Three regulatory actions in as many months, lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in hormone-sensitive disease, capivasertib (Truqap) plus abiraterone (Zytiga) in CAPItello-281, and a pending approval for talazoparib (Talzenna) plus enzalutamide (Xtandi) from TALAPRO-3, have widened the frontline armamentarium faster than the field’s vocabulary has kept pace.¹
Faculty meeting during a recent OncLive® Scientific Interchange and Workshop noted that “androgen pathway modulator–naive” and “–sensitive” are now replacing “hormone-sensitive” terminology. With more regimens than any trial can compare head-to-head, the panel debated which patients warrant intensification and which are being overtreated.
Which factors should guide selection among ADT plus ARPI doublet regimens?
Across LATITUDE (NCT01715285), STAMPEDE (NCT00268476), ENZAMET (NCT02446405), ARCHES (NCT02677896), TITAN (NCT02489318), and ARANOTE (NCT04736199), androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) roughly halved the risk of progression vs ADT alone (progression-free survival [PFS] HRs, 0.44-0.63), with overall survival HRs of 0.61 to 0.81.²⁻⁷ Depth of prostate-specific antigen (PSA) response tracked with outcomes: In ARANOTE, patients reaching a PSA nadir below 0.2 ng/mL had a radiographic PFS HR of 0.09 vs those who did not. With efficacy relatively similar across the 4 ARPIs, faculty said differentiation comes down to practical factors. Sai Gadde, MD, cited a roughly 3,000-patient retrospective analysis showing no difference in thrombotic risk with direct oral anticoagulants across the class, calling the drug-interaction concern “a bit overblown.” Dosing logistics mattered, too: Rhonda Stamey, RN, and Stephanie Corbett, NP, described patients struggling with twice-daily, food-dependent dosing and steroid pairing with abiraterone, while David Chism, MD, said cognitive and fall-risk data favoring darolutamide shape his choice in older patients.
Top Takeaways From an OncLive Workshop on Optimizing Care in Advanced Prostate Cancer
- Selecting among ADT plus ARPI doublets increasingly hinges on comorbidities, pill burden, and dosing logistics as much as differences in trial hazard ratios.
- Biomarker-selected regimens, niraparib plus abiraterone (AMPLITUDE), talazoparib plus enzalutamide (TALAPRO-3), and capivasertib plus abiraterone (CAPItello-281), extend rPFS benefit to HRR-altered and PTEN-deficient subsets, but carry durable toxicity, including myelodysplastic syndrome risk with PARP inhibitors.
- Faculty were split on ATM as a predictive biomarker; TALAPRO-3's positive signal was viewed by several panelists as an outlier against the broader PARP inhibitor evidence base.
When do the data support intensifying to triplet or biomarker-selected therapy?
Triplet regimens (ADT, docetaxel, and abiraterone or darolutamide) from PEACE-1 (NCT01957436) and ARASENS improved overall survival (HRs, 0.75 and 0.68, respectively) over doublet- or docetaxel-based regimens, chiefly in high-volume disease.8,9 Newer biomarker-selected triplets extend intensification to molecularly defined subsets: AMPLITUDE (niraparib plus abiraterone) showed an rPFS HR of 0.52 in BRCA-mutated disease; TALAPRO-3 (talazoparib plus enzalutamide) showed a stronger rPFS HR of 0.48 in homologous recombination repair (HRR)–altered disease; and CAPItello-281 (capivasertib plus abiraterone) showed an rPFS HR of 0.81 in PTEN-deficient disease, about a quarter of the mCSPC population.¹⁰⁻¹² Paul Eber, MD, said he currently favors triplet therapy with docetaxel over yearslong PARP inhibitor exposure, because chemotherapy “gets through it” in 6 defined cycles. Billy Ahmed, MD, said he is “still hold[ing] off” on frontline PARP inhibition outside near-complete PTEN loss, citing docetaxel-based triplet’s more mature survival data. Daniel Vaena, MD, said he would favor a PARP inhibitor for BRCA-altered patients given attrition risk to later lines, but was more cautious on capivasertib, calling it “even more toxic than a PARP” for extended use. Sai Gadde, MD, cautioned that docetaxel-based triplet trials lack an ADT-plus-ARPI comparator arm, the regimen most panelists actually use, complicating cross-trial comparisons.
How is the mCRPC landscape shifting with PSMAfore and PEACE-3 data?
PSMAfore randomized ARPI-pretreated, taxane-naive mCRPC patients to 177Lu-PSMA-617 or a second ARPI, showing an rPFS HR of 0.49; final overall survival was less separated (HR, 0.91) against a comparator arm faculty considered weak given substantial crossover.¹³ PEACE-III (NCT02194842) added radium-223 to enzalutamide in ARPI-naive mCRPC, showing rPFS (HR, 0.71) and an overall survival benefit (HR, 0.76; 24% reduction in death; P = .0096).¹⁴ Zin Myint, MD, questioned how generalizable PEACE-III is to current practice, as most patients now receive frontline ARPI doublets rather than reaching mCRPC ARPI-naive. Paul Eber, MD, said his group is “using less and less” radium-223 as PSMA PET identifies more extensive disease and 177Lu-PSMA-617 access has expanded. Stephanie Corbett, NP, said sipuleucel-T (Provenge) remains underused despite its survival benefit, largely due to access barriers for rural patients.
