both in Boston, Massachusetts.
D'Amico began the session with a presentation on the current status of radiation therapy for patients with mHSPC. “Treating the prostate [with radiation therapy] may extend survival in patients with oligometastatic disease. Metastasis-directed radiation is associated with delays in time to PSA [prostate-specific antigen] progression. It also appears to delay [time to] radiographic progression [as well as] time to castrate resistance and may prolong survival.”
Findings from the prospective HORRAD trial (ISRCTN06890529) demonstrated that, at a median follow-up of 47 months, patients with minimal M1 disease who received external beam radiation therapy (EBRT) in addition to androgen deprivation therapy (ADT) experienced a significant overall survival (OS) benefit compared with those who received ADT alone (HR, 0.68; 95% CI, 0.42-1.10).3 Similarly, at a median follow-up of 37 months, data from the phase 3 STAMPEDE trial (NCT00268476) showed that patients with minimal M1 disease who received standard-of-care (SOC) treatment plus radiotherapy experienced a significant OS benefit compared with those who received SOC alone (HR, 0.68; 95% CI, 0.52-0.90; P = .007).4
“[These data show] that in patients with minimal or oligometastatic disease, treatment of the primary appears to prolong OS,” D’Amico explained. “I use the word appears because this was post randomization, but we have 2 studies showing the same HR of 0.68, [which is] fairly remarkable. To be clear, prolonging OS doesn’t mean you’re curing these patients.”
In the phase 3 PEACE-1 trial (NCT01957436), patients with castration-sensitive prostate cancer were randomly assigned 1:1:1:1 to receive SOC ADT, SOC plus radiation therapy, SOC plus abiraterone acetate (Zytiga), or SOC plus abiraterone and radiation therapy.5 Findings from the study revealed that in the overall study population, castrate resistance-free survival was prolonged with SOC plus abiraterone and radiation therapy compared with SOC plus abiraterone (HR, 0.79; 95% CI, 0.64-0.98; P = .028).
“We consider treating the prostate, certainly in the oligometastatic setting, but even in patients with more than oligometastatic disease, when there’s high-volume disease locally that is likely to get into a retention or obstruction down the road,” D’Amico commented.
D’Amico concluded his portion of the session by noting that there may be a role for lutetium Lu 177 vipivotide tetraxetan in patients with high-volume mHSPC; however, longer follow-up is likely needed. Specifically, at a median follow-up of 2.5 years, data from the phase 2 UpFrontPSMA trial (NCT04343885) revealed that patients who received sequential lutetium Lu 177 vipivotide tetraxetan with docetaxel (n = 61) experienced an undetectable PSA level (≤ 0.2 ng/mL) at 48 weeks at a rate of 41% (95% CI, 30%-54%) compared with 16% (95% CI, 9%-28%) of patients who received docetaxel alone (n = 61; odds ratio, 3.88; 95% CI, 1.61-9.38; P = .0020).6 There was no increased toxicity related to the addition of lutetium Lu 177 vipivotide tetraxetan, D’Amico noted.
“We know that getting to an undetectable PSA [level] is prognostic,” D’Amico said. “That’s important, but is it predictive of what will happen down the road? Time will tell. I do believe that radionuclide therapy will be on the map.”
The session transitioned to Kim’s presentation, which focused on data from notable recently reported and ongoing clinical trials of surgical approaches in mHSPC.2 “Data [from a database analysis] published in 2014 showed that patients with de novo metastatic prostate cancer [who underwent radical prostatectomy or brachytherapy] had a much better OS [compared with those who did not].7 That said, compared with the radiation literature, the data are pretty limited in the surgical arena.”
Kim explained that the interventional g-RAMPP study (NCT02454543), which evaluated the effect of radical prostatectomy as primary treatment in patients with limited bone metastatic prostate cancer, likely offers the best data for the addition of radical prostatectomy to best supportive care.8At a median follow-up of 5 years, the 5-year cancer-specific mortality (CSM) rate in the surgery arm (n = 66) was 13% compared with 23% in the best supportive care alone arm (n = 66). The 5-year cumulative incidence of clinical progression rates were 59% and 60%, respectively (HR, 1.11; 95% CI, 0.67-1.84; P = .7), and the 5-year OS rates were 81% and 74%, respectively (HR, 0.55; 95% CI, 0.25-1.22; P = .1).
“This trial did not hit its accrual, but they did continue to attract patients, and the data were published just last year,” Kim noted. “It was promising that CSM, the primary end point, did favor the surgical arm.”
Kim concluded his presentation by highlighting the ongoing SIMCAP study, which aims to evaluate the therapeutic effect of cytoreductive radical prostatectomy in patients with newly diagnosed metastatic prostate cancer.9 Kim and his colleagues hypothesized that cytoreductive radical prostatectomy would render systemic therapy more effective and enhance the quality of life in this group of patients.
The study will include patients with clinical M1 disease who have received no prior local therapy, have resectable disease, have an ECOG performance status of 0 or 1, and have received prior ADT for less than 6 months. The primary end point is the 2-year failure-free survival (FFS) rate. Secondary end points include cancer-specific survival, overall complication rate, time to biochemical progression, and OS.
Eligible patients will be randomly assigned 1:1 to receive surgery plus best systemic therapy or best systemic therapy alone; the best systemic therapy will be chosen by the investigator. The study employs an adaptive design that allows for a transition from phase 2 to phase 3. If there is at least a 30% improvement in FFS in the surgery arm, the study will switch to a phase 3 trial with OS as the primary end point.
“Our fundamental hypothesis is that by removing the local disease, the systemic therapy will become more effective,” Kim explained. “We are going through the data very carefully right now, and I can tell you that the study looks positive at this point. We plan to present the data once every end point has been validated and verified within the next 12 months or so.”
Disclosures: D’Amico did not list any financial disclosures. Kim reported serving as an ad hoc member of the urology advisory board for Intuitive Surgical, Inc, as a clinical trial primary investigator and an ad hoc advisory board member for Janssen (Johnson & Johnson), as a consultant for Aura Biosciences, and as a clinical advisory board member for MedPacto.
