Updated Findings Spur Excitement In nmCRPC, mHSPC, mCRPC

Oncology Live®, Vol. 24/No. 9, Volume 24, Issue 9
Pages: 30

An increased focus on long-term and genomic analyses on established treatments in prostate cancer have revealed new opportunities for patients across disease states.

An increased focus on long-term and genomic analyses on established treatments in prostate cancer have revealed new opportunities for patients across disease states.

“There’s excitement that when physicians see the target, there’s a drug to get to the target--there’s a sense of satisfaction with that,” Elisabeth Heath, MD, FACP, said. “The world of genomic sequencing has changed what we do. We’re asking harder and deeper questions and that’s exciting because it’s great for a group of drugs, but there will be more coming that will also use this type of approach. [It’s] a little more complicated because we have a lot of options. There [are] data to show that [in the] second and third line, a lot of [individuals are] still not getting treated, which is astonishing when you have all these different agents. It makes our approach in the beginning critical.”

During a recent OncLive Peer Exchange®, experts in the field of prostate cancer contextualized updates from clinical trials evaluating treatments for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), metastatic hormone-sensitive prostate cancer (mHSPC), and metastatic castration-resistant prostate cancer (mCRPC). The findings were presented during the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium.

nmCRPC

Androgen receptor inhibitors have become standard in practice for the treatment of patients with nmCRPC, with agents such as apalutamide (Erleada) or darolutamide (Nubeqa). The former was approved based on results of the phase 3 SPARTAN (NCT01946204) trial, which used metastasis-free survival (MFS) as the primary end point.1 Darolutamide was examined for the treatment of patients with nmCRPC in the phase 3 ARAMIS trial (NCT04464226).2

Post hoc and long-term data from these trials, respectively, have solidified the role of these therapies and provided insight to sequencing strategies for investigators to build on.2,3

“MFS was the primary end point for [both] these trials and it certainly was met across the board,” Tian Zhang, MD, MHS, said. “We’ve also learned that MFS is a good surrogate end point for OS [overall survival]. Not only are we delaying time until metastasis for these patients, we’re also getting [patients] to live longer. Subsequently, multiple analyses of these trials post hoc have added to our knowledge of this space.”

In a post hoc analysis of SPARTAN, study authors set out to evaluate the efficacy of subsequent therapies for patients who progressed after initial treatment with apalutamide plus androgen deprivation therapy (ADT).3 At the end of the SPARTAN study 237 patients remained on treatment, leaving 311 patients to be included in the exploratory cohort. These patients had received 1 line of subsequent therapy of either enzalutamide (Xtandi), docetaxel, or abiraterone acetate (Zytiga) plus prednisone.

Findings from the analysis were compared with outcomes from the intention-to-treat population of SPARTAN who were randomly assigned to receive apalutamide (n = 806). With subsequent treatment, 51% of patients had a prostate-specific antigen (PSA) reduction of at least 90%, vs 62% of patients who received apalutamide under the SPARTAN protocol. The median MFS was 40.5 months in the initial SPARTAN analysis and 25.8 months from randomization for patients in the secondary cohort. When comparing subsequent progression-free survival (PFS) and subsequent OS between therapies used following SPARTAN, the outcomes did not demonstrate a differential efficacy, according to investigators.3

In ARAMIS, following the primary analysis, investigators aimed to assess the long-term safety and tolerability of continuous treatment with darolutamide. In a rollover study, patients with no evidence of metastases who were experiencing clinical benefit and could continue on treatment with the agent (n = 954) were evaluated. At the data cutoff of January 31, 2022, 37.6% of patients had received darolutamide for less than 2 years, 32.3% for 2 to 4 years, 17.3% for 4 to 5 years, 30.1% for at least 4 years, and 12.8% for at least 5 years; 24% were still being treated with the agent.2

Treatment-emergent adverse events (TEAEs) of any grade were present at a rate of 85.7%, 89.8%, and 91.5% among patients treated for less than 2 years, 2 to 4 years, and 4 to 5 years, respectively. Grade 3 or 4 events were present in 26.3%, 31.8%, and 35.5% of patients, respectively. TEAEs leading to treatment discontinuation were reported in 8.9%, 10.5%, and 12.9% of patients, respectively.2

Investigators concluded that the favorable safety profile of darolutamide persisted with prolonged treatment.

“Potential adverse events [with these agents] might be worse for one patient with a set of comorbidities vs another,” Heath said. “The good news here is that...if that doesn’t fit for your patient, that is OK; you have other options.”

mHSPC

Efforts to move androgen pathway–targeting agents to the first-line setting for the treatment of patients with mHSPC have been underway. In the phase 3 ARASENS trial (NCT02799602), investigators evaluated darolutamide in combination with ADT and docetaxel compared with placebo plus ADT and docetaxel in patients with mHSPC.4 Findings showed that the addition of darolutamide resulted in a significant improvement in OS vs placebo (HR, 0.68; 95% CI, 0.57-0.80; P < .0001). TEAE rates were similar between the 2 arms.3

In a post hoc analysis, investigators wanted to determine whether disease burden and risk affected efficacy and safety (TABLE 1).4 The addition of darolutamide resulted in an OS benefit compared with placebo in the subgroups examined, and study authors wrote in conclusion that the combination of darolutamide, ADT, and docetaxel should be considered a new standard of care in mHSPC.4

“The ARASENS trial has been a very big deal for our field,” Edwin M. Posadas, MD, said. “This is a very large trial. We [have] the ability to really dive deep into these [data]. For me, it was interesting to see that, at least statistically speaking, low-volume patients had a benefit.”

Posadas added that for the higher-risk group the triplet makes sense as an option and that he is comfortable also recommending this regimen for patients with high-volume disease. “What we do with the lower-volume patients, [those with] low-volume, high-risk disease, maybe I’d think about it…. We still need to know more.” Posadas added that questions remain regarding what portion of the triplet therapy is driving the efficacy. “One thing a lot of us have been concerned about is how much the triplet is driven by the chemotherapy. How much of it is really driven by the hormonal manipulation? Hopefully, trials [such as] ARANOTE [NCT04736199] will have better insight into that,” he said.

ARANOTE is investigating efficacy and safety of darolutamide in combination with standard ADT vs placebo and ADT in patients with mHSPC.

mCRPC

For patients with mCRPC, encouraging efficacy has been observed when treating patients with PARP inhibitors. The FDA has approved 2 PARP inhibitors for the treatment of patients with mCRPC: rucaparib (Rubraca) and olaparib (Lynparza). The agency granted rucaparib accelerated approval in May 2020 for patients with mCRPC harboring a deleterious BRCA mutation who have received androgen receptor–directed therapy and a taxane-based chemotherapy.5 Also in May 2020, olaparib received regular approval for adult patients with mCRPC who have experienced progression following prior treatment with enzalutamide or abiraterone acetate and whose disease displays deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutations.6

“We’re starting to see some real significant advances down [the] molecular avenue; certainly, there’s a lot of interest with TALAPRO-2 [NCT03395197], PROpel [NCT03732820], and other studies looking at the role of PARP inhibitors that are leaving us asking a lot of questions,” Posadas said. “[Looking at] the risk-benefit ratio for the patients, which do you choose, how do you choose? Are our tools appropriate? At this point I would still answer we’ve got some insight but not enough.”

The phase 3 PROpel trial investigators randomly assigned first-line patients with mCRPC 1:1 to receive abiraterone acetate 1000 mg daily plus olaparib 300 mg twice daily (n = 399) or the same dosing of abiraterone plus placebo (n = 397). Radiographic progression-free survival (rPFS) served as the primary end point.7

Findings from the final OS analysis showed that at 47.9% maturity, the median OS was over 7 months longer in the combination arm (42.1 months) vs the placebo arm (34.7 months; HR, 0.81; 95% CI, 0.67-1.00; P = .0544). Patients who received the combination also maintained a significant benefit in terms of median rPFS compared with those in the placebo group, at 27.6 months vs 16.4 months, respectively (HR, 0.61; 95% CI, 0.49-0.74; P < .0001).

The combination was also favored in terms of OS benefit regardless of age, BRCA status, treatment with docetaxel, or distant metastases site. “In the HRR-mutated group there was some excitement to say that [these] data look really compelling,” Heath said. “With these newer data and the final [PROpel] OS [analysis], I think that sort of confirms that feeling.”

The OS in the population who were HRR mutant, which comprised 28.4% of the study participants, was not reached (NR) with abiraterone acetate and olaparib (n = 111) compared with 28.5 months with placebo (n = 116; HR, 0.66; 95% CI, 0.45-0.95). In the non-HRR cohort, the median OS in the experimental arm was 42.1 months vs 36.9 months with placebo (HR, 0.89; 95% CI, 0.70-1.14).7

In the phase 3 MAGNITUDE study (NCT03748641), investigators enrolled patients with treatment-naïve mCRPC and randomly assigned them to receive either niraparib plus abiraterone and prednisone (n = 212) or placebo plus abiraterone and prednisone (n = 211). The primary end point was rPFS.8 Findings from the second interim analysis also showed a modest improvement in the BRCA-mutant subgroup. At a median follow-up of 26.8 months, treatment with niraparib reduced the risk of progression or death by 45% compared with placebo (HR, 0.55; 95% CI, 0.39-0.78; P = .0007). The median rPFS in this subgroup was 19.5 months vs 10.9 months, respectively.

Another trial examining a PARP inhibitor in the first-line setting is the phase 3 TALAPRO-2 study. Patients were randomly assigned 1:1 to receive either talazoparib 0.5 mg plus enzalutamide 160 mg daily (n = 402) or placebo plus enzalutamide (n = 403).9

The median rPFS by blinded independent central review was NR (95% CI, 27.5-NR) compared with 21.9 months (95% CI, 16.6-25.1) in the talazoparib and placebo arms, respectively (HR, 0.63; 95% CI, 0.51-0.78; P < .001). The median follow-up times were 24.9 and 24.6 months, respectively. The talazoparib-containing combination was also favored in terms of rPFS across the prespecified subgroups, including those that were HRR-deficient (HR, 0.46; 95% CI, 0.30-0.70; P < .001). Investigators wrote that the statistically significant and clinically meaningful improvements in rPFS over placebo support the combination of talazoparib plus enzalutamide as a first-line treatment option for patients with mCRPC, irrespective of HRR status.9

Finally, TRITON3 (NCT02975934), a phase 3 trial that enrolled patients with chemotherapy-naïve mCRPC with a BRCA or ATM alteration, sought to assess the efficacy of the PARP inhibitor rucaparib (n = 270) vs physician’s choice of docetaxel, enzalutamide, or abiraterone (n = 135).10

In the interim efficacy analysis, the median rPFS in the rucaparib arm was 10.2 months (95% CI, 8.3-11.2) compared with 6.4 months (95% CI, 5.6-8.2) in the physician’s choice arm (HR, 0.61; 95% CI, 0.47-0.80; log-rank P = .003). An even greater rPFS benefit was seen with rucaparib in the BRCA-mutant subgroup (HR, 0.50; 95% CI, 0.36-0.69; log-rank P < .0001). The median OS was 23.6 months (95% CI, 19.7-25.0) vs 20.9 months (95% CI, 17.5-24.4), respectively (HR, 0.94; 95% CI, 0.72-1.23; log-rank P = .67). Investigators noted that the trial met its primary end point.10

Heath noted that despite a plethora of effective options with efficacy across subgroups, this presents a challenge for the community oncologist who is not spending their time only on prostate-specific findings. Posadas added that the differences across trials regarding HRR status further complicate things, but all signal progress with PARP in this setting. “If you take a big step back, [these findings] put PARP on the map for prostate cancer. It’s here to stay,” Posadas said. “We’re going to have to get smarter with it and the field will have to start adapting to do molecular testing…. The positive message is there’s hope that we’re getting smart enough to use biology to our advantage. We [have] just got to come up with the right hypothesis and get the signal from the noise that we have in our trials.”

Alternative Options in mCRPC

In addition to PARP inhibitors, investigators have also been collecting data for immunotherapy regimens, which have proved effective in several other cancer types. The phase 2 CheckMate 650 (NCT02985957) and phase 3 KEYNOTE-921 trials (NCT03834506) evaluated the safety and efficacy of nivolumab (Opdivo) plus ipilimumab (Yervoy) and pembrolizumab (Keytruda) plus docetaxel, respectively.

In CheckMate 650, patients with mCRPC were randomly assigned 2:2:1:2 to receive either nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 cycles followed by nivolumab 480 mg every 4 weeks (cohort D1); nivolumab 1 mg/kg every 3 weeks for 8 cycles plus ipilimumab 3 mg/kg every 6 weeks for 4 cycles followed by nivolumab 480 mg every 4 weeks (cohort D2); ipilimumab 3 mg/kg every 3 weeks for 4 cycles (cohort D3); or cabazitaxel 20 or 25 mg/m2 every 3 weeks plus 10 mg of daily prednisone for 10 days (cohort D4) (TABLE 2).11

At a median follow-up of 23.3 months (range, 6.0-31.5) among efficacy-evaluable patients in cohorts D1 (n = 43), D2 (n = 41), D3 (n = 22), and D4 (n = 41), the objective response rate was 9.3% (95% CI, 2.6%-22.1%), 19.5% (95% CI, 8.8%-34.9%), 4.5% (95% CI, 0.1%-22.8%), and 12.2% (95% CI, 4.1%-26.2%), respectively. The median duration of response was NR (95% CI, 5.6-not estimable [NE]), NR (95% CI, 3.7-NE), 6.5 months (95% CI, NE-NE), and 6.5 months (95% CI, 3.8-8.5), respectively.

Survival results showed that the median rPFS was 3.9 months (95% CI, 2.2-7.6), 4.2 months (95% CI, 3.3-5.6), 3.5 months (95% CI, 2.1-5.8), and 7.9 months (95% CI, 5.6-9.3), respectively. The median OS was 15.9 months (95% CI, 12.8-17.7), 13.5 months (95% CI, 10.4-16.7), 18.5 months (95% CI, 10.7-NE), and 14.8 months (95% CI, 11.4-16.0), respectively.

Study authors noted that OS results in cohorts D3 and D4 could have been affected by crossover to cohort D1 and anticancer therapy that was given to patients who completed study treatment. Further evaluation of characteristics of patients who responded to the combination, and more in-depth biomarker analyses, are warranted, they wrote.11

“There was at least an initial signal that there was maybe some benefit with the combination ipilimumab/nivolumab regimen,” Benjamin H. Lowentritt, MD, FACS, said. “There [are] going to be some follow-up data there and a follow-up trial, which is promising.”

KEYNOTE-921 enrolled patients with mCRPC with an ECOG Performance Status Scale score of 1 or less who failed treatment with or were intolerant to 1 previous next-generation hormonal agent therapy for mHSPC or mCRPC. Patients were randomly assigned to receive pembrolizumab 200 mg every 3 weeks up to 35 cycles plus docetaxel 75 mg/m2 every 3 weeks for up to 10 cycles and prednisone 5 mg twice daily (n = 515) or placebo in place of pembrolizumab with the same regimen or docetaxel and prednisone (n = 515).12

At a median time from randomization to data cutoff of 22.7 months (range, 12.1-36.7), findings showed that patients in the investigational arm experienced a minor numerical improvement in median rPFS compared with those in the placebo arm, at 8.6 months (95% CI, 8.3-10.2) vs 8.3 months (95% CI, 8.2-8.5), respectively (HR, 0.85; 95% CI, 0.71-1.01; P = .0335). Additionally, the median OS was 19.6 months (95% CI, 18.2-20.9) vs 19.0 months (95% CI, 17.9-20.9), respectively (HR, 0.92; 95% CI, 0.78-1.09; P = .1677).

“Unfortunately, [KEYNOTE-921] was a negative trial,” Lowentritt said. “But there weren’t any terrible safety signals. We at least got some information that the combination remains safe in these patients, although there wasn’t a lot of positive effect on the disease. Certainly, [there is] more to come, more combinations down the road.”

As for the future, Posadas noted that imaging advances stand to change outcomes for patients with metastatic disease. “When we have patients without obvious metastasis, one of our biggest goals is to stop them from developing metastatic disease,” Posadas said. “For those of us that have been doing prostate cancer trials, we need to be able to show efficacy earlier. The data that we have in the nonmetastatic space from trials of drugs such as darolutamide, enzalutamide, and apalutamide, were done on [using] conventional imaging. You don’t want to under or over serve patients, but we don't know enough about the natural history of PSMA-positive disease at this point. As a field, we’re taking on that challenge, but preserving quality of life, and extending life are terribly important in the nonmetastatic setting.”

References

  1. FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. FDA. Updated May 3, 2018. Accessed April 14, 2023. bit.ly/41xdfv9
  2. Shore ND, de Almeida Luz M, Ulys A, et al. Long-term safety and tolerability of darolutamide and duration of treatment in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) from the ARAMIS Rollover Study. J Clin Oncol. 2023;41(suppl 6):147. doi:10.1200/JCO.2023.41.6_suppl.147
  3. Oudard S, Hadaschik BA, Antoni L, et al. Efficacy of subsequent treatments in patients who progressed to mCRPC following treatment with apalutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC): a post-hoc analysis of the SPARTAN phase III trial. J Clin Oncol. 2023;41(suppl 6):157. doi:10.1200/JCO.2023.41.6_suppl.157
  4. Hussain MHA, Tombal BF, Saad F, et al. Efficacy and safety of darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel (DOC) by disease volume and disease risk in the phase 3 ARASENS study. J Clin Oncol. 2023;41(suppl 6):15. doi:10.1200/JCO.2023.41.6_suppl.15
  5. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 15, 2020. Accessed April 5, 2023. bit.ly/3mfF2RO
  6. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. Updated May 20, 2020. Accessed April 5, 2023. bit.ly/40Njqey
  7. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Final overall survival (OS) in PROpel: abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl 6):LBA16. doi:10.1200/JCO.2023.41.6_suppl.LBA16
  8. Efstathiou E, Smith MR, Sandhu S, et al. Niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations: second interim analysis (IA2) of MAGNITUDE. J Clin Oncol. 2023;41(suppl 6):170. doi:10.1200/JCO.2023.41.6_suppl.170
  9. Agarwal N, Azad A, Carles J, et al. TALAPRO-2: phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl 6):LBA17. doi:10.1200/JCO.2023.41.6_suppl.LBA17
  10. Bryce AH, Piulats JM, Reaume MN, et al. Rucaparib for metastatic castration-resistant prostate cancer (mCRPC): TRITON3 interim overall survival and efficacy of rucaparib vs docetaxel or second-generation androgen pathway inhibitor therapy. J Clin Oncol. 2023;41(suppl 6):18. doi:10.1200/JCO.2023.41.6_suppl.18
  11. Sharma P, Krainer M, Saad F, et al. Nivolumab plus ipilimumab for the treatment of post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC): additional results from the randomized phase 2 CheckMate 650 trial.J Clin Oncol. 2023;41(suppl 6):22. doi:10.1200/JCO.2023.41.6_suppl.2
  12. Petrylak DP, Ratta R, Matsubara N, et al. Pembrolizumab plus docetaxel for patients with metastatic castration-resistant prostate cancer (mCRPC): randomized, double-blind, phase 3 KEYNOTE-921 study. J Clin Oncol. 2023;41(suppl 6):19. doi:10.1200/JCO.2023.41.6_suppl.19