The challenges of treating non-metastatic and metastatic castration-resistant prostate cancer (mCRPC) are many, which has prompted researchers to test many different approaches including androgen receptor inhibitors (ARI) combined with androgen deprivation therapy (ADT) and poly (ADP-ribose) polymerase (PARP) inhibitor therapies combined with an array of androgen-receptor-axis targeted therapies.
For example, the ARI apalutamide plus ADT produced rapid, deep, and durable prostatic-specific antigen (PSA) responses in most patients with non-metastatic, castration-resistant prostate cancer (nmCRPC), regardless of the molecular subtype treated, a post-hoc analysis of the phase III, placebo-controlled SPARTAN trial found.
More importantly, robust PSA responses improved time to PSA progression, metastatic-free survival (MFS), and overall survival (OS) compared with placebo, the same analysis indicated.
In a different trial, led by the same researcher—Fred Saad, MD, of the Universite de Montreal, Montreal, Quebec—when apalutamide was combined with a PARP inhibitor, niraparib, the findings were not in the ARI’s favor.
Noting that mCRPC is incurable but that monotherapy with PARP inhibitors has demonstrated some benefit, Saad and colleagues hypothesized that combining a PARP inhibitor with an androgen-receptor-axis therapy (ARAT) could be effective. They tested two PARP inhibitor combinations—niraparib plus apalutamide and niraparib plus abiraterone acetate 1,000 mg/prednisone 10 mg (AAP)—in the phase Ib BEDIVERE trial.
In that trial, published in Cancer Chemotherapy and Pharmacology, they recruited 33 men who had previously undergone at least two lines of systemic therapy (including at least one androgen-receptor-axis targeted therapy) and tested both combinations.
But there were more dose-limiting toxicities observed with the PARP-ARI combination, and pharmacokinetic analysis suggested that apalutamide appeared to reduce niraparib exposure. As a result, Saad and colleagues concluded that the optimal combination would be 200 mg of the PARP inhibitor plus AAP.
“The combination of niraparib 200 mg with AAP was tolerable in patients with mCRPC, with no new safety signals; the combination is currently being studied in a randomized, placebo-controlled, phase III study in patients with mCRPC, regardless of HRR mutations,” Saad and colleagues concluded.
By contrast, when Saad’s team conducted an analysis of PSA responses to apalutamide plus androgen deprivation therapy, the results were more impressive.
In a group of 1,207 patients—806 of whom received apalutamide 240 mg/day, and 401 of whom received placebo—90% of apalutamide-treated patients achieved the protocol-defined best ≥50% PSA reduction by 6 months after treatment initiation at a median interval of 1 month, Saad et al reported in European Urology.
A deep PSA response (≥90%) was achieved by 57% of patients in the apalutamide group while 32% of patients achieved a PSA response of ≤0.2 ng/mL, again by 6 months of treatment. The median times to these responses were 1.9 months and 2.8 months, respectively.
In contrast, only 1.5% of patients on the placebo arm achieved a ≥50% PSA reduction by 6 months.
“To our knowledge, our study is the first to assess molecular subtypes in relation to PSA kinetics and androgen receptor inhibitors,” Saad and colleagues pointed out.
“Our analysis demonstrates that PSA nadir was achieved approximately 7 months after the initiation of apalutamide treatment in SPARTAN and that patients achieving a PSA response at 6 months had improved outcomes,” the authors concluded.
At the first interim analysis of SPARTAN, investigators found that apalutamide plus ADT improved MFS and increased time to PSA progression in nmCRPC and a PSA doubling time (PSADT) ≤10 months at baseline.
In the current post-hoc analysis, Saad et al explored whether the results obtained on the Decipher test along with molecular subtypes correlated with PSA kinetics. The Decipher test evaluates the expression of 22 genes known to be important for disease progression and is used to determine the risk of metastases and aid in treatment decision-making.
Investigators also evaluated the association of PSA responses and clinical outcomes in patients treated with apalutamide or placebo.
“By 3 months of treatment, the majority of apalutamide-treated patients had reduced PSA from baseline while most placebo-treated patients had increased PSA,” the authors reported.
The best ≥50% PSA reductions, as well as deeper PSA reductions or the attainment of a PSA ≤0.2 ng/mL, were observed in the majority of responding patients as early as 3 months, although a small proportion of patients achieved the same level of PSA response by 12 months after treatment initiation.
In contrast, 98% of placebo controls exhibited little reduction in PSA during the entire course of the study.
Achievement of deep PSA response and nadir levels of PSA at 6 months after treatment initiation was also associated with improved clinical outcomes.
For example, achievement of ≥50% PSA reduction at 6 months was associated with a 79% improvement in time to PSA progression at a hazard ratio (HR) of 0.21 (95% CI, 0.13-0.35), compared with placebo patients, the study authors wrote.
Similarly, a deep PSA response of ≥90% at 6 months was associated with a 75% improvement in time to PSA progression at an HR of 0.25 (95% CI, 0.18-0.33) while achievement of a PSA ≤0.2 ng/mL was associated with an 87% improvement in time to PSA progression at an HR of 0.13 (95% CI, 0.08-0.21 [P<0.001 for all endpoints]).
The median time to PSA progression was at least doubled in patients on active therapy compared with placebo, while median OS was prolonged by as much as 20 months for those who achieved a exemplary PSA response, investigators added.
Achievement of a deep PSA response of ≥90% or ≤0.2 ng/mL also significantly prolonged MFS.
“Our findings have important implications for nmCRPC management,” the authors suggested.
For one, they suggested that early onset plus depth of a PSA response to dual androgen blockade are both associated with long-term clinical benefits in patients with nmCRPC.
They also emphasized the importance of maintaining lower PSA levels and slower PSA kinetics for better long-term prognosis.
As they also noted, other ARIs, enzalutamide and darolutamide, “have shown a comparable overall PSA response, but the speed of achievement and the depth of PSA response for these agents have not been reported.”
Limitations to the current analysis include the fact that nonmetastatic status on study enrollment was determined by conventional imaging.
The authors added an additional caution noting that next-generation imaging (NGI) has been shown to detect metastases in more than 50% of patients with nmCRPC, a large proportion of SPARTAN patients could have had baseline metastatic disease on NGI, potentially altering the interpretation of the study’s findings.
The BEDIVERE and SPARTAN trials were funded by Janssen Research & Development.
Saad has had advisory roles for Astellas Pharma, AstraZeneca/MedImmune, Bayer, Janssen Oncology, and Sanofi; has received honoraria from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Janssen Oncology, and Sanofi and research funding grants provided to his institution from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Pfizer, and Sanofi.
Pam Harrison, Contributing Writer, BreakingMED™
Kaiser Health News
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