Objective Computerized Cognitive Assessment in Men With Metastatic Castrate-Resistant Prostate Cancer Randomly Receiving Darolutamide or Enzalutamide in the ODENZA Trial
The second-generation androgen receptor inhibitor enzalutamide has been associated with cognitive changes and adverse events related to the central nervous system, such as fatigue.1 Penetration of the blood-brain barrier is lower with darolutamide than enzalutamide, which may reduce the risk of fatigue and cognitive impairment.2 The phase 2 ODENZA trial was an open-label, multicenter, prospective, randomized, crossover study that compared patient preferences for darolutamide vs enzalutamide.3,4 The trial randomly assigned 250 patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) to treatment with darolutamide (1200 mg/day for 12 weeks) followed by enzalutamide (160 mg/day for 12 weeks) or the opposite sequence. Darolutamide is a structurally distinct androgen receptor antagonist approved by the US Food and Drug Administration (FDA) for treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC).
As reported at the 2021 American Society of Clinical Oncology annual meeting, 48.5% of patients preferred darolutamide, 40.0% preferred enzalutamide, and 11.5% had no preference.3 This difference did not reach statistical significance. Decreased fatigue was reported as the most common factor influencing patient preference.
A key secondary endpoint of the ODENZA trial was assessment of cognitive function with computerized cognitive tests. At the 2021 European Society for Medical Oncology (ESMO) congress, Emeline Colomba, MD, presented an analysis of the ODENZA trial that focused on differences in cognitive changes with enzalutamide vs darolutamide.4 The patients completed cognitive tests measuring psychomotor function, visual attention, working memory, executive function, verbal learning, and verbal memory prospectively at baseline and during each 12-week treatment period.
Data were available for 193 patients. Performance on verbal learning, assessed using the International Shopping List Test, was significantly better with darolutamide vs enzalutamide in both treatment periods, reaching clinically meaningful differences in the second period (effect size, 0.62; P=.0001) and overall (effect size, 0.54; P<.0001). Performance on the International Shopping List Test–Delayed Recall, which measured verbal memory, was also significantly better with darolutamide vs enzalutamide, although the effect sizes were less pronounced, at 0.4 (P=.01) for the second period and 0.29 (P=.0075) overall.
The investigators noted that the improvements with darolutamide vs enzalutamide on episodic memory impacted both the learning of new information and the recall of that information following a short delay. Composite memory scores also showed a moderate benefit in episodic memory with darolutamide vs enzalutamide (Figure 1). Tests measuring executive function showed nonsignificant trends toward a benefit with darolutamide.
References
1. Ryan C, Wefel JS, Morgans AK. A review of prostate cancer treatment impact on the CNS and cognitive function. Prostate Cancer Prostatic Dis. 2020;23(2):207-219.
2. Crawford ED, Stanton W, Mandair D. Darolutamide: an evidenced-based review of its efficacy and safety in the treatment of prostate cancer. Cancer Manag Res. 2020;12:5667-5676.
3. Colomba E, Jonas SF, Eymard JC, et al. ODENZA: a French prospective, randomized, open-label, multicenter, cross-over phase II trial of preference between darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer (CRPC) [ASCO abstract 5046]. J Clin Oncol. 2021;39(15 suppl).
4. Colomba E, Jonas SF, Eymard JC, et al. Objective computerized cognitive assessment in men with metastatic castrate-resistant prostate cancer randomly receiving darolutamide or enzalutamide in the ODENZA trial [ESMO abstract 603P]. Ann Oncol. 2021;32(suppl 5).
Darolutamide Maintenance in Metastatic Castration-Resistant Prostate Cancer Previously Treated With Novel Hormonal Agents and Nonprogressive Disease After Subsequent Treatment With a Taxane: A Randomized, Double-Blind, Placebo-Controlled Phase II Trial (SAKK 08/16)
The FDA approval of darolutamide for patients with nmCRPC was based on the results of the randomized, double-blind phase 3 ARAMIS trial. The trial compared darolutamide plus androgen deprivation therapy (ADT) vs placebo plus ADT in men with nmCRPC with a prostate-specific antigen (PSA) doubling time of 10 months or less. Patients were assigned 2:1 to treatment with darolutamide at 600 mg twice daily (n=955) or placebo (n=554), along with ADT.1 In the primary analysis, the median metastasis-free survival was 40.4 months in the darolutamide arm vs 18.4 months in the placebo arm (hazard ratio [HR] for metastasis or death in the darolutamide group, 0.41; 95% CI, 0.34-0.50; P<.001).1 Given the benefit of darolutamide among patients with nmCRPC, trials are underway evaluating the potential role of this treatment in other prostate cancer settings.
At the 2021 ESMO congress, Richard Cathomas, MD, presented the results of SAKK 08/16, an international, double-blind, placebo-controlled, proof-of-concept phase 2 trial that evaluated darolutamide as maintenance therapy among patients with mCRPC previously treated with a novel hormonal agent.2 The trial enrolled 92 patients with mCRPC who had received enzalutamide and/or abiraterone acetate for at least 8 weeks before receiving a taxane. The patients had nonprogressive disease after treatment with docetaxel (at a cumulative dose of ≥300 mg/m2) or cabazitaxel (at a dose of ≥80 mg/m2) and were continuing to receive ADT.
Patients were randomly assigned to receive darolutamide at 600 mg twice daily or placebo twice daily, each with best supportive care. Stratification factors included country of residence, performance status, sites of metastases, prior treatment, and planned start of maintenance treatment after the last taxane dose (<35 days vs ≥35 days). The start of maintenance was planned for 2 to 8 weeks after the last taxane dose. The primary endpoint was radiographic progression-free survival (rPFS) at 12 weeks after initiation of treatment. The baseline characteristics for the 90 evaluable patients were well balanced between the arms. The patients’ median age was 71 years. Prior novel hormonal agents included abiraterone acetate in 60%, enzalutamide in 31%, and both in 9%; 26% of patients had a response to their novel hormonal agent.
The trial met its primary endpoint. At week 12, rPFS was 64.7% (95% CI, 47.6%-77.5%) with darolutamide vs 52.2% with placebo (95% CI, 36.1%-66.1%).2 The median rPFS was 5.5 months vs 4.5 months, respectively (HR, 0.54; 95% CI, 0.32-0.91; log-rank P=.017; Figure 2). Dr Cathomas noted that the improvement was statistically significant but clinically modest. The median event-free survival was 5.4 months with darolutamide vs 2.9 months with placebo (HR, 0.46; 95% CI, 0.29-0.73; log-rank P<.001; Figure 3). The median overall survival (OS) was 24.0 months vs 21.3 months, respectively, a difference that did not reach statistical significance (P=.18).
PSA response rates were higher with darolutamide vs placebo. A PSA response of 30% was reported in 31% of the darolutamide arm vs 9% of the placebo arm. A PSA response of 50% was reported in 22% vs 4%, respectively. A PSA response of 90% was seen in 2% vs 0%. The median duration of a 50% decrease in PSA was 7.7 months with darolutamide vs 2.8 months with placebo.
Subgroup analyses suggested that the benefit of darolutamide may vary based on the patient’s response to the previous new hormonal agent.2 The 29 patients with a complete or partial response to a previous novel hormonal agent appeared to have a greater rPFS and OS benefit with darolutamide vs placebo. This benefit was not observed among the 61 patients in whom the prior novel hormonal agent led to stable or progressive disease.
Treatment with maintenance darolutamide appeared to be well tolerated. Grades 1, 2, and 3 treatment-related adverse events (TRAEs) were reported in 26%, 13%, and 2%, of patients, respectively. Rates in the placebo arm were 22%, 15%, and 2%, respectively. Fatigue was reported in 11% of the darolutamide arm vs 20% of the placebo arm. The most common TRAE reported with darolutamide was bone pain and arthralgia, which occurred in 13% of patients (vs 2% in the placebo arm).
In summary, this proof-of-concept study met its primary endpoint, demonstrating an improvement in rPFS with maintenance darolutamide. Darolutamide had a favorable toxicity profile. Dr Cathomas noted that findings from the subgroup analysis—which identified an association between a patient’s response to a prior new hormonal agent and benefit from maintenance darolutamide—may help inform the design of a phase 3 trial.
References
1. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
2. Cathomas R, Procopio G, Hayoz S, et al. Darolutamide maintenance in metastatic castration resistant prostate cancer previously treated with novel hormonal agents and non-progressive disease after subsequent treatment with a taxane: a randomized double-blind placebo-controlled phase II trial (SAKK 08/16) [ESMO abstract LBA26]. Ann Oncol. 2021;32(suppl 5).
Cabozantinib in Combination With Atezolizumab in Patients With Metastatic Castration-Resistant Prostate Cancer: Results of Expanded Cohort 6 of the COSMIC-021 Study
Cabozantinib is a multitargeted tyrosine kinase inhibitor (TKI) that is approved by the FDA for use in certain patients with advanced renal cell carcinoma, hepatocellular carcinoma, and locally advanced or metastatic differentiated thyroid cancer.1 Biomarker analyses and preclinical studies have suggested that cabozantinib activates the immune system,2,3 providing a rationale for combination with immune checkpoint inhibitors.
The phase 1b COSMIC-021 study is evaluating cabozantinib in combination with atezolizumab, an antibody that binds to programmed death ligand 1 (PD-L1), in patients with various solid tumors.4 Cohort 6 focuses on patients with mCRPC who developed radiographic progression after enzalutamide and/or abiraterone acetate. The patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, and they had not received prior chemotherapy, except for docetaxel for metastatic castration-sensitive prostate cancer. Patients received cabozantinib orally at 40 mg/day plus atezolizumab intravenously at 1200 mg every 3 weeks.
The primary endpoint of the COSMIC-021 study was investigator-assessed objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors v1.1. Secondary and exploratory endpoints included safety, progression-free survival (PFS), OS, and biomarker analysis. The subset of patients with visceral metastases or extrapelvic lymphadenopathy was noted as a key subgroup.
In an early analysis of this cohort, presented in 2020, cabozantinib in combination with atezolizumab demonstrated encouraging activity and a manageable toxicity profile, including in patients with visceral metastases and/or extrapelvic lymphadenopathy.4 At the 2021 ESMO congress, Neeraj Agarwal, MD, reported updated findings for 132 enrolled patients, with a median follow-up of 15.2 months.5 The patients’ median age was 70 years (range, 49-90). The Gleason score at diagnosis was 8 or higher in 63%, 41% had undergone a prior prostatectomy, and 25% had received docetaxel for metastatic castration-sensitive prostate cancer. Visceral metastases were present in 32% of patients, and extrapelvic lymphadenopathy was reported in 60%. Metastatic sites included the lymph nodes (80%), bone (54%), lungs (19%), and liver (13%).
Treatment with cabozantinib plus atezolizumab led to an investigator-assessed ORR of 23% (including complete responses in 2%) and stable disease in 61%, for a disease control rate of 84%.5 Among the 101 patients with visceral metastases or extrapelvic lymphadenopathy, the investigator-assessed ORR was 27%, which included a complete response rate of 2%. Stable disease was reported in 61%. The disease control rate was therefore 88%. The regimen therefore appears to be active in this subgroup of patients with a poor prognosis. The median duration of response was 6.9 months in patients with and without visceral metastases or extrapelvic lymphadenopathy. The median time to response was 1.7 months in both sets of patients.
The blinded independent review committee reported ORR rates of 15% to 18%.5 PD-L1 status was known for 75 patients and did not correspond to response. The median PFS was 5.5 months per investigator assessment and 5.7 months per assessment by the independent review committee. The median OS was 18.4 months. Reductions in PSA were observed in 47% of evaluable patients (55 of 118); the PSA reduction was 50% or higher in 23% of patients. Similar rates of PSA reductions were reported for patients with visceral metastases and/or extrapelvic lymphadenopathy. Analyses of best change from baseline in the sum of the target lesions showed regression in 77% of 128 evaluable patients according to investigator review and in 70% of 120 evaluable patients according to independent review (Figure 4).
The median duration of treatment was 5.7 months (range, 0.4-27 months). Adverse events (AEs) led to dose reductions in 43% of patients and dose delays in 43%. Disease progression was the most common reason for discontinuation of study treatment, and reported in 45% of patients. Discontinuations owing to TRAEs were attributed to cabozantinib and/or atezolizumab in 21% of patients, cabozantinib in 18%, atezolizumab in 14%, and both in 10%.
Dr Agarwal noted that the safety profile was manageable and consistent with prior reports.5 The most common TRAEs of any grade included diarrhea (55%), fatigue (43%), nausea (42%), decreased appetite (34%), dysgeusia (27%), palmar-plantar erythrodysesthesia (25%), vomiting (23%), weight loss (23%), and aspartate aminotransferase elevation (20%). The most common grade 3/4 TRAEs included pulmonary embolism (8.3%), diarrhea (6.8%), fatigue (6.8%), and hypertension (6.8%). Grade 4 TRAEs were infrequent, occurring in 3% of patients. The single grade 5 event was dehydration in a 90-year-old patient. Potential immune-related AEs were reported in 66% of patients; these events were grade 3/4 in 20%. Corticosteroids were needed to treat AEs in 17% of patients.
The study investigators concluded that cabozantinib plus atezolizumab showed encouraging activity in patients with mCRPC, including in the subgroup of patients with visceral disease or distant lymph node metastasis. The phase 3 CONTACT-02 trial is evaluating cabozantinib plus atezolizumab vs a second novel hormonal therapy in patients with mCRPC with visceral or extrapelvic lymph node metastasis after 1 prior novel hormonal therapy.6
References
1. Cabometyx [package insert]. Alameda, CA: Exelixis, Inc; 2021.
2. Kwilas AR, Ardiani A, Donahue RN, Aftab DT, Hodge JW. Dual effects of a targeted small-molecule inhibitor (cabozantinib) on immune-mediated killing of tumor cells and immune tumor microenvironment permissiveness when combined with a cancer vaccine. J Transl Med. 2014;12:294.
3. Tolaney SM, Ziehr DR, Guo H, et al. Phase II and biomarker study of cabozantinib in metastatic triple-negative breast cancer patients. Oncologist. 2017;22(1):25-32.
4. Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): results of cohort 6 of the COSMIC-021 study [ASCO abstract 139]. J Clin Oncol. 2020;38(suppl 15).
5. Agarwal N, McGregor B, Maughan BL, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results of expanded cohort 6 of the COSMIC-021 study [ESMO abstract LBA24]. Ann Oncol. 2021;32(suppl 5).
6. ClinicalTrials.gov. Study of cabozantinib in combination with atezolizumab versus second NHT in subjects with mCRPC (CONTACT-02). https://clinicaltrials.gov/ct2/show/NCT04446117. Identifier: NCT04446117. Accessed October 16, 2021.
Impact of Darolutamide on Local Symptoms in Patients With Nonmetastatic Castration-Resistant Prostate Cancer
In the phase 3 ARAMIS trial, the addition of darolutamide to ADT improved median metastasis-free survival.1 At the 2021 meeting of the American Urological Association (AUA), Neal Shore, MD, presented an analysis of the ARAMIS trial that evaluated the relationships between PSA response and the following factors: urinary and bowel AEs, time to deterioration in quality of life, and prostate cancer–related invasive procedures with darolutamide vs placebo.2 A prior prostatectomy was reported in 25.0% of the darolutamide arm and 24.2% of the placebo arm. Prior radiotherapy was reported in 18.5% vs 16.1% of patients, respectively.
There were minimal differences with darolutamide vs placebo in the incidences of urinary tract infections (5.3% vs 5.6%), abnormally frequent urination (4.4% vs 3.2%), and hematuria (4.5% vs 5.4%).2 Rates were lower with darolutamide vs placebo for urinary retention (3.8% vs 7.4%) and dysuria (2.6% vs 5.2%). In the darolutamide arm, greater PSA responses appeared to be associated with lower rates of urinary retention and dysuria. These events were each reported in 5.1% of patients with a PSA response below 50%. Among patients with a PSA response between 50% to 90%, urinary retention occurred in 4.2% and dysuria occurred in 3.2%. Among those with a PSA response higher than 90%, they were reported in 2.2% and 0.5%, respectively.
Darolutamide was also associated with a significant delay vs placebo in the time to deterioration of quality of life, defined as the first occurrence of a minimally important difference in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Prostate Cancer (EORTC QLQ-PR25) subscales of urinary symptoms (25.8 vs 14.8 months; HR, 0.64; 95% CI, 0.54-0.76; P<.01; Figure 5) and bowel symptoms (18.4 vs 11.5 months; HR, 0.78; 95% CI, 0.66-0.92; P<.01). The time to first occurrence of a 3-point or higher decline from baseline in the Functional Assessment of Cancer Therapy–Prostate, Prostate Cancer Subscale (FACT-P PCS) was also extended with darolutamide vs placebo (11.1 vs 7.9 months; HR, 0.80; 95% CI, 070-0.91; P=.0005).
The need for locally invasive procedures differed between the treatment arms. An invasive procedure related to prostate cancer was required by 4.7% of the darolutamide arm vs 9.6% of the placebo arm. The time to first procedure was significantly delayed with darolutamide vs placebo (HR, 0.416; 95% CI, 0.279-0.620; P<.001).
In summary, this analysis of local symptoms reported in the ARAMIS trial showed that darolutamide reduced local urinary and bowel symptoms, improved quality of life, and decreased requirements for locally invasive procedures among men with nmCRPC.
References
1. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
2. Shore N, Stenzl A, Pieczonka C, et al. Impact of darolutamide on local symptoms in patients with nonmetastatic castration-resistant prostate cancer [AUA abstract PD34-10]. J Urol. 2021;206(suppl 3).
Abiraterone Acetate Plus Prednisolone With or Without Enzalutamide Added to Androgen Deprivation Therapy (ADT) Compared to ADT Alone for Men With High-Risk Nonmetastatic Prostate Cancer: Combined Analysis From Two Comparisons in the STAMPEDE Platform Protocol
Among patients with high-risk nonmetastatic prostate cancer, the current standard treatment of 3 years of ADT plus local radiotherapy is associated with high rates of post-treatment failure.1 The randomized, open-label phase 2/3 STAMPEDE trial evaluated various approaches to the treatment of men with hormone-naive prostate cancer. Although docetaxel has demonstrated a significant OS benefit in patients with M1 prostate cancer, it provided no significant improvement in OS or metastasis-free survival in patients with M0 prostate cancer in the STAMPEDE trial or the GETUG-12 trial.2,3 Similarly, the addition of abiraterone acetate, enzalutamide, or apalutamide to ADT improved outcomes among patients with M1 prostate cancer in the STAMPEDE study and other trials.4-8 However, initial analyses indicated that there was no clear benefit seen with the addition of abiraterone acetate and prednisolone/prednisone (AAP) to ADT in patients with M0 prostate cancer.
At the 2021 ESMO congress, Gerhardt Attard, MD, PhD, presented an analysis from the STAMPEDE trial that evaluated the benefit of adding AAP, with or without enzalutamide, to ADT in patients with high-risk M0 prostate cancer.9 For newly diagnosed patients, high risk was defined as the presence of node-positive disease or at least 2 of the following criteria: stage T3 or T4, PSA of 40 ng/mL or higher, or a Gleason score of 8 to 10. Patients who relapsed after prior radical prostatectomy or radiation therapy were eligible for enrollment if they had node-positive disease, a PSA of 4 ng/mL or higher that was rising at a doubling time of less than 6 months, or a PSA of 20 ng/mL or higher. Patients received the standard of care plus 2 years of AAP with or without enzalutamide. Local radiotherapy was planned when appropriate.
The trial enrolled 1974 patients. Their median age was 68 years, their median PSA was 34 ng/mL, and 39% had N1 disease.9 Only 3% of patients were experiencing relapsed disease after their prior treatment. Local radiotherapy was planned for 99% of newly diagnosed patients with N0 disease, 71% with N1 disease, and 7% of previously treated patients.
After a median follow-up of 72 months, the addition of AAP (with or without enzalutamide) to ADT was associated with a significant improvement in metastasis-free survival (HR, 0.53; P=2.9 × 10-11; Figure 6) and OS (HR, 0.60; P=9.3 × 10-7).9 The 6-year metastasis-free survival rate improved from 69% to 82% with the addition of AAP-based therapy, and the 6-year OS rate improved from 77% to 86%. Improvements were also reported for prostate cancer-specific survival (HR, 0.49; P=1.3 × 10-6) and PFS (HR, 0.44; P=5.2 × 10-15). Subgroup analyses showed no differences in the benefit of AAP according to baseline factors. A prespecified subgroup analysis by randomization period showed no difference in treatment effect with AAP alone vs AAP with enzalutamide.
The addition of enzalutamide to AAP was associated with increased toxicity, including higher rates of grade 3 erectile dysfunction, hypertension, fatigue, and grade 3/4 transaminitis. The investigators concluded that AAP-based therapy should be considered a new standard of care for patients with high-risk M0 prostate cancer who are initiating treatment with ADT.
References
1. Helgstrand JT, Røder MA, Klemann N, et al. Diagnostic characteristics of lethal prostate cancer. Eur J Cancer. 2017;84:18-26.
2. James ND, Ingleby FC, Clarke NW, et al. Docetaxel for hormone-naïve prostate cancer (PCa): results from long-term follow-up of non-metastatic (M0) patients in the STAMPEDE randomised trial (NCT00268476) [ESMO abstract 2945]. Ann Oncol. 2019;30(suppl 5).
3. Fizazi K, Carmel A, Joly F, et al. Updated results of GETUC-12, a phase 3 trial of docetaxel-based chemotherapy in high-risk localized prostate cancer, with a 12-year follow-up [ESMO abstract 2933]. Ann Oncol. 2018;29(suppl 8).
4. James ND, de Bono JS, Spears MR, et al; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351.
5. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986.
6. Chi KN, Agarwal N, Bjartell A, et al; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24.
7. Davis ID, Martin AJ, Stockler MR, et al; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131.
8. Fizazi K, Tran N, Fein L, et al; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360.
9. Attard G, Finn RS, Galle PR, et al. Abiraterone acetate plus prednisolone with or without enzalutamide added to androgen deprivation therapy compared to ADT alone for men with high-risk non-metastatic prostate cancer: combined analysis from two comparisons in the STAMPEDE platform protocol [ESMO abstract LBA4 PR]. Ann Oncol. 2021;32(suppl 5).
Time Course Profile of Adverse Events of Interest and Serious Adverse Events With Darolutamide in the ARAMIS Trial
Treatment-related toxicity is a significant concern for patients with nmCRPC, who are often asymptomatic. These patients may be treated with long-term androgen receptor inhibitor therapy, which can lead to significant toxicities that affect quality of life, including fatigue, falls, fractures, hypertension, mental impairment, and rash.1,2 In the pivotal phase 3 ARAMIS trial, darolutamide was associated with a low incidence of AEs, with rates similar to placebo.3,4 The only AE occurring in more than 10% of patients receiving darolutamide was fatigue, reported in 13.2% of patients vs 8.3% for placebo.
To gain further understanding regarding the timing of AEs associated with darolutamide, Christian Gratzke, MD, and colleagues conducted an analysis of the ARAMIS trial that focused on the time intervals in which AEs arose.5 Throughout the first 24 months of the double-blind treatment period, fatigue was the only AE with an incidence that was more than 2% higher with darolutamide than placebo (12.6% vs 8.3%). Darolutamide and placebo were associated with similar rates of other AEs, including hypertension (7.3% vs 6.3%), falls (4.8% vs 4.7%), fractures (4.6% vs 3.4%), rash (2.9% vs 1.1%), and mental impairment (1.8% in each arm).
Fatigue tended to develop early during treatment in both arms. Cases of fatigue occurred during the first month of treatment in 5.9% of patients in the darolutamide arm vs 4.0% of those in the placebo arm. Conversely, falls and fractures most often occurred after the first month of treatment in both arms (Figure 7). Development of new-onset hypertension did not correspond to a specific time interval. Rash most often occurred during the first 4 months of treatment and was usually grade 1 or 2. The rates of initial onset and cumulative incidence of grade 3/4 toxicities were similar between the arms (Figure 8). Investigators concluded that the analysis confirmed the safety profile of darolutamide, showing a similar time of onset and cumulative incidence as placebo for most AEs.
References
1. Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418.
2. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474.
3. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
4. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049.
5. Gratzke C, Fizazi K, Shore N, et al. Time course profile of adverse events of interest and serious adverse events with darolutamide in the ARAMIS trial [ESMO abstract 630P]. Ann Oncol. 2021;32(suppl 5).
Biomarker Analysis of Men With Enzalutamide-Resistant Metastatic Castration-Resistant Prostate Cancer Treated With Pembrolizumab + Enzalutamide in KEYNOTE-199
KEYNOTE-199 was a 5-cohort open-label phase 2 trial that evaluated the antitumor activity and safety of pembrolizumab in patients with mCRPC.1 Cohorts 1 through 3 focused on patients previously treated with chemotherapy, whereas cohorts 4 and 5 enrolled chemotherapy-naive patients who developed progressive disease after an initial response to enzalutamide. Patients in cohort 4 (n=81) had measurable disease. Patients in cohort 5 (n=45) had bone-predominant disease. Patients in cohorts 4 and 5 received pembrolizumab at 200 mg every 3 weeks, plus continuation of enzalutamide, for up to 2 years or until progression, toxicity, or withdrawal. Key endpoints included ORR, duration of response, time to PSA progression, rPFS, OS, and safety.2
Results from cohorts 4 and 5 were previously reported. Pembrolizumab demonstrated an ORR of 12% in cohort 4, with a median duration of response of 6 months.2 The disease control rate in cohorts 4 and 5 was 51%, and the PSA response rate was 14%.2
At the 2021 ESMO congress, Julie Graff, MD, presented results from a biomarker analysis of cohorts 4 and 5 from the KEYNOTE-199.3 Assessments included tumor mutational burden as measured by whole exome sequencing (n=64), the PD-L1 combined positive score by immunohistochemistry (n=124), and an 18-gene T-cell–inflamed gene expression profile (n=51). Researchers investigated associations between these biomarkers and clinical outcomes, including ORR in cohort 4 only and disease control rate (≥6 months), PSA response, PFS, PSA progression, and OS in cohorts 4 and 5.
The analyses identified potential trends toward a positive association between responses to pembrolizumab and tumor mutational burden (Figure 9), with potential correlations noted for ORR, disease control rate, disease control rate of at least 6 months, and PSA response, as well as time-to-event outcomes (PFS, PSA progression, and OS).3 No associations were noted for the PD-L1 combined positive score or T-cell–inflamed gene expression profile. Dr Graff noted that this study was an exploratory analysis with small sample sizes, and therefore results should be interpreted with caution.
References
1. Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J Clin Oncol. 2020;38(5):395-405.
2. Hoimes CJ, Graff JN, Tagawa ST, et al. KEYNOTE-199 cohorts (C) 4 and 5: phase II study of pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC) [ASCO abstract 5543]. J Clin Oncol. 2020;38(15 suppl).
3. Graff JN, Tagawa S, Hoimes C, et al. Biomarker analysis of men with enzalutamide (enza)-resistant metastatic castration-resistant prostate cancer treated with pembrolizumab (pembro) + enza in KEYNOTE-199 [ESMO abstract 61MO]. Ann Oncol. 2021;32(suppl 5).
Health-Related Quality of Life, Pain, and Safety Outcomes in the Phase III VISION Study of 177Lu-PSMA-617 in Patients With Metastatic Castration-Resistant Prostate Cancer
Lutetium-177 (177Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation in a targeted manner to cells that express the prostate-specific membrane antigen (PSMA) and to the microenvironment. The international, open-label phase 3 VISION trial evaluated the addition of 177Lu-PSMA-617 to standard of care in men with PSMA-positive, previously treated mCRPC.1 The patients had received previous treatment with at least 1 androgen receptor pathway inhibitor and 1 or 2 taxane regimens. Protocol-permitted standard of care, as selected by the investigator, was planned before randomization and excluded chemotherapy, immunotherapy, radium-223, and investigational drugs. An ECOG performance status of 0 to 2 was required for enrollment, as was adequate organ and bone marrow function. Patients were randomly assigned 2:1 to 177Lu-PSMA-617 plus standard of care or standard of care alone.
The study met the primary endpoints of rPFS and OS. The addition of 177Lu-PSMA-617 to the standard of care significantly improved the median rPFS (8.7 vs 3.4 months; HR, 0.40; 99.2% CI, 0.29-0.57; P<.001) and the median OS (15.3 vs 11.3 months; HR, 0.62; 95% CI, 0.52-0.74; P<.001).1
At the 2021 ESMO congress, Karim Fizazi, MD, PhD, presented additional secondary outcomes from the VISION trial, including health-related quality of life, pain, and safety.2 Health-related quality of life was assessed with the FACT-P questionnaire. Pain was assessed using the Brief Pain Inventory–Short Form.
The analyses revealed significant improvements with 177Lu-PSMA-617 plus standard of care vs standard of care alone in the median time to worsening of health-related quality of life (9.7 vs 2.4 months; HR, 0.46; 95% CI, 0.35-0.61; P<.001; Figure 10) and the median time to worsening of pain (14.3 vs 2.9 months; HR, 0.45; 95% CI, 0.33-0.60; P<.001).2 The median time to first symptomatic skeletal event was also significantly longer with 177Lu-PSMA-617 plus standard of care vs standard of care alone (11.5 vs 6.8 months; HR, 0.50; 95% CI, 0.40-0.62; P<.001).
The most common treatment-emergent AE was fatigue, reported in 49.1% of patients in the 177Lu-PSMA-617 arm vs 29.3% in the control arm. Grade 3 or higher bone marrow suppression occurred in 23.4% vs 6.8% of patients, respectively. The most common hematologic AE was anemia, which was reported in 31.8% and 13.2% of patients, respectively. The incidence of dry mouth was 39.3% in the 177Lu-PSMA-617 arm and 1.0% in the control arm. Nausea and vomiting occurred in 39.3% and 17.1% of patients, respectively, and renal events occurred in 8.7% and 5.9% of patients.
References
1. Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103.
2. Fizazi K, Herrmann K, Krause BJ, et al. Health-related quality of life, pain and safety outcomes in the phase III VISION study of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer [ESMO abstract 576MO]. Ann Oncol. 2021;32(suppl 5).
Final Overall Survival Analysis From ARCHES: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Enzalutamide Plus Androgen Deprivation Therapy in Men With Metastatic Hormone-Sensitive Prostate Cancer
For men with metastatic hormone-sensitive prostate cancer (also known as castration-sensitive prostate cancer), recommended therapeutic options include ADT with either an androgen pathway inhibitor (eg, abiraterone acetate, apalutamide, or enzalutamide) or docetaxel.1 For patients who have de novo low-volume disease, external beam radiation therapy to the primary tumor is also recommended.
The FDA approved the combination of enzalutamide plus ADT for patients with metastatic hormone-sensitive prostate cancer based on results of the phase 3 ARCHES trial. This study demonstrated a significant improvement in outcomes with the addition of enzalutamide to ADT.2 The ARCHES trial enrolled 1150 men with metastatic hormone-sensitive prostate cancer with an ECOG performance status of 0 to 1. Upon enrollment, the patients’ current duration of ADT in the metastatic setting was 3 months or less; the duration could reach 6 months in patients who had received prior docetaxel. The patients were stratified based on the volume of disease and the duration of any prior docetaxel therapy. They were randomly assigned to receive enzalutamide at 160 mg/day plus ADT (n=574) or placebo plus ADT (n=576). Discontinuation criteria included radiographic progression, unacceptable toxicity, or initiation of a new or investigational therapy for prostate cancer.
In the primary analysis, the addition of enzalutamide to ADT was associated with a significant improvement in the primary endpoint of rPFS (HR, 0.39; P<.001), along with reductions in the risk of PSA progression, initiation of new therapy, first symptomatic skeletal event, castration resistance, and pain progression.2 The patients’ baseline quality of life was high and maintained over time. The addition of enzalutamide was well tolerated. Grade 3 or higher AEs occurred in 24.3% of the enzalutamide arm vs 25.6% of the placebo arm. Based on the demonstrated benefit of enzalutamide, the trial was unblinded to allow patients in the placebo arm to cross over to receive enzalutamide plus ADT as part of an ongoing open-label extension trial. Overall, 184 patients in the placebo arm (31.9%) gave consent to cross over, and 180 patients (31.3%) received treatment with enzalutamide plus ADT. The median time to crossover was 21.5 months.
At the time of the primary analysis of the ARCHES trial, the OS data were immature. At the 2021 ESMO congress, Andrew Armstrong, MD, MSc, presented updated results from ARCHES, including the final prespecified analyses of OS, time to subsequent therapy, and safety data.3 The baseline characteristics were well balanced between the 2 arms. The patients’ median age was 70 years, and 77% had an ECOG performance status of 0.2 Patients in the placebo crossover group tended to have more favorable characteristics. Their rate of high-volume disease was 50%, vs 64.8% in the overall placebo arm and 61.7% in the enzalutamide arm. Distant metastases at diagnosis were reported in 58.3% of the crossover arm, 63.4% of the placebo arm, and 70.0% of the enzalutamide arm.
After a median follow-up of 44.6 months, the addition of enzalutamide to ADT was associated with a significant improvement in OS (HR, 0.66; 95% CI, 0.53-0.81; P<.0001; Figure 11).3 The median OS was not reached in either arm. The rates of 4-year OS were 71% with enzalutamide plus ADT vs 57% with ADT alone. Subgroup analyses showed a consistent benefit with enzalutamide based on age, geographic region, ECOG performance status, Gleason score, disease localization, baseline PSA, and disease volume. There was no significant difference in OS between the treatment arms among the 18% of patients who had received prior docetaxel or the 11% of patients with visceral metastases.
The time to next antineoplastic therapy was not reached with enzalutamide vs 40.54 months with placebo (HR, 0.38; 95% CI, 0.31-0.48). Subsequent therapies included docetaxel, enzalutamide, and abiraterone acetate. Including the crossover group, 70% of patients in the placebo arm received some type of life-extending therapy after the study treatment and 42% received enzalutamide plus ADT.
Safety findings were consistent with previous reports. Rates of some TRAEs were higher in the enzalutamide arm. However, the investigators noted that this increase should be considered in the context of the substantially longer treatment duration in the enzalutamide arm of 40.2 months, compared with 13.8 months in the placebo arm and 23.9 months in the crossover arm. Key TRAEs included musculoskeletal events (39.0% with enzalutamide plus ADT vs 29.8% with placebo plus ADT), fatigue (32.2% vs 20.6%), hypertension (14.3% vs 6.8%), fractures (13.5% vs 5.4%), falls (10.1% vs 3.3%), cognitive/memory impairment (6.6% vs 2.6%), and hepatic disorder (5.9% vs 6.1%). The only grade 3/4 event reported in 5% or more of patients receiving enzalutamide plus ADT was hypertension (5.1%). Dr Armstrong noted that cardiovascular risks remained low, but the incidence was slightly increased at this later follow-up. Ischemic heart disease was reported in 4.5% of patients receiving enzalutamide plus ADT vs 1.9% of patients receiving placebo plus ADT. Other cardiovascular events occurred in 4.4% vs 1.7%, respectively.
In summary, this extended analysis confirmed the benefit of adding enzalutamide to ADT in men with metastatic hormone-sensitive prostate cancer, showing a long-term survival benefit that was maintained across many subgroups, and a delay in the need for subsequent therapies. Dr Armstrong concluded that additional follow-up was needed to assess the benefit of enzalutamide in men treated with docetaxel and in those with visceral metastases.
References
1. National Comprehensive Cancer Network® (NCCN) Guidelines: Prostate Cancer. Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Updated September 10, 2021. Accessed October 17, 2021.
2. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986.
3. Armstrong AJ, Iguchi T, Azad AA, et al. Final overall survival analysis from ARCHES: a phase 3, randomized, double-blind, placebo-controlled study of enzalutamide plus androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer [ESMO abstract LBA25]. Ann Oncol. 2021;32(suppl 5).
Highlights in Prostate Cancer From the 2021 European Society for Medical Oncology Congress and the 2021 American Urological Association Meeting: Commentary
Several studies presented at the 2021 European Society for Medical Oncology (ESMO) congress and the 2021 American Urological Association (AUA) meeting provided important insights into the management of patients with prostate cancer. Studies provided new data for darolutamide, abiraterone acetate, cabozantinib plus atezolizumab, enzalutamide plus androgen deprivation therapy (ADT), 177Lu-PSMA-617, and pembrolizumab combinations.
Darolutamide
At the ESMO meeting, Dr Emeline Colomba and colleagues presented an analysis of the phase 2 ODENZA trial that focused on objective computerized cognitive assessment.1 Darolutamide and enzalutamide are androgen receptor (AR) antagonists that are approved by the US Food and Drug Administration (FDA) for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). The ODENZA trial compared patient preferences for darolutamide or enzalutamide in the setting of metastatic castration-resistant prostate cancer (mCRPC).2 The analysis by Dr Colomba evaluated the potential differential impact of darolutamide vs enzalutamide on cognitive function, the rationale being that darolutamide has very minimal penetration of the central nervous system (CNS). In murine studies, the CNS concentrations are approximately 3% of plasma concentrations.3 Patients enrolled in the ODENZA trial took defined cognitive tests every 12 weeks. As expected, there was a meaningful reduction in cognitive impairment with darolutamide as compared with enzalutamide. The improvement was especially apparent in episodic memory recall, for both the acquisition of new information and the recall of information after a brief delay.
At the ESMO meeting, Dr Richard Cathomas and colleagues presented results from a double-blind, placebo-controlled phase 2 trial that evaluated darolutamide maintenance in men with mCRPC.4 The trial enrolled patients who had received a taxane, discontinued it, and had nonprogressive disease. The patients had also received another AR targeting agent prior to study entry. The patients were randomly assigned to darolutamide or placebo to evaluate disease progression. At least some of the agents that target the AR are known to be less effective as second-line therapy compared with first-line therapy. For example, in the mCRPC setting, enzalutamide leads to prostate-specific antigen (PSA) responses rates of approximately 30% to 35% when administered after abiraterone acetate vs close to 90% when given as first-line treatment.5 When abiraterone acetate is administered after enzalutamide, the PSA response rates are less than 10%. The study by Dr Cathomas showed a modest impact of darolutamide on delaying progression,4 which was not surprising. It is yet to be determined whether this difference will translate into a meaningful clinical benefit. It is uncertain whether this regimen will advance to a phase 3 study.
At the AUA meeting, Dr Neal Shore and colleagues presented a study evaluating the impact of darolutamide on local symptoms in patients with nmCRPC.6 As expected, darolutamide reduced local symptoms, especially in patients who had a PSA response to treatment. Urinary retention was reported in 3.8% of the darolutamide arm vs 7.4% of the placebo arm. Dysuria occurred in 2.6% vs 5.2%, respectively. This finding supports the efficacy of darolutamide in the nmCRPC setting.
At the ESMO meeting, Dr Christian Gratzke and coworkers presented an analysis of the time course profile of adverse events among men enrolled in the randomized, double-blind, placebo-controlled phase 3 ARAMIS trial of darolutamide in nmCRPC.7 The results of the ARAMIS trial led to the FDA approval of darolutamide in these patients.8 As previously published, the ARAMIS study showed a marked improvement in metastasis-free survival with the addition of darolutamide to ADT.8 Remarkably, only 3 adverse events—fatigue, rash, and lower extremity pain—were at least 2% more frequent with darolutamide vs placebo. The analysis by Dr Gratzke focused on adverse events that are common with other AR inhibitors, as well as events related to darolutamide.7 The study found no difference in the rates of falls and fractures, hypertension, or mental impairment for darolutamide vs placebo. The mental impairment reported with other AR inhibitors may be related to CNS penetration, which is expected to be minimal with darolutamide based on preclinical in vivo studies.3 There was a small difference over time in the incidence of fatigue and rash in the darolutamide arm vs the placebo. The greatest difference in incidence was for fatigue. At 24 months during the double-blind treatment period, fatigue occurred in 12.6% of the darolutamide arm vs 8.3% of the placebo arm. This analysis adds to the data showing that darolutamide has an outstanding adverse event and safety profile. Darolutamide may be a particularly good choice for patients who are at risk for falls and fractures, as well as those who might experience fatigue after treatment with ADT or other AR inhibitors.
Abiraterone Acetate
Dr Gerhardt Attard and colleagues presented a combined analysis from 2 comparisons in the STAMPEDE trial at the ESMO meeting.9 STAMPEDE is the largest controlled trial of patients with castration-sensitive prostate cancer. The study was initiated in 2005,10 and it has made important contributions to the management of metastatic castration-sensitive prostate cancer and nonmetastatic high-risk castration-sensitive prostate cancer. The analysis by Dr Attard evaluated the role of abiraterone acetate plus prednisolone added to ADT in men with high-risk nonmetastatic prostate cancer or metastatic castration-sensitive prostate cancer.9 The initial results, which were published in 2017, demonstrated a clear, unequivocal benefit for the addition of abiraterone acetate and prednisolone to ADT, but the improvement was largely restricted to patients with metastatic (M1) disease.11 The current analysis had longer follow-up, plus more endpoints for statistical power. Importantly, the investigators made a prospective change in the protocol to allow for metastasis-free survival to be the primary endpoint for the nonmetastatic patients. This change was based on results from the ICECaP study, which demonstrated that metastasis-free survival is a good surrogate for overall survival in nonmetastatic patients.12 Radiation was administered to most of the nonmetastatic patients as part of their initial management. The duration of abiraterone acetate and prednisolone when added to ADT was 2 years, along with 3 years of ADT.
The analysis showed a significant improvement in metastasis-free survival when abiraterone acetate and prednisolone were added to ADT as compared with ADT alone.9 There was also a marked improvement in overall survival. Given the magnitude of the effect, these results are practice-changing. There were 2 groups of patients treated with abiraterone acetate. The first group received abiraterone acetate plus prednisolone alone. This treatment was subsequently changed to include the addition of enzalutamide. The addition of enzalutamide to the abiraterone acetate arm did not have a meaningful impact on efficacy, but it did add toxicity. Similarly, the addition of enzalutamide to abiraterone acetate does not improve overall survival in the mCRPC setting.
The study population had very high-risk disease; patients typically had 2 of the following features: stage T3 or T4 disease, lymph-node positive disease, and a high Gleason score. The results, therefore, do not necessarily apply to all high-risk patients. It is important to be mindful of the inclusion criteria of this study when adding abiraterone acetate to ADT in patients with nonmetastatic castration-sensitive prostate cancer.
Cabozantinib Plus Atezolizumab
The phase 1b COSMIC-021 study is evaluating the tyrosine kinase inhibitor cabozantinib plus the checkpoint inhibitor atezolizumab in patients with several types of solid tumors, including CRPC, renal cell carcinoma, and advanced urothelial carcinoma.13 At the ESMO meeting, Dr Neeraj Agarwal and colleagues presented the results of expanded cohort 6, which enrolled 132 patients with mCRPC, including those with visceral metastases and/or extrapelvic lymphadenopathy.14 Cabozantinib had previously been studied as a single agent in prostate cancer, but it did not improve outcomes.15
The combination of cabozantinib plus atezolizumab led to a reasonably high objective response rate of approximately 25% (as assessed by the investigators).14 This benefit, along with the biochemical response rate, has led to the development and initiation of a phase 3 study.16 If results of the phase 3 study are positive, mCRPC may gain another combination regimen that consists of 2 agents that are not used as monotherapies in this setting.
Enzalutamide Plus ADT
At the ESMO meeting, Dr Andrew Armstrong and colleagues presented results from a final overall survival analysis of the randomized, double-blind, placebo-controlled phase 3 ARCHES trial, which evaluated the addition of enzalutamide to ADT in men with metastatic hormone-sensitive prostate cancer.17 There are now 4 different therapies—docetaxel, abiraterone acetate plus prednisone, enzalutamide, and apalutamide—that improve overall survival in patients with metastatic castration-sensitive prostate cancer.18-21 In the large phase 3 ENZAMET trial, enzalutamide improved overall survival in metastatic castration-sensitive prostate cancer.19 Overall survival was the primary endpoint in the ENZAMET trial.19 Interestingly, in the ARCHES trial, radiographic progression-free survival was the primary endpoint, and overall survival was a secondary endpoint.18
The final analysis of overall survival in the ARCHES trial showed an improvement with the addition of enzalutamide to ADT, with a hazard ratio that was similar to those for other drugs approved in this setting.17 These agents all have a hazard ratio for overall survival of approximately 0.6 to 0.7.18-21 In general, efficacy is similar for docetaxel, abiraterone acetate, enzalutamide, and apalutamide in patients with metastatic castration-sensitive prostate cancer. These agents do have different side effect profiles, contraindications, and drug-drug interactions. In the United States, docetaxel is largely used in patients with high-volume disease, and abiraterone acetate is used in patients with high-risk disease (which is similar, but not identical, to high-volume disease). In contrast, enzalutamide and apalutamide have improved overall survival irrespective of tumor burden. This analysis of the ARCHES trial lends further support to the role of enzalutamide as a potential option to improve overall survival for patients with metastatic castration-sensitive prostate cancer.17
177Lu-PSMA-617
At the ESMO meeting, Dr Karim Fizazi and coworkers presented an analysis of health-related quality of life, pain, and safety in the phase 3 VISION study, which evaluated the effect of 177Lu-PSMA-617 on overall survival among patients with mCRPC who had received at least 1 androgen-receptor signaling inhibitor and docetaxel-based chemotherapy.22 The results for the primary endpoints of overall survival and radiographic progression-free survival were previously published.23 The trial compared the addition of 177Lu-PSMA-617 to the protocol-permitted standard of care vs the standard of care alone. The standard of care excluded chemotherapy, immunotherapy, radium-223, and investigational drugs because of safety issues associated with combining these agents with 177Lu-PSMA-617. Therefore, the control arm did not reflect the best available therapy.
The VISION study had key secondary endpoints related to safety and tolerability.22 These endpoints included time to first skeletal-related event, health-related quality of life, and pain as measured by the FACT-P Brief Pain Inventory Short Form and EQ-5D-5L instruments. The analysis showed that patients in the prostate-specific membrane antigen (PSMA)-based radionuclide therapy arm had a significant improvement in these quality-of-life endpoints. 177Lu-PSMA-617 delayed the onset of the first symptomatic skeletal event and improved quality of life. This study adds to the data suggesting that 177Lu-PSMA-617 cannot only improve quantity of life, but also quality of life. This study will provide further support for the use of 177Lu-PSMA-617 after it is approved by the FDA, which is expected in the first half of 2022.
Dr Shahneen Sandhu and colleagues presented results from an interim analysis of the phase 1b PRINCE study, which evaluated 177Lu-PSMA-617 in combination with pembrolizumab in mCRPC, at the ESMO meeting.24 The idea behind this study is that lutetium can serve as an immunomodulator by resulting in the immunogenic cell death of targeted cells, in this case prostate cancer cells. By inducing cell death, 177Lu-PSMA-617 can trigger the release of novel tumor antigens that are detectable to infiltrating T cells and thereby prime these infiltrating T cells to respond to an immunotherapy, such as the checkpoint inhibitor pembrolizumab. Utilization of pembrolizumab may therefore be particularly effective in this population. In addition, there is a clinical need for an agent that can be added to PSMA-based radionuclide therapy, which is administered for a finite period of no more than 6 cycles. Typically, after a patient receives 6 cycles of therapy, he will develop disease progression after a relatively short duration. The addition of a drug like pembrolizumab, which could be continued beyond this time-frame, could in principle influence long-term outcomes by prolonging the duration of response.
This interim analysis did not detect any unexpected side effects of the combination.24 There were some immune-related side effects, which are consistent with pembrolizumab, but not at a high frequency. The side effects of 177Lu-PSMA-617 were also similar to those observed in prior studies. These adverse events typically include fatigue, dry mouth, and gastrointestinal toxicities, such as nausea and vomiting, which are mostly grades 1 and 2. The PSA response rate was high, at more than 70%. In the phase 3 VISION study of 177Lu-PSMA-617 alone, the PSA response rate was 66%. It is therefore difficult to know whether the addition of pembrolizumab improved the impact of 177Lu-PSMA-617 on PSA. In addition, the follow-up was too short to assess the long-term impact of treatment. However, based on the strong rationale behind the combination and the lack of unexpected safety signals, this treatment will likely advance to phase 2 or phase 3 studies.
Pembrolizumab Combinations
At the AUA meeting, Dr Luke Nordquist and colleagues presented updated results from patients in cohort A of the KEYNOTE-365 study.25 This study evaluated pembrolizumab in combination with several different agents in patients with mCRPC. The investigators presented the results of cohort A, which included patients previously treated with docetaxel who received pembrolizumab plus olaparib.26 The analysis included patients with a minimum of 11 months of follow-up. Pembrolizumab was administered every 3 weeks. The primary endpoints were PSA response and objective response. The confirmed PSA response was very low, at 14.7%. The objective response rate in patients who had measurable disease was only 6.9%. Importantly, these patients were not selected based on next-generation sequencing, so they were not necessarily expected to respond to olaparib monotherapy, which is known to be effective for tumors with BRCA2, BRCA1, or PALB2 mutations.27 The results of this trial are disappointing. The combination of pembrolizumab and olaparib did not enhance response in this unselected population. Better patient selection would be needed for continued research of this regimen.
At the ESMO meeting, Dr Julie Graff and colleagues presented a biomarker analysis of cohorts 4 and 5 of the KEYNOTE-199 trial.28 The analysis focused on men with enzalutamide-resistant mCRPC who received pembrolizumab plus enzalutamide. These patients had not yet received chemotherapy for mCRPC. They had an initial response to enzalutamide, but then developed progressive disease. They were receiving maintenance therapy with enzalutamide. Pembrolizumab was subsequently added to treatment. There had been some early signals that the addition of enzalutamide to pembrolizumab would result in relatively high and deep PSA responses beyond those expected with pembrolizumab monotherapy.29 In this study, the patients were not selected based on programmed death ligand 1 (PD-L1) status or tumor mutational burden. The goal was to determine if there were any biomarkers that could predict for outcome. The investigators evaluated tumor mutational burden, PD-L1 expression via immunohistochemistry, and an 18-gene, T cell–inflamed gene expression profile. The analysis found very little association between these factors and outcome. The only factor that was predictive of outcome was tumor mutational burden, which showed a modest prediction for disease control rate, but not for PSA response rate. There is much to learn about the combination of enzalutamide and pembrolizumab. The early signal that this combination might be effective may not persist as more patients are studied.
Disclosure
Dr Rettig is a consultant for Amgen, Clovis, and Ambrx. He is a speaker for Janssen and Bayer. He has received research support from Novartis, Janssen, Exini, and Merck.
References
1. Colomba E, Jonas SF, Eymard JC, et al. Objective computerized cognitive assessment in men with metastatic castrate-resistant prostate cancer randomly receiving darolutamide or enzalutamide in the ODENZA trial [ESMO abstract 603P]. Ann Oncol. 2021;32(suppl 5).
2. Colomba E, Jonas SF, Eymard JC, et al. ODENZA: a French prospective, randomized, open-label, multicenter, cross-over phase II trial of preference between darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer (CRPC) [ASCO abstract 5046]. J Clin Oncol. 2021;39(15 suppl).
3. Moilanen A-M, Riikonen R, Oksala R, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007.
4. Cathomas R, Procopio G, Hayoz S, et al. Darolutamide maintenance in metastatic castration resistant prostate cancer previously treated with novel hormonal agents and non-progressive disease after subsequent treatment with a taxane: a randomized double-blind placebo-controlled phase II trial (SAKK 08/16) [ESMO abstract LBA26]. Ann Oncol. 2021;32(suppl 5).
5. Azad AA, Eigl BJ, Murray RN, Kollmannsberger C, Chi KN. Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients. Eur Urol. 2015;67(1):23-29.
6. Shore N, Stenzl A, Pieczonka C, et al. Impact of darolutamide on local symptoms in patients with nonmetastatic castration-resistant prostate cancer [AUA abstract PD34-10]. J Urol. 2021;206(suppl 3).
7. Gratzke C, Fizazi K, Shore N, et al. Time course profile of adverse events of interest and serious adverse events with darolutamide in the ARAMIS trial [ESMO abstract 630P]. Ann Oncol. 2021;32(suppl 5).
8. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
9. Attard G, Finn RS, Galle PR, et al. Abiraterone acetate plus prednisolone with or without enzalutamide added to androgen deprivation therapy compared to ADT alone for men with high-risk non-metastatic prostate cancer: combined analysis from two comparisons in the STAMPEDE platform protocol [ESMO abstract LBA4 PR]. Ann Oncol. 2021;32(suppl 5).
10. Clarke NW, Ali A, Ingleby FC, et al. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019;30(12):1992-2003.
11. James ND, de Bono JS, Spears MR, et al; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351.
12. Sweeney C, Nakabayashi M, Regan M, et al; ICECaP Working Group. The development of Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP). J Natl Cancer Inst. 2015;107(12):djv261
13. ClinicalTrials.gov. Study of cabozantinib in combination with atezolizumab to subjects with locally advanced or metastatic solid tumors. https://www.clinicaltrials.gov/ct2/show/NCT03170960. Identifier: NCT03170960. Accessed November 8, 2021.
14. Agarwal N, McGregor B, Maughan BL, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results of expanded cohort 6 of the COSMIC-021 study [ESMO abstract LBA24]. Ann Oncol. 2021;32(suppl 5).
15. Smith M, De Bono J, Sternberg C, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016;34(25):3005-3013.
16. Agarwal N, Azad A, Carles J, et al. A phase III, randomized, open-label, study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy (NHT) in patients (pts) with metastatic, castration-resistant prostate cancer (mCRPC) [ASCO GU abstract TPS190]. J Clin Oncol. 2021;39(6 suppl).
17. Armstrong AJ, Iguchi T, Azad AA, et al. Final overall survival analysis from ARCHES: a phase 3, randomized, double-blind, placebo-controlled study of enzalutamide plus androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer [ESMO abstract LBA25]. Ann Oncol. 2021;32(suppl 5).
18. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986.
19. Davis ID, Martin AJ, Stockler MR, et al; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131.
20. Chi KN, Agarwal N, Bjartell A, et al; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24.
21. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20(5):686-700.
22. Fizazi K, Herrmann K, Krause BJ, et al. Health-related quality of life, pain and safety outcomes in the phase III VISION study of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer [ESMO abstract 576MO]. Ann Oncol. 2021;32(suppl 5).
23. Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103.
24. Sandhu S, Joshua AM, Emmett L, et al. PRINCE: interim analysis of the phase Ib study of 177Lu-PSMA-617 in combination with pembrolizumab for metastatic castration-resistant prostate cancer [ESMO abstract 577O]. Ann Oncol. 2021;32(suppl 5)
25. Nordquist LT, Yu EY, Piulats JM, et al. Pembrolizumab plus olaparib in patients with docetaxel-pretreated metastatic castration-resistant prostate cancer: updated results from KEYNOTE-365 cohort A with a minimum of 11 months of follow-up for all patients [AUA abstract M24-14]. J Urol. 2021;206(suppl 3).
26. Yu EY, Piulats JM, Gravis G, et al. KEYNOTE-365 cohort A updated results: pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) [ASCO GU abstract 100]. J Clin Oncol. 2020;38(6 suppl).
27. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708.
28. Graff JN, Tagawa S, Hoimes C, et al. Biomarker analysis of men with enzalutamide (enza)-resistant metastatic castration-resistant prostate cancer treated with pembrolizumab (pembro) + enza in KEYNOTE-199 [ESMO abstract 61MO]. Ann Oncol. 2021;32(suppl 5).
29. Graff JN, Beer TM, Alumkal JJ, et al. A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone. J Immunother Cancer. 2020;8(2):e000642.