Fred Saad, CQ, MD, FRCS, FCAHS, discusses next steps for the investigation of darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer.  

Dr Saad on the Continued Investigation of Darolutamide Plus ADT in mHSPC  

Fred Saad, CQ, MD, FRCS, FCAHS, director, Prostate Cancer Research, Montreal Cancer Institute; full professor, Department of Surgery, Université de Montréal; uro-oncologist, Urology Department, CHUM, discusses next steps and potential clinical implications for the investigation of darolutamide (Nubeqa) plus androgen-deprivation therapy (ADT) vs ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Findings from the phase 3 ARANOTE trial (NCT04736199), which evaluated the combination, were presented at the 

 and demonstrated that combining darolutamide with ADT significantly reduced the risk of radiographic progression or death by 46% compared with placebo plus ADT. This translated to a hazard ratio of 0.54 (95% CI, 0.41-0.71; P < .0001). Moreover, all subgroups, including the 70% of patients with de novo and high-volume disease experienced benefit with the darolutamide and ADT combination. Although overall survival (OS) data are still immature, all secondary end points favored the combination therapy.

The safety and efficacy profile of darolutamide in this trial supports further exploration of the combination in earlier disease settings, such as non-metastatic HSPC, Saad states. He notes that ongoing trials are investigating these potential benefits. Given the safety of darolutamide in combination with other therapies, investigators are optimistic about its use in combination with various agenta without exacerbating adverse effects or drug-drug interactions, Saad adds.

The hope is that darolutamide will soon become a standard of care for MHSPC, complementing the current baseline of ADT plus an androgen receptor pathway inhibitor, Saad continues. With several ARPIs already in use globally, darolutamide would expand therapeutic options, enabling treatment to be tailored to individual patient profiles and preferences, he says. Additionally, its combination with docetaxel offers the flexibility to consider ADT plus darolutamide with or without docetaxel, depending on patient needs, Saad concludes.

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Fred Saad, CQ, MD, FRCS, FCAHS, discusses next steps for the investigation of darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer.

Dr Saad on the Continued Investigation of Darolutamide Plus ADT in mHSPC

Dr Saad on the Efficacy and Safety of Darolutamide Plus ADT in mHSPC

Fred Saad, CQ, MD, FRCS, FCAHS, director, Prostate Cancer Research, Montreal Cancer Institute; full professor, Department of Surgery, Université de Montréal; uro-oncologist, Urology Department, CHUM, discusses efficacy findings from the global phase 3 ARANOTE trial (NCT04736199) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Notably, this trial evaluated the combination of darolutamide (Nubeqa) plus androgen-deprivation therapy (ADT) vs ADT alone, and findings were presented at the 

Eligible patients with mHSPC were randomly assigned in a 2:1 ratio to receive either darolutamide at 600 mg twice daily (n = 446) or placebo (n = 223), both in combination with ADT. The primary end point of the study was radiological progression-free survival. Secondary end points included overall survival (OS), time to the start of subsequent anticancer therapy, time to castration-resistant prostate cancer (CRPC), time to prostate-specific antigen (PSA) progression, time to pain progression, and safety outcomes.

Saad begins by stating that investigators were pleased with the results of the study, as the trial successfully met its primary end point. The combination of darolutamide and ADT reduced the risk of radiographic progression or death by 46% compared with placebo plus ADT, translating to a hazard ratio of 0.54 (95% CI, 0.41-0.71; 

 < .0001). This clearly demonstrates a delay in disease progression or death, he says. Moreover, all subgroups within the study—including patients with de novo disease and those with high-volume disease, both comprising over 70% of the population—experienced benefits from the addition of darolutamide to ADT compared with ADT alone. Additionally, all secondary end points favored the combination therapy, Saad explains.

Although OS data are still immature, investigators observed a 19% reduction in the risk of death with the darolutamide regimen vs ADT alone, he continues. Other key end points also supported the efficacy of the addition of darolutamide to ADT, including delaying the onset of CRPC and slowing pain progression in patients. There was a significant increase in the rate of undetectable PSA levels in the darolutamide arm, with more than a threefold increase in patients reaching the target of less than 0.2 ng/mL, a critical milestone in prostate cancer management, Saad emphasizes. Furthermore, the study showed substantial delays in PSA progression, which plays an essential role in determining future lines of therapy for these patients, he concludes.

Fred Saad, CQ, MD, FRCS, FCAHS, discusses efficacy findings from the ARANOTE trial in patients with metastatic hormone-sensitive prostate cancer.

Fred Saad, MD, FRCS, principal scientist, University of Montreal Hospital Center (CHUM) Research Center (CRCHUM), head, Urology, CHUM, director, prostate cancer research, Montreal Cancer Institute/CRCHUM, full professor, Department of Surgery, Raymond Garneau Chair in Prostate Cancer, University of Montreal, discusses prostate-specific antigen (PSA) response and time to PSA progression with the combination of abiraterone acetate (Zytiga) and olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Primary results from the phase 3 PROpel trial (NCT03732820) demonstrated improved radiographic progression-free survival with the combination of abiraterone acetate and olaparib compared with abiraterone acetate alone as frontline therapy in all-comers with mCRPC (HR, 0.66, 95% CI, 0.54-0.81; 

<.001). In the trial, patients were randomly assigned 1:1 to receive 300 mg of olaparib twice daily or placebo, plus 1000 mg of abiraterone acetate once daily and 5 mg of prednisone or prednisolone twice daily until disease progression, unacceptable toxicity, or withdrawal of consent.

Post-hoc exploratory analyses presented at the 2023 AUA Annual Meeting demonstrated that first PSA response was significantly improved with the combination vs abiraterone acetate alone, reflecting an absolute difference of approximately 10%, Saad says. The chance of PSA response was 35% in patients with 

 mutations compared with only 8% of those without mutations in the homologous recombination repair (HRR) pathway. PSA response rate was defined as the percentage of patients with a 50% reduction in PSA from baseline to lowest post-baseline result.

Time to PSA progression was also notably improved with the combination, at 35 months compared with 9 months in patients without HRR gene mutations. Time to PSA progression was defined as the time from randomization to first PSA progression per Prostate Cancer Working Group 3 criteria. Without the addition of olaparib, patients with 

 mutations generally progress within 6 months of therapy, and to have improved time to progression to approximately 3 years in this patient population with historically aggressive disease is practice changing, Saad concludes.

Fred Saad, MD, FRCS, discusses prostate-specific antigen (PSA) response and time to PSA progression with the combination of abiraterone acetate and olaparib in patients with metastatic castration-resistant prostate cancer.

Dr Saad on PSA Response and Time to PSA Progression With Abiraterone Acetate and Olaparib in mCRPC

Fred Saad, MD, FRCS, professor and chief of Urology; director of Genitourinary Oncology; Raymond Garneau Chair in Prostate Cancer, University of Montreal Hospital Center; and director ofProstate Cancer Research at Montreal Cancer Institute, discusses the impact of apalutamide (Erleada) on nonmetastatic castration-resistant prostate cancer (nmCRPC) in the phase 3 SPARTAN trial.

The results from the SPARTAN trial regarding metastases-free survival were beyond what was expected when starting the clinical trial, says Saad. As the first agent approved for the treatment of patients with high-risk nmCRPC, apalutamide completely changed the field. There is now something to offer patients who are at high risk of metastases, which was a big concern, as being in a state of limbo between having a treatment to offer or doing nothing until the patient’s disease became metastatic isn't ideal. However, no action could be taken until the field had proven that they had a useful treatment. To this end, apalutamide completely changed what the field is able to offer patients.

Questions regarding the delay of metastases as worthwhile action remain; the field wanted to see significant improvement in overall survival (OS), though this is an extremely high bar when following patients very closely, especially when starting therapy in the metastatic setting much earlier than in the real world. This is cause for cautious optimism because patients were treated very well in the SPARTAN trial and many of the therapies available in the placebo arm were able to catch up in terms of OS, concludes Saad.

Fred Saad, MD, FRCS, discusses the impact of apalutamide on nonmetastatic castration-resistant prostate cancer in the phase 3 SPARTAN trial.
 

Dr. Saad on the Clinical Impact of Apalutamide in nmCRPC

Fred Saad, MD, FRCS, professor and chief of Urology, director of Genitourinary Oncology, Raymond Garneau Chair in Prostate Cancer, University of Montreal Hospital Center, and director, Prostate Cancer Research, Montreal Cancer Institute, discusses unanswered questions from the randomized phase 3 SPARTAN trial in nonmetastatic castration-resistant prostate cancer (M0CRPC).

The vast majority of patients with M0CRPC will respond well to apalutamide (Erleada), explains Saad. However, optimizing treatment for patients who do not have a robust response to apalutamide remains an unmet need. 

Identifying early signals that indicate a need for treatment intensification with apalutamide may provide insight on treating this more aggressive disease subtype, says Saad. Moreover, given the overall survival benefit that was reported with apalutamide in metastatic castration-sensitive prostate cancer, a case may be building for combination regimens with apalutamide in M0CRPC, Saad concludes.

Fred Saad, MD, FRCS, discusses unanswered questions from the randomized phase 3 SPARTAN trial in nonmetastatic castration-resistant prostate cancer.

Dr. Saad on Unanswered Questions From the SPARTAN Trial in M0CRPC

Fred Saad, MD, FRCS, professor and chief of Urology, director of Genitourinary Oncology, Raymond Garneau Chair in Prostate Cancer, University of Montreal Hospital Center, and director, Prostate Cancer Research, Montreal Cancer Institute, discusses unique characteristics of apalutamide (Erleada) compared with other antiandrogen agents in nonmetastatic castration-resistant prostate cancer (M0CRPC).

Apalutamide, enzalutamide (Xtandi), and darolutamide (Nubeqa) have shown similar efficacy and quality of life (QoL) data in patients with M0CRPC, says Saad.

In a QoL analysis of apalutamide, asymptomatic patients were given antiandrogen therapy that had the potential to cause adverse events, explains Saad. However, patients’ QoL remained stable with no signs of deterioration compared with placebo.

Apalutamide, an androgen receptor-targeted agent, differs from androgen synthesis inhibitors such as abiraterone acetate (Zytiga) in that it has a different mechanism of action, says Saad. Additionally, rates of fatigue appear to be lower with apalutamide compared with historical rates in this setting.

Fred Saad, MD, FRCS, discusses unique characteristics of apalutamide compared with other antiandrogen agents in nonmetastatic castration-resistant prostate cancer. 



Dr. Saad on Unique Characteristics of Apalutamide in M0CRPC

Fred Saad, MD, FRCS, professor and chief of Urology, director of Genitourinary Oncology, Raymond Garneau Chair in Prostate Cancer, University of Montreal Hospital Center, and director, Prostate Cancer Research, Montreal Cancer Institute, discusses the safety profile of apalutamide (Erleada) in nonmetastatic castration-resistant prostate cancer (M0CRPC).

Final survival results of the SPARTAN trial showed that patients who received apalutamide plus androgen-deprivation therapy (ADT) had a significant overall survival improvement and prolonged risk of second progression or death compared with placebo plus ADT in men with M0CRPC.

Regarding safety, an increased rate of fatigue and rash were observed in patients who received apalutamide versus placebo, says Saad. However, these toxicities are a class effect of antiandrogen agents and were expected and manageable.

Additionally, some patients developed low-grade hypothyroidism that was also manageable, explains Saad. The uptick of hypothyroidism could be explained by the older patient population that was evaluated and the significantly longer follow-up period patients receiving apalutamide had compared with those who received placebo.

Ultimately, patients’ quality of life was not negatively impacted by the addition of apalutamide. In February 2018, apalutamide received regulatory approval for the treatment of men with M0CRPC, concludes Saad.

Fred Saad, MD, FRCS, discusses the safety profile of apalutamide in nonmetastatic castration-resistant prostate cancer.



Dr. Saad on the Safety Profile of Apalutamide in M0CRPC

Fred Saad, MD, FRCS, professor and chief of Urology, director of Genitourinary Oncology, Raymond Garneau Chair in Prostate Cancer, University of Montreal Hospital Center, and director, Prostate Cancer Research, Montreal Cancer Institute, discusses the randomized phase 3 SPARTAN trial in nonmetastatic castration-resistant prostate cancer (M0CRPC).

The SPARTAN trial randomized men with M0CRPC 2:1 to apalutamide (Erleada) or placebo, says Saad. These patients were considered to be at high risk of developing metastatic disease based on a prostate-specific antigen doubling time of less than 10 months.

The study’s primary end point was metastasis-free survival, although the risk of second progression or death (PFS2) was also evaluated to determine whether starting subsequent therapy up front or when patients developed metastases was superior, explains Saad.

The final survival results of the SPARTAN trial that were presented at the 2020 ASCO Virtual Scientific Program showed that the patients who received apalutamide plus androgen-deprivation therapy (ADT) had a significant overall survival improvement compared with those who received placebo plus ADT.

Additionally, apalutamide prolonged median PFS2 by 14.4 months compared with placebo, concludes Saad.

Fred Saad, MD, FRCS, discusses the randomized phase 3 SPARTAN trial in nonmetastatic castration-resistant prostate cancer.



Fred Saad, MD, FRCS

Articles

Dr Saad on the Continued Investigation of Darolutamide Plus ADT in mHSPC

Dr Saad on the Efficacy and Safety of Darolutamide Plus ADT in mHSPC

Dr Saad on PSA Response and Time to PSA Progression With Abiraterone Acetate and Olaparib in mCRPC

Dr. Saad on the Clinical Impact of Apalutamide in nmCRPC

Dr. Saad on Unanswered Questions From the SPARTAN Trial in M0CRPC

Dr. Saad on Unique Characteristics of Apalutamide in M0CRPC

Dr. Saad on the Safety Profile of Apalutamide in M0CRPC

Dr. Saad on the SPARTAN Trial in M0CRPC