Courtney Marabella 

Findings from the pivotal phase 3 PROfound trial presented during the 2021 AUA Annual Meeting provided fresh insight into the optimal use of olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Specifically, the investigators showed that the PARP inhibitor still produced a greater clinical benefit than enzalutamide (Erleada) or abiraterone acetate (Zytiga) in patients with mCRPC when the 2 novel hormonal agents (NHAs) were examined separately rather than combined.

The median radiographic progression-free survival (rPFS) with olaparib was 7.4 months vs 3.5 months (hazard ratio [HR], 0.35; 95% CI, 0.24-0.51) with abiraterone and 3.6 months (HR, 0.33; 95% CI, 0.21-0.52) with enzalutamide. Additionally, olaparib resulted in a median OS of 19.1 months vs 14.5 months (HR, 0.72; 95% CI, 0.48-1.11) with abiraterone and 14.9 months (HR, 0.65; 95% CI, 0.43-1.03) with enzalutamide.

Additionally, results from the trial indicated that there is limited benefit to sequential use of NHA and olaparib, suggesting that giving olaparib earlier in the treatment sequence may be beneficial.

“There is little, if any, benefit for sequential use of NHAs on rPFS, and this practice may actually be harmful by delaying the use of more effective therapies,” according to Fred Saad, MD, FRCS, professor and chairman of urology, as well as director of genitourinary oncology at the University of Montreal Hospital Center. “The practice of prescribing a second-line NHA needs revisiting, given available treatment options that are potentially superior when used in the appropriate patient population.”

PROfound (NCT02987543) was the first positive phase 3 trial with a PARP inhibitor conducted in patients with mCRPC; it was also the first phase 3 trial that was done in the post-NHA treatment setting. The trial enrolled patients with confirmed mCRPC who experienced disease progression on prior NHA treatment. Patients had to have alterations in at least 1 qualifying gene with a direct or indirect role in homologous recombination repair (HRR). Patients were stratified by previous taxane treatment received and measurable disease.

Cohort A of the study enrolled 245 patients with 

 mutations who were randomized 2:1 to receive either olaparib at 300 mg twice daily (n = 162) or enzalutamide or abiraterone (n = 83). Cohort B enrolled 142 patients with other alterations and randomized them 2:1 to olaparib at the same dose/schedule (n = 94) or enzalutamide or abiraterone (n = 48).

The primary end point for cohort A was rPFS per RECIST v1.1 criteria, Prostate Cancer Working Group 3 criteria, and blinded independent central review. Secondary end points included confirmed radiographic overall response rate in cohort A, rPFS in cohorts A and B, time to prostate-specific antigen (PSA) progression in cohort A, and OS in cohort A.

Across the 2 arms, 64.1% of patients had previous taxane use, 23.2% had metastatic disease at initial diagnosis, and 57% had measurable disease at baseline. Moreover, 31.5% had bone-only metastases, 33.5% had visceral metastases, and 29.0% had other metastases. The median baseline PSA was 87.55 μg/L, and 94.8% of patients had an ECOG performance status of 0 to 1.

Olaparib significantly prolonged rPFS and OS compared with physicians’ choice of enzalutamide or abiraterone in patients with alterations in 

 whose disease had progressed on a prior NHA.

Earlier data from the trial showed that the median rPFS with olaparib was 7.4 months vs 3.6 months in the control arm, which had combined data with enzalutamide and abiraterone (HR, 0.34; 95% CI, 0.25-0.47; 

 < .001). The median OS in the investigative and control arms was 19.1 months vs 14.7 months, respectively (HR, 0.69; 95% CI, 0.50-0.97; 

 = .02). Additionally, 43.1% of patients in the olaparib arm had a PSA response vs 7.8% of those in the control arm.

Olaparib was also found to have improved multiple clinical and patient-reported outcomes, and was thus, the PARP inhibitor was FDA approved for use in patients with mCRPC and qualifying alterations in HRR genes following treatment with enzalutamide or abiraterone.

Additional results were presented during the 2021 AUA Annual Meeting. Specifically, a multivariate analysis adjusted for key baseline characteristics such as prior taxane use, metastatic disease at initial diagnosis, site of disease, measurable disease, median PSA, and ECOG performance status, did not have an impact on the efficacy of olaparib with respect to rPFS and OS.

The adjusted analysis showed that the HR for rPFS was 0.33 (95% CI, 0.23-0.47); it was 0.34 (95% CI, 0.25-0.47) in the primary analysis. The adjusted analysis demonstrated that the HR for OS was 0.68 (95% CI, 0.45-1.04); it was 0.64 (95% CI, 0.43-0.97) in the primary analysis.

The best percentage change from baseline in PSA in cohort A with olaparib was 43.1% vs 7.8% with the control. These data suggest that best percentage change from baseline in PSA was not influenced by sequence of NHA.

“Twenty to twenty-five percent of patients with mCRPC are known to harbor deleterious alterations in genes with a role in HRR,” Saad said. “Therefore, routinely testing patients for alterations in HRR genes will enable patient-specific treatments to be considered that can make a real difference to patient outcomes.”

Combination therapies may build upon the efficacy achieved in PROfound and results from the phase 3 PROpel trial (NCT03732820) are highly anticipated, according to Saad.

1. Saad F, Shore N, Feyerabend S, et al. Efficacy of physician's choice of enzalutamide or abiraterone in the control arm of PROfound. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. PD34-09.

Articles

The latest findings for the PARP inhibitor in prostate cancer come from an analysis of the pivotal phase 3 PROfound trial presented during the 2021 AUA Annual Meeting.

Update offers clues to optimal olaparib use in prostate cancer

Findings shared during the 2021 AUA Annual Meeting showed that prior antiandrogen therapy had no impact on the efficacy of adding enzalutamide to androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Results from a posthoc analysis of the phase 3 ARCHES trial showed that the addition of enzalutamide to ADT reduced the risk of radiographic progression or death by 61% (95% CI, 0.30-0.50) vs ADT alone in the overall patient population. The hazard ratio (HR) for radiographic progression-free survival (rPFS) was 0.39 (95% CI, 0.26-0.59) in those who had received prior antiandrogen therapy, and 0.39 (95% CI, 0.29-0.54) in those who had not.

Notably, these results were maintained in a gonadotropin-releasing hormone agonist (GnRHa) sensitivity analysis, which controlled for potential confounding effects of GnRH antagonists and bilateral orchiectomies.

“Observed HRs for the prior antiandrogen subgroups were comparable to those [observed in] the overall population from the original ARCHES primary analysis of all end points,” lead study author Neal Shore, MD, FACS, medical director of the Carolina Urologic Research Center, said during an oral presentation on the data.

Enzalutamide is approved for use in patients with castration-resistant prostate cancer in multiple countries, and well as for those with mHSPC. The establishment the agent’s efficacy in those with metastatic hormone-sensitive disease was based on results from the ARCHES trial, as well as the phase 3 ENZAMET trial (NCT02446405), both of which demonstrated superior clinical outcomes with enzalutamide.

Patients with mHSPC often receive short-term first-generation antiandrogen treatment to prevent or block testosterone flares and symptomatic progression at the time that ADT is started. However, the impact of prior antiandrogen treatment on outcomes with enzalutamide is largely unknown.

Due to this, investigators conducted an analysis of the population enrolled to the ARCHES trial, as the study’s eligibility criteria permitted prior antiandrogen therapy. The objective of the analysis was to determine the impact of prior antiandrogen therapy on the efficacy of enzalutamide plus ADT vs placebo plus ADT in patients with mHSPC. Prior therapy could include short-term use, defined as 4 to 6 weeks of exposure, and longer-duration use.

In total, the ARCHES study enrolled a total of 1150 patients who were randomized 1:1 to receive either enzalutamide at dose of 160 mg daily plus ADT, or ADT alone. The primary end point of the study was rPFS.

To be eligible for enrollment, patients had to have a confirmed diagnosis of mHSPC, histologically confirmed adenocarcinoma, and an ECOG performance status of 0 or 1. Patients were stratified by volume of disease (low vs high) and prior docetaxel therapy (0 vs 1 to 5 vs 6 cycles. Discontinuation criteria for the study included radiographic progression, unacceptable toxicity, or initiation of an investigational agent or new therapy for prostate cancer.

For the post-hoc analysis, prior antiandrogen treatment was allowed if it was given concurrently with less than 6 months of ADT, using luteinizing hormone–releasing agonists/antagonists or bilateral orchiectomy before day 1.

The populations examined on the study included those in the overall population who did or did not receive prior antiandrogen therapy, those who received GnRH analogs with or without prior antiandrogen therapy, and those who received prior antiandrogen therapy for 1 month or less or more than 1 month.

The primary end point of the analyses was rPFS. Key secondary end points included time to prostate-specific antigen (PSA) progression, time to initiation of new antineoplastic therapy, time to castration resistance, PSA undetectable rate defined as PSA less than 0.2 ng/mL, time to first symptomatic skeletal event (SSE), overall response rate (ORR), and safety.

Among those who received prior antiandrogen therapy (n = 205 with enzalutamide/ADT and n = 230 with ADT alone), the median age across the arms was 69.5 years, 78.5% had an ECOG performance status of 0, 62% had high disease volume, and 69% had a Gleason score of 8 or higher at initial diagnosis. Sixty-eight percent of patients had distant metastasis at initial diagnosis, the median PSA at study entry was 3.33µg/L. Moreover, 22% of patients previously received docetaxel. Regarding ADT, 91.5% of patients received a GnRHa, 5.5% received a GnRH antagonist, and 1% received a bilateral orchiectomy.

Among those who did not previously receive antiandrogen agents (n = 369 with enzalutamide/ADT and n = 346 with ADT alone), the median age across the arms was 69.5 years, 77% had an ECOG performance status of 0, 64% had high disease volume, 64.5% had a Gleason score of 8 or higher at diagnosis, and 65.5% had distant metastasis at initial diagnosis. Moreover, the median PSA at study entry was 6.65 µg/L. Fifteen percent of patients received prior docetaxel. Moreover, 42% had a GnRHa, 34.5% had a GnRH antagonist, and 9.5% had a bilateral orchiectomy.

Additional data showed that the HR for time to PSA progression in the prior antiandrogen therapy group was 0.13 (95% CI, 0.07-0.025) vs 0.22 (95% CI, 0.15-0.32) in the no prior antiandrogen therapy group. As such, the treatment effect of enzalutamide/ADT on time to PSA progression was maintained vs ADT alone; this was true, irrespective of prior antiandrogen therapy, duration of antiandrogen use, or administration of GnRH analogs.

Regarding the time to new antineoplastic therapy, the HR was 0.19 (95% CI, 0.10-0.036) in the prior antiandrogen therapy group vs 0.37 (95% CI, 0.25-0.56) in the no prior antiandrogen therapy group. Again, the effect of enzalutamide/ADT on time to new antineoplastic therapy was maintained versus ADT alone.

In terms of time to castration resistance, the HR was 0.28 (95% CI, 0.19-0.41) in the prior antiandrogen therapy group vs 0.29 (95% CI, 0.21-0.39) in the no prior antiandrogen therapy group. Regarding the time to first SSE, the HR was 0.55 (95% CI, 0.28-1.11) in the prior antiandrogen therapy group vs 0.51 (95% CI, 0.29-0.89) in the no prior antiandrogen therapy group.

The PSA undetectable rate difference among the study arms was 50.3% (95% CI, 41.5%-59.1%) for those with prior antiandrogen therapy vs 51.4% (95% CI, 44.9%-57.9%) in those with no prior antiandrogen therapy. Enzalutamide plus ADT increased the proportion of patients with an objective response across treatment subsets. The ORR difference was 22.6% (95% CI, 7.2%-38.1%) vs 20.5% (95% CI, 9.4%-31.6%) in the 2 groups, respectively.

In terms of safety, the most frequently reported adverse effects included musculoskeletal events, fatigue, and hypertension, and no significant differences in the safety profile of enzalutamide plus ADT by prior antiandrogen therapy were observed.

1. Shore N, Iguchi T, Villers A, et al. Enzalutamide in metastatic hormone-sensitive prostate cancer patients who received prior antiandrogen therapy: post hoc analysis of ARCHES. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PD34-07.

The results come from a posthoc analysis of the pivotal phase 3 ARCHES trial.

Efficacy of enzalutamide in mHSPC unaffected by prior ADT

Data from the phase 2/3 QUILT-3.032 trial showed that the combination of the novel interleukin-15 superagonist N-803 (ALT-803) and Bacille Calmette-Guérin (BCG) achieved a complete response (CR) in nearly three-fourths of patients with BCG-unresponsive, non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS).

The results, which were presented during the 2021 American Urological Association Annual Meeting, showed that the novel combination reached a CR rate of 72% and a 58.6% probability of maintaining a CR for at least 12 months. Additionally, at a median follow-up of 20.4 months, the median duration of CR was 19.9 months.

“Eighty-five percent of our patients avoided a cystectomy,” according to lead study author Karim Chamie, MD, associate professor of urology at the University of California, Los Angeles. “This intravesical administration is quite favorable, and quite familiar amongst those who normally treat patients with BCG-unresponsive bladder cancer.”

N-803 is an interleukin-15 superagonist that activates and proliferates endogenous natural killer and CD8-positive T cells without inducing T-regulatory simulation.

QUILT-3.032 (NCT03022825) enrolled 81 patients with histologically confirmed BCG-unresponsive NMIBC, with persistent or recurrent CIS within 12 months of receiving adequate BGC treatment. Patients were treated with 50 mg of BCG plus 400 mg of intravesical N-803 weekly for 6 weeks, followed by re-induction for re-induction and maintenance for up to 3 years.

The primary end point was biopsy confirmed CR at 3 and 6 months, with a lower bound 95% confidence interval of at least 20%. Secondary end points included duration of CR, cystectomy avoidance, and time to cystectomy. Furthermore, safety end points included incidence of serious adverse effects (AEs) and immune AEs.

Notably, the analysis included patients who achieved a CR at 3 months, as well as those who achieved a CR after rescue and reinduction at 6 months.

Those were enrolled were heavily pretreated patients with a median of 5.0 transurethral resections of a bladder tumor, and a median of 12.0 prior BCG instillations. Additionally, 42% of patients had received prior treatment with chemotherapy, and 17% were previously treated with checkpoint inhibitors, vicinium, interferon, etc.

Additional data showed that among patients who achieved an initial complete response at 3 months, there was a 64% probability of maintaining that response at 12 months, and a 61% probability of maintaining it at 18 months.

Notably, as of May 2021, the combination showed a 30% durable response at 18 months. Eighty-five percent of patients have not progressed to radical cystectomy through a data analysis as of this time point, as well.

In terms of safety, the combination was well tolerated, with no incidence of treatment-related serious AEs, immune-related AEs, or treatment-related AEs (TRAEs) that were grade 4/5 in severity. Grade 3 TRAEs occurred in just 2 patients and included urinary tract infection and arthralgia. The most frequent grade 1/2 AEs were dysuria (22%), hematuria (16%), and pollakiuria (19%).

In comparison to other FDA-approved treatments for this patient population, N-803 plus BCG significantly improved outcomes. Previous data with pembrolizumab (Keytruda) showed that the agent induced at CR rate of 41% at any time, and a median duration of CR of 16.2 months at 24.1 months follow-up. Similarly, valrubicin elicited an 18% CR rate, and a median duration of CR of less than 6 months. Moreover, the cystectomy-free rate for the two drugs was 63% and 76%, respectively.

1. Chamie K, Chang S, Gonzalgo M, et al. Phase 2/3 clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in-situ (CIS) patients (cohort A). Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PD09-05.

Adding N-803 to Bacille Calmette-Guérin achieved a complete response in nearly three-fourths of patients with BCG-unresponsive, non-muscle invasive bladder cancer. 

IL-15 superagonist N-803 achieves strong antitumor activity in NMIBC

Results of the phase 2 SWOG 1500 study presented during the 2021 Genitourinary Cancers Symposium showed that cabozantinib (Cabometyx) significantly improved progression-free survival (PFS) versus sunitinib (Sutent) in patients with metastatic papillary renal cell carcinoma (pRCC).

The median PFS with cabozantinib was 9.0 months versus 5.6 months with sunitinib, translating to 40% reduction in the risk of disease progression or death (HR, 0.60; 

The agent also led to a significantly higher response rate relative to sunitinib, at 23% versus 4.0%, respectively, in this population (

 = .010). Complete responses were only observed among those who were given cabozantinib. Moreover, although sunitinib was also compared with crizotinib (Xalkori) and savolitinib (AZD6094), those arms of the study were terminated prematurely in a futility analysis, as neither showed benefit in PFS relative to sunitinib.

“Although discordances were observed in subtype classification, cabozantinib had a homogeneous effect across treatment groups,” presenting author Sumanta K. Pal, MD, FASCO, who is also a medical oncologist and assistant clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, said in an oral presentation of the data. “With this in mind, cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC.”

Papillary RCC is a rare malignancy, accounting for 15% of all RCC cases. VEGF-targeted therapies, such as sunitinib, have previously comprised the standard of care in these patients; however, the estimates of efficacy of these options vary, noted Pal. Response rates for these therapies across retrospective and prospective series, range from 0% to 24%, and PFS has ranged from 1.6 months to 8.0 months.

“To date, there have been no randomized data specifically in [patients with] papillary RCC showing an advantage of 1 systemic therapy over another,” Pal noted.

Multiple studies have suggested that the 

 proto-oncogene may be a potential driver of papillary RCC. Although it is more common in type I compared with type II disease, the 

 mutation and copy number alteration occur in a proportion of both subtypes. In the SWOG 1500 trial, investigators sought to determine whether different MET inhibitors could improve clinical outcome relative to sunitinib in patients with metastatic papillary RCC.

Notably, SWOG 1500 (NCT02761057) is the first randomized trial to exclusively enroll patients with metastatic papillary RCC and complete accrual. To be eligible for enrollment, patients had to have a histologically confirmed diagnosis of papillary RCC and measurable disease. Patients were permitted for inclusion if they had received 0 to 1 prior lines of therapy, provided they had not received previous treatment with sunitinib. Additionally, patients had to have a Zubrod performance status ranging from 0 to 1.

Patients were randomized 1:1:1:1 to the sunitinib, cabozantinib, crizotinib, or savolitinib arms. Participants were stratified based on disease subtype (type I vs II vs not otherwise specified [NOS] per local review) and number of prior therapies (0 vs 1). The primary end point of the study was PFS, while key secondary end points included overall survival (OS), response rate, adverse effects (AEs). Exploratory evaluations of 

A central component of the overall study design was the use of a coordinated central pathologic review, Pal noted. Images of tissues reviewed locally were secondarily reviewed by 3 central pathologists, and classified as either type I pRCC, type II pRCC, or pRCC NOS. Mixed features in specimens were deemed pRCC NOS, and any disagreements in specimen type were classified by majority opinion. If no agreement was reached, specimens were either re-reviewed or classified as pRCC NOS, explained Pal.

Notably, the study design permitted dose reduction for each agent used. In the trial, oral sunitinib was delivered on the conventional 4-weeks-on, 2-weeks-off schedule, at a daily dose of 50 mg, with dose reductions to 37.5 mg and 25 mg permitted. Oral cabozantinib was delivered at a daily dose of 60 mg, with dose reductions to 40 mg and 20 mg allowed. Moreover, oral crizotinib was given at a twice-daily dose of 250 mg, with reductions to twice-daily 200 mg and once-daily 250 mg permitted. Lastly, oral savolitinib was administered at a daily dose of 600 mg, with dose reductions to 400 mg and 200 mg allowed.

Investigators’ key assumptions were that PFS for sunitinib would be approximately 6 months, with comparator arms achieving a PFS of 10.5 months. As is standard for a randomized phase 2 study, investigators explored a 1-sided a of 0.1 with a b of 85%. With these considerations in mind, 41 patient per study arm would be required, for a total of 164 patients overall. In accounting for 10% ineligible patients, investigators assumed they would need to accrue an additional 4 patients per study arm, for a total of 180 patients.

Additionally, a prespecified futility analysis was implemented after 15 PFS events were reported in each of the experimental arms and 20 PFS events occurred in the sunitinib arm. If the PFS HR was greater than 1 for a MET inhibitor versus sunitinib, the arm was recommended for closure.

From April 2016 to December 2019, a total of 152 patients were enrolled to the SWOG 1500 trial at 65 cancer centers across the United States and Canada. As a result of the futility analysis, the savolitinib and crizotinib arms were closed in December 2018.

Patients had a median age of 66 years (range, 29-89), and the majority were male (75%) and white (77%). Few patients had received prior systemic therapy (7%), and as anticipated by investigators, a minority of patients had type I histology, ranging from 17% to 20% across study arms. Additionally, the majority of patients had intermediate risk by International Metastatic RCC Database Consortium Risk Group criteria (61%). Moreover, 61% had a performance status of 0, while 39% had a status of 1. Mixed histologies were observed in 15% to 24% of patients and over 70% of patients had prior nephrectomy. Few patients had central nervous system metastases (less than 1%).

A preliminary assessment of discordances based on pathologic subtype was also presented. Thirteen patients were categorized by local assessment with type I disease and they were noted to have type 2 disease on central assessment, Pal said. In contrast, 3 patients with type II disease per local assessment were characterized to have type I by central assessment.

“Ultimately these didn’t appear to have a key bearing on the key finding from our study,” said Pal. “Irrespective of central and local assessment, patients with type I and type II disease appeared to have benefit with cabozantinib.”

OS will continue to be followed among studies arms, but in a preliminary assessment, no significant differences were seen between the arms examined, said Pal. Notably, however, there is a slight trend toward improved OS in the cabozantinib arm relative to the sunitinib arm, at 20.0 months versus 16.4 months, respectively.

Grade 3/4 AEs were reported in 68% of patients in the sunitinib arm, 74% of patients in the cabozantinib arm, 37% of patients in the crizotinib arm, and 39% of patients in the savolitinib arm. Toxicities seen with the agents in SWOG 1500 were similar to those reported in larger studies, noted Pal. Moreover, the rate of treatment discontinuation due to AEs linked with study medication was highest with sunitinib (24%), followed by cabozantinib (23%), crizotinib (16%), and savolitinib (10%). Sixteen patients remained on protocol at the time of last follow-up.

Grade 3/4 laboratory toxicities with sunitinib, cabozantinib, crizotinib, and savolitinib occurred in 68%, 74%, 37%, and 39%, of patients, respectively. One grade 5 effect was observed in the cabozantinib arm, secondary to a thromboembolic event, concluded Pal.

1. Sumanta K. Pal, Catherine Tangen, et al. Sunitinib versus cabozantinib, crizotinib or savolitinib in metastatic papillary renal cell carcinoma (pRCC): Results from the randomized phase II SWOG 1500 study. 

. 2021;339(suppl 6):270. doi:10.1200/JCO.2021.39.6_suppl.270

Papillary renal cell carcinoma (RCC) is a rare malignancy, accounting for 15% of all RCC cases. 

Courtney Marabella

Articles

Update offers clues to optimal olaparib use in prostate cancer

Efficacy of enzalutamide in mHSPC unaffected by prior ADT

IL-15 superagonist N-803 achieves strong antitumor activity in NMIBC

Cabozantinib significantly delays progression in papillary RCC