Library Resources

Introduction

Intravesical Bacillus Calmette-Guerin (BCG) currently remains the standard of care, guideline recommended treatment of choice in the adjuvant setting for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) due to its ability to reduce the risk of disease recurrence and disease progression.^1-3 However, despite adequate BCG, up to 50% of patients develop a BCG-refractory, relapsing, or failure disease state.⁴ Currently, radical cystectomy remains the gold standard approach in this setting.¹ However, many patients are either unfit or refuse cystectomy.

Given the shortage of options in this disease space, along with the modest efficacy of Valstar (21% complete response with a median response duration of one year),⁵ in 2018 the FDA issued a guidance document to promote the development of drugs and biologics for BCG-unresponsive NMIBC:⁶

• Persistent or recurrent CIS within 12 months of adequate BCG therapy
• Recurrent high-grade Ta/T1 disease within six months of completion of adequate BCG therapy
• High-grade T1 disease detected on the first evaluation following an induction BCG course

The focus of this Center of Excellence article is to highlight the currently available evidence and ongoing studies for Nogapendekin alfa-inbakicept (NAI; Anktiva, ie. N-803) in NMIBC in the BCG-unresponsive disease space, as well as other ongoing trials in progress for other indications.

QUILT-3.032: Initial Results

Impaired T-cell and cytotoxic cellular response play a key role in the development of BCG failure for patients with NMIBC. N-803 is an interleukin-15 (IL-15) superagonist that acts as an activation and proliferation factor for natural killer and effector/memory T-cells: 

Given that BCG has been shown to establish ‘trained immunity’ as the molecular basis for its immunotherapeutic effect in bladder cancer, it has been hypothesized that N-803 could further enhance the immune response by mediating a second, unrelated stimulus.

QUILT-3.032 is an ongoing, open label, multicenter, single arm trial that is evaluating intravesical N-803 + BCG or N-803 alone in patients with BCG-unresponsive, high-grade NMIBC⁷. This study includes three patient cohorts⁸:

• Cohort A (CIS +/- papillary disease): Intravesical N-803 (400 μg/instillation) + BCG (50 mg/installation) given once weekly for 6 consecutive weeks (induction)
• Cohort B (High grade Ta/T1 papillary disease): N-803 + BCG
• Cohort C (CIS +/- papillary): N-803 alone 

In this trial, surveillance included a cystoscopy + urinary cytology every 3 months for the first 24 months, followed by every six months thereafter until 60 months. Importantly, biopsy was mandated at week 12 in all patients, irrespective of cystoscopy or cytology findings. Re-induction was offered to patients without a complete response, conditional on the absence of T1 or worse disease in the specimen. These patients would then undergo a mandatory 6-month biopsy. The primary endpoints in Cohorts A and C were 3- and 6-month complete response, defined by one of the following three scenarios:

• Negative cystoscopy and cytology (including atypical cytology)
• Biopsy-proven benign or low-grade Ta disease and negative cytology
• Negative cystoscopy with malignant urinary cytology, if cancer found in the upper tract or prostatic urethra and random bladder biopsies were negative

In Cohort A (n = 82), a complete response was observed in 71% of patients (13/58 responders required a re-induction). Response rates were as follows:

• 3 months: 55%
• 6 months: 56%
• 12 months: 45%

The median duration of response in complete responders was 26.6 months. The 24-month progression-free, overall, and disease-specific survival rates were 85%, 94%, and 100% respectively.  

In 72 evaluable patients in Cohort B, the median disease-free survival was 19.3 months (95% CI 7.4 – NR), with disease-free survival rates as follows:

• 12 months: 55.4% (95% CI 42.0 – 66.8)
• 18 months: 51.1% (95% CI 37.6 – 63.1)
• 24 months: 48.3% (95% CI 34.5 – 60.7) 

The 24-months progression-free, overall, and disease-specific survival rates were 88.8%, 91.7%, and 97.7%, respectively.

In the 10 evaluable patients in Cohort C, a complete response at 3 months was observed in only 2 (20%) patients with N-803 alone. Of the 8 initial non-responders, 6 underwent re-induction with only 1 of these 6 patients demonstrating evidence of a complete response at 6 months. On the basis of protocol-defined stopping rules, the independent data monitoring committee recommended that cohort C be discontinued for futility.

The most common treatment-related adverse events with the combination of N-803 + BCG were lower genitourinary in nature (dysuria, pollakiuria, hematuria). The incidence of grade 3 or worse adverse events was 23%, most frequently hematuria and urinary tract infections (2% each). One patient experienced a grade 5 treatment-related adverse event (cardiac arrest with subsequent death) and 3 had evidence of immune-related adverse events:⁷ 

QUILT-3.032: After the Initial Results

On April 22, 2024, the Food and Drug Administration (FDA) approved N-803 + BCG for patients with BCG-unresponsive NMIBC with CIS +/- papillary tumors based on results from the QUILT-3.032 trial.

Quality of Life Assessment

In Cohort A, the mean baseline ECOG score was 0.183, with 82% of patients having a score of 0. Quality of life was measured by the EORTC QOL Questionnaire Core 30 (QLQ-C30) and QOL NIMBC-Specific 24 Questionnaire (QLQ-NMIBC24). During the study, hospitalizations for any reason remained low (0% - 6% per assessment). Moreover, participant quality of life from completion rate was high, with 90% or greater at most time points. There was a modest decrease in mean physical function and global health from baseline at all assessed on-study time points that became less by week 104: 

When responders (those with a complete response) were compared with non-responders, they showed less of a decrease in physical function and global health scores with time, although both parameters were higher at baseline for responders: 

At month 12, >3 prior TURBTs were significantly associated (p = 0.0729) with lower global health scores as compared to <= prior TURBTs. At month 6, achievement of complete response was associated (p = 0.0659) with higher physical function scores as compared to no complete response. No other baseline variable had a significant level of association: 

QUILT-3.032 Updated Results

At AUA 2024, Dr. Patrick Soon-Shiong presented updated results of the QUILT-3.032 trial. At the time of the data cutoff of November 30, 2023, patients with an ongoing complete response at month 25 and later, maintenance instillations were administered once a week for 3 weeks at months 25, 31, and 37 for a maximum of 9 additional instillations. In this highly pre-treated group, the complete response rate was 65%. Among patients who had received ≥12 prior BCG doses (n = 74), the complete response rate was 69%. Conversely, among those who received <12 doses of prior BCG, the complete response rate was 70%. A total of 53 patients were BCG-unresponsive/BCG-relapsed, and the complete response rate in this group was 72%. Thus, both BCG-unresponsive/BCG-refractory and BCG-unresponsive/BCG-relapsed had complete response rates comparable to the efficacy population. The median duration of response was 26.6 months (95% CI: 0.9 – not reached). By the Kaplan-Meier method, 61.3% of subjects had a duration of complete response lasting >12 months and 53.2% had a duration of >24 months.

Looking Ahead: QUILT-2.005 in BCG-Naïve Patents

Also at AUA 2024, Dr. Sandeep Reddy discussed the QUILT-2.005 trial comparing intravesical BCG in combination with N-803 to BCG alone in patients with BCG-naïve NMIBC. In phase 1 of this trial, there was durable complete remission among 9 patients with CIS and papillary NMIBC treated with BCG + N-803. As requested by the Agency, there was an unplanned interim analysis of the efficacy results in CIS patients for the phase 2 QUILT-2.005 trial, which showed an improvement in complete response rate over time and contribution of effect of N-803 inducing memory T-cells

The trial design for the phase IIb QUILT-2.005 is for participants to be randomized 1:1 to one of two independent treatment arms based on disease and ECOG status. Participants receive either intravesical 400 ug N-803/instillation + 50 mg BCG or BCG alone weekly for six consecutive weeks, followed by maintenance treatment for 3 consecutive weeks at 3, 6, 12, and 18 months. At 3 months, re-induction with another 6 weeks of therapy for eligible patients is an option. Cohort A of QUILT-2.005 will have CIS +/- Ta or T1 disease patients, and Cohort B will have high grade papillary Ta or 1 disease patients. Participants must have a diagnostic biopsy within 3 months of treatment start and a cystoscopy demonstrating no resectable disease within 6 weeks. Participants must be BCG-naïve (or last BCG > 3 years prior) and have not received more than a single post-operative dose of mitomycin C or gemcitabine following the most recent screening TURBT/biopsy.

The primary outcomes of QUILT-2.005 are complete response rate and disease free survival with the time frames of 12 and 24 months, respectively. The complete response rate for Cohort A and disease free survival for Cohort B will be compared between treatment arms using cystoscopy, confirmatory biopsy and urine cytology. Safety will be assessed by number/severity of treatment related adverse events over 48 months. As of April 2024, cohort A had enrolled 121 of 366 planned participants, and cohort B had enrolled 74 of 230 planned participants. 

N-803 + BCG Logistics and Insurance Coverage

In May 2024, it was announced that ImmunityBio had signed a global agreement with Serum Institute of India (the world’s largest manufacturer of vaccines) to supply ImmunityBio with BCG. The agreement covers manufacturing of standard BCG (approved outside of the US), as well as next generation recombinant BCG (undergoing testing), for the intended use in combination with N-803. Importantly, the aim of this deal is to increase the available supply of BCG and address shortages for the combination with N-803. Furthermore, there are plans to conduct clinical trials to study recombination BCG and standard BCG manufactured by Serum Institute in combination with N-803 for NMIBC.

As of August 2024, N-803 is approved for coverage by more than a dozen insurance plans (corresponding to ~100 million individuals), only months after the FDA approval in the US. Additionally, ImmunityBio has filed for EMA regulatory approval in the European Union, as well as approval to enroll patients in India for the QUILT-2.005 trial. Plans are also underway to apply for approval in South Africa to enroll patients in QUILT-2.005.

Conclusions

Results from the QUILT-3.032 trial in BCG-unresponsive NIMBC have led to the FDA approval of N-803 + BCG in 2024. Importantly, this combination therapy is now approved by several insurance plans and has been recognized as a therapeutic option in the NCCN guidelines. In light of the global BCG shortages, ImmunityBio has successfully partnered with Serum Institute of India to increase BCG availability. Results of the ongoing QUILT-2.005 trial in BCG naïve NMIBC are eagerly anticipated, with continued site expansion in the US, as well as India and potentially South Africa.

Published November 2024

Introduction

Introduction

At the ESMO 2024 annual meeting in Barcelona, Spain, the results of numerous practice-changing trials were presented, including those from three highly-anticipated clinical trials in the advanced prostate cancer space:

ESMO 2024 Quick Take Insights: A Focus on PEACE-3

The ESMO 2024 annual meeting in Barcelona, Spain, featured many practice-changing trials and hypothesis-generating data in genitourinary cancer. One of the most highly anticipated trials in the metastatic castration-resistant prostate cancer (mCRPC) disease space was the phase III PEACE-3 trial – the focus of this ESMO 2024 Quick Take Insights.

ESMO 2024 Quick Take Insights: A Focus on SPLASH

The ESMO 2024 annual meeting in Barcelona, Spain, featured many practice-changing trials and hypothesis-generating data in genitourinary cancer. One of the most highly anticipated trials in the metastatic castration-resistant prostate cancer (mCRPC) disease space was the phase III SPLASH trial – the focus of this ESMO 2024 Quick Take Insights.

Introduction

Classical theories of metastasis have followed ‘the seed and soil’ hypothesis, the Halstedian model, which proposes an orderly spread of disease from local to distant sites, with the presumption that cancer is an inherently systemic process even in the earliest cases. More contemporary spectrum theories now suggest that the propensity for distant spread exists along a ‘metastatic continuum’. Tumors with limited metastatic potential (i.e., oligometastases) represent a unique subset along this spectrum that could be potentially cured with local ablative therapy (i.e., metastasis-directed therapy [MDT]). This concept is not unique to prostate cancer and has been evaluated in other disease sites including non-small cell lung, colorectal, esophageal, and breast cancers.¹

The majority of the evidence for MDT in the prostate cancer space, to date, has been for patients with recurrent, oligometastatic hormone sensitive prostate cancer. MDT has been evaluated both in lieu of, to avoid/delay the use of systemic therapy, and in combination with systemic therapy to potentially improve efficacy outcomes. In this Center of Excellence article, we discuss the evidence and practical applications for MDT in the recurrent oligometastatic hormone sensitive setting.

Trials of MDT versus Observation/Surveillance for Recurrent Oligometastatic Prostate Cancer

To date, three prospective phase II trials have compared MDT to observation for patients with recurrent oligometastatic hormone sensitive prostate cancer.

The STOMP trial was a multicenter, randomized phase II trial that prospectively evaluated the effects of MDT for eugonadal men with evidence of oligometastatic disease on choline PET/CT (up to three extracranial sites) who had received prior treatment with curative intent and had evidence of biochemical recurrence. Between 2012 and 2015, 62 patients were randomized 1:1 to either surveillance or MDT, consisting of stereotactic body radiotherapy (SBRT) or metastasectomy. The primary endpoint was time to initiation of ADT (i.e., ADT-free survival). ADT was initiated for symptoms, progression beyond three metastases, or local progression of known metastatic disease

After a median follow up of 5.3 years, the five-year ADT-free survival was 8% in the surveillance arm compared to 34% for the MDT group (HR: 0.57, 95% CI: 0.38–0.84, log-rank p = 0.06). No differences were seen between groups when stratified by nodal versus non-nodal metastases:

The secondary endpoint of 5-year CRPC-free survival was 53% in subjects under surveillance and 76% in those receiving MDT (HR 0.62, 80% CI: 0.35-1.09):² 

The ORIOLE trial was a randomized phase II trial of men with recurrent oligometastatic hormone-sensitive prostate cancer (up to three sites). Between 2016 and 2018, 80 men were screened, of which 54 men had 1 to 3 metastases detectable by conventional imaging and had not received ADT within 6 months of enrollment or 3 or more years total. These 54 men were randomized in a 2:1 fashion to receive SBRT or observation. The primary outcome was disease progression at 6 months, defined by a serum PSA increase, radiographic progression on conventional imaging, symptomatic progression, ADT initiation for any reason, or death. 

After a median follow-up of 19 months, disease progression at six months occurred in 19% of patients in the SBRT arm versus 61% of patients in the observation arm (p = 0.005). Patients in the SBRT treatment arm had superior median progression-free survival rates (median: not reached versus 5.8 months; HR: 0.30; 95% CI: 0.11–0.81; p = 0.002):

Secondary to the blinding of the investigative team to the PSMA-targeted PET data during treatment planning, 16 of 36 men treated with SBRT had baseline PET-avid lesions that were not included in the treatment fields. The proportion of men with no untreated lesions with progression at 6 months was 1 of 19 (5%) compared with 6 of 16 (38%) for those with any untreated lesions (p = 0.03). The median progression free survival was unreached among men with no untreated lesions vs 11.8 months among participants with any untreated lesions (HR, 0.26; 95% CI, 0.09-0.76; p = 0.006):³

As such, this was among the first data to suggest the importance of treating all PSMA PET-visible lesions for maximal oncologic benefit in the oligometastatic mHSPC space. 

In 2022, pooled data from the ORIOLE and STOMP trials demonstrated that MDT improves progression free survival from 5.9 months to 11.9 months (HR: 0.44, p<0.001), however without any significant improvements seen in radiographic progression-free survival, time to castration-resistant disease, or overall survival:⁴

SABR-COMET was a randomized, open-label phase II study of patients with oligometastatic disease (up to five sites) between February 2012 and August 2016. This trial was not restricted to patients with prostate cancer and also included lung, breast, and colorectal cancer patients. Of the 99 patients in this trial, 18 (18.2%) had prostate cancer. After stratifying by the number of metastases (1–3 versus 4–5), patients were randomized in a 1:2 fashion to receive either palliative standard of care alone or standard of care plus SBRT. 

At a median follow-up of 5.7 years, the primary outcome of overall survival was superior for SBRT-treated patients. The 8-year overall survival rates were 27% and 14% in the intervention and control arms, respectively (HR: 0.50, 95% CI: 0.30–0.84, p = 0.008). The 8-year progression-free survival estimates were 21% and 0%, respectively (HR: 0.45, 95% CI: 0.28–0.72, p < 0.001):

The rates of grade ≥2 acute or late toxic effects were 30% versus 9% (p = 0.019), and the FACT-G quality of life scores declined over time in both arms, but with no differences in quality-of-life scores between the study arms.⁵ 

Combination of MDT + Systemic Therapy for Recurrent Oligometastatic Prostate Cancer

The EXTEND trial was a single center, phase II randomized controlled trial of 87 oligorecurrent men, mostly with mHSPC (>90%), who were randomized 1:1 to intermittent hormone therapy +/- MDT (definitive radiation therapy to all sites of disease). All patients had ≤5 metastases, as defined by conventional imaging (75%) or fluciclovine PET/CT (25%). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. At a median follow-up of 22 months, progression free survival was improved in the combined therapy arm (HR: 0.25, 95% CI: 0.12 – 0.55, p < 0.001). Significantly, ‘eugonadal’ progression free survival was also improved with this combination approach (HR: 0.32, p = 0.03):⁶

SATURN is a phase II trial of 28 men with oligorecurrent extra-pelvic metastases on PSMA-PET/CT following initial treatment with radical prostatectomy. Patients were treated with 6 months of ‘androgen annihilation therapy’, defined as leuprolide + abiraterone acetate/prednisone + apalutamide. After the 1^st month of this systemic therapy, patients received SBRT to all metastases with or without radiotherapy directed to the prostate bed and pelvic lymph nodes. Results of the primary endpoint, the percentage of patients who maintained PSA <0.05 ng/mL six months after testosterone recovery to ≥150 ng/dL, were presented at ASCO GU 2024. Overall, 50% of patients maintained a PSA <0.05 ng/mL six months after testosterone recovery. After a median follow-up of 20 months, the median progression free survival was 19.3 months. Moreover, 81% of patients recovered eugonadal testosterone levels, at a median of 9.4 months from the start of systemic therapy, and the median eugonadal progression free survival was 11.4 months. Grade 3 adverse events related to androgen therapy were observed in 21% of patients, and SBRT had 7.7% grade 2 and no grade 3 toxicity.⁹

There are several important ongoing trials combining systemic therapy with the site specific control offered by MDT. The ADOPT trial is an ongoing phase III trial that is randomizing 280 patients with evidence of recurrent oligometastatic disease (≤4 lesions) on PSMA-PET/CT 1:1 to either MDT (radiotherapy) alone or MDT + 6 months of ADT. The primary endpoint of this trial is 30 month metastases progression free survival, with key secondary endpoints including overall survival, adverse events, and quality of life outcomes:⁷

NRG GU011 (PROMETHEAN) is a randomized phase II trial of SBRT with or without relugolix for early PET-detected recurrent oligometastatic prostate cancer. Eligible patients are those with biochemical recurrence following prior curative intent radiation or surgery for localized prostate cancer, PSA < 10 ng/mL, negative conventional imaging, and 1–5 PET-visible metastases (≥1 extra-pelvic). The primary endpoint is conventional imaging-based radiographic progression free survival. Key secondary endpoints include PET-based radiographic progression free survival, overall survival, and quality-of-life outcome measures:

The VA STARPORT study is a phase II/III randomized trial that evaluates the value of adding PET-directed local therapy to standard systemic therapy for biochemically recurrent patients with evidence of ≤5 metastatic lesions on PSMA-PET/CT. PET-directed local therapy is defined as surgery or radiation to all visible metastases and any prostate/prostatectomy bed local recurrences. Systemic therapy will be administered indefinitely, consistent with current guidelines. The primary study endpoint is castrate-resistant prostate cancer-free survival. Key secondary endpoints include clinical and radiographic progression free survival, overall survival, toxicity, and quality of life outcomes:

PERSIAN is a randomized phase II trial of recurrent oligometastatic, hormone-sensitive patients (<5 non-visceral lesions). Eligible patients will undergo 1:1 randomization to apalutamide + ADT +/- SBRT to all visible lesions. The primary outcome is 6-month complete biochemical response. The trial design and key secondary endpoints are illustrated below:

The POSTCARD GETUG P13 is a French randomized phase II trial that is randomizing patients with recurrent oligometastatic disease following primary local therapy with curative intent to either SBRT alone (to all visible metastases) or SBRT + durvalumab. Oligometastasis is defined as ≤5 bone or lymph node metastases on ⁶⁸Ga-PSMA PET/CT or ≤3 bone or lymph node metastases on ¹⁸F-choline PET/CT. The primary endpoint is two-year progression-free survival, with key secondary endpoints of androgen deprivation therapy free survival, quality of life, toxicity, prostate cancer specific survival, overall survival, and immune response.⁸

Incorporating PSMA-PET/CT into the MDT Paradigm

The next ‘frontier’ of MDT trials is incorporating PSMA-PET/CT for staging oligometastatic patients and determining eligibility for MDT. Given the increased sensitivity of PSMA-PET/CT compared to conventional imaging,¹⁰ it is likely that this may lead to a ‘stage migration’ phenomenon, where future cohorts of oligometastatic prostate cancer patients, matched for the same number of metastatic lesions, have more favorable prognoses. However, there has been a shift away from defining the ‘upper limit’ of oligometastatic disease by the number of metastatic lesions. A recent survey of participants from the ESTRO-ASTRO consensus conference demonstrated that the majority of respondents concur that the ‘upper limit’ of oligometastatic disease should be defined by the ability to safely deliver curative intent metastasis-directed radiotherapy and not by the number of metastatic lesions.

Existing evidence suggests that PSMA-PET/CT provides additional information in patients with evidence of recurrent oligometastatic disease on conventional imaging. In the ORIOLE trial, as highlighted above, pre-treatment ¹⁸F-DCFPyL-PET/CT was performed in all patients assigned to the MDT arm (n = 36). Of the 36 patients treated with SBRT, 16 (44.4%) had baseline PET-avid lesions that were not included in the treatment fields. These patients had significantly worse 6-month progression rates of 38% compared to those without untreated lesions (5%; p = 0.03). Furthermore, those with untreated sites of disease had higher rates of new metastases (per conventional imaging) at 6 months (62.5% versus 15.8%, p = 0.006), and worse median distant metastasis-free survival of 6 versus 29 months (HR: 0.19; 95% CI: 0.07–0.54, p < 0.001). These results highlight the importance of targeting all sites of disease, and the value of PSMA PET/CT for defining this with increased sensitivity compared to conventional imaging.³

A single arm phase II study evaluated the role of MDT (SBRT or surgery) in 37 patients with a rising PSA (0.4–3 ng/ml) following maximal local therapy (radical prostatectomy + adjuvant/salvage radiotherapy) who had not received prior salvage hormonal therapy and had negative conventional imaging, but evidence of oligometastasis on ¹⁸F-DCFPyL PET-MR/CT. Ten and 27 patients underwent surgery and SBRT, respectively. At a median follow-up of 16 months, the overall response rate was 60%, including 22% who had biochemical ‘no evidence of disease. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed.¹¹

MDT for De Novo Oligometastatic Hormone-sensitive Prostate Cancer

There are numerous ongoing trials evaluating the role of MDT in combination with systemic therapy in the de novo oligometastatic hormone-sensitive setting. In this section, we will highlight key trials in this space.

SOLAR (NCT03298087) is a single arm phase II trial of 28 patients with de novo M1a/b disease and 1–5 radiographically visible M1 lesions (majority detected via PSMA PET-CT) who all underwent radical local treatment, intensified systemic therapy for six months (leuprolide, abiraterone acetate with prednisone, apalutamide), and metastasis-directed SBRT. Radical local therapy was either radical prostatectomy (n = 12) with lymph node dissection and postoperative radiotherapy (for ≥pT3a, N1, or positive margins) or radical radiotherapy (n=12) directed to the prostate, seminal vesicles, and pelvic lymph nodes. The initial results of this trial were presented at GU ASCO 2024. At a median follow-up of 30 months, 62% of patients completed all planned systemic therapy without dose modification. Of the 22 patients with >6 months follow-up after testosterone recovery, 86% remained free of any progression, defined as an undetectable serum PSA after radical prostatectomy or <2 ng/ml after radical radiotherapy. Grade 2 and 3 toxicities for primary tumor therapy were 46% and 4%, respectively. There were no grade 2–3 toxicities relating to SBRT.¹²

PLATON (NCT03784755) is a two-arm phase II RCT exploring sequential treatment with ADT +/- chemotherapy followed by cytoreductive prostatectomy or external beam radiotherapy and then SBRT for oligometastases in 410 men. The comparator arm consists of systemic therapy alone, although low-volume men will be allowed to receive conventional local prostate radiotherapy. The primary study outcome is failure-free survival:

IP2-ATLANTA (NCT03763253) is a three-arm phase II randomized trial exploring sequential systemic, local, physical cytoreductive therapy and finally SBRT versus standard of care in 918 men with any-volume metastatic disease. All patients will receive doublet systemic therapy (ADT + docetaxel or enzalutamide or abiraterone). Patients in experimental arm 1 will receive minimally invasive ablative therapy +/- lymph node dissection, whereas those randomized to experimental arm 2 will receive local external beam radiotherapy +/- lymph nodes or radical prostatectomy +/- pelvic lymph node dissection. Patients in both experimental arms will further receive SBRT to oligometastases following receipt of of systemic and local treatment. Patients in the control arm will receive planned systemic therapy only, although patients with low-volume metastases will be eligible for prostate external beam radiotherapy:¹³

Finally, TERPs (NCT05223803) is a phase II trial of patients with de novo oligometastatic disease (<3 on conventional imaging or <5 on PET/CT) who will be randomized 1:1 to best systemic therapy + primary prostate radiotherapy +/- MDT (SBRT). The primary study endpoint is two-year failure-free survival.¹⁴

Conclusions and Future Directions

MDT has emerged as a guideline-recommended treatment option for prostate cancer patients with oligometastatic disease. The evidence to date suggests that MDT can be used in lieu of systemic therapy to delay time-to-hormone therapy or in combination with systemic therapy as a consolidative measure. The latest NCCN guidelines recommend considering SBRT for MDT in oligometastatic patients when ablation is the goal or in oligometastatic patients with limited progression or limited residual disease on otherwise effective systemic therapy (i.e., consolidation), where progression free survival is the goal.

The next ‘frontier’ of clinical trials for MDT will be evaluating its efficacy and safety in patients with PSMA-PET/CT-defined oligometastases and defining its role in the de novo metastatic hormone-sensitive setting. The results of these exciting trials will become available over the next few years.

Published August 2024

Introduction

The treatment landscape of metastatic castrate-resistant prostate cancer (mCRPC) has long been dominated by androgen receptor pathway inhibitors (ARPIs) and chemotherapeutic agents. There are currently, however, two radioligands that are United States Food and Drug Administration (FDA)-approved for the treatment of mCRPC patients:

Click Here to View or Download the Full PDF 

Introduction

Introduction

• Olaparib plus abiraterone for BRCA1/2-mutated patients⁵
• Niraparib plus abiraterone for BRCA1/2-mutated patients⁶
• Talazoparib plus enzalutamide for HRR-mutated patients⁷

PARP Inhibitors + Radium-223

PARP Inhibitors + 177Lu-PSMA-617

• PSMA SUVmax >15 at any site
• SUVmax >10 at other sites
• No FDG discordance

PARP Inhibitors + Immune Checkpoint Inhibitors

• Cohort A1: Post-chemotherapy mCRPC (1–2 taxanes and ≤2 ARPIs)
• Cohort A2: Chemotherapy-naïve mCRPC (Received prior ARPI)

PARP Inhibitors + Bipolar Androgen Therapy

PARP Inhibitors + Chemotherapy

PARP Inhibitors + Targeted Therapies

Conclusions and Future Trials

Introduction

Over the past decade, there have been significant advances in defining the genomic landscape of prostate cancer. The landmark study by Pritchard et al. published in The New England Journal of Medicine in 2016 demonstrated that germline DNA-repair gene mutations were present in approximately 12% of metastatic prostate cancer patients, most commonly BRCA2 (5.3%), CHEK2 (1.9%), and ATM (1.6%). Significantly, the frequency of such mutations increases across the prostate cancer spectrum – 2% in patients with NCCN localized low-to-intermediate risk tumors, 6% in those with localized high-risk tumors, and as high as 24% in patients with metastatic castrate-resistant prostate cancer (mCRPC).¹ This is of utmost clinical importance as such mutations, both inherited and acquired (i.e., somatic), represent actionable clinical targets for drug therapy.

Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are drugs that prevent the repair of DNA single-stranded breaks and promote their conversion to double-stranded breaks leading to a synthetic lethality. These agents are most effective in homologous recombination repair (HRR)-deficient tumors (e.g., BRCA1/2), due to their compromised ability to repair DNA double strand breaks.² In addition to breast and ovarian malignancies, PARP inhibitors have gained regulatory approval for the treatment of mCRPC patients:

• Rucaparib for BRCA1/2-mutated patients (FDA approved in 2020)³
• Olaparib for HRR-mutated patients (FDA approved in 2020)⁴
• Olaparib plus abiraterone for BRCA1/2-mutated patients (FDA approved in 2023)⁵
• Niraparib plus abiraterone for BRCA1/2-mutated patients (FDA approved in 2023)⁶
• Talazoparib plus enzalutamide for HRR-mutated patients (FDA approved in 2023)⁷

In this Center of Excellence article, we will provide an in-depth overview of the current evidence for PARP inhibitor monotherapy in prostate cancer, summarizing efficacy results from major trials and discussing the adverse event profile of these agents.

Current Evidence for PARP Inhibitor Monotherapy

Olaparib

TOPARP-A was a pivotal phase II trial of olaparib in mCRPC in which 50 patients were treated with olaparib 400 mg twice daily until disease progression.⁸ The primary endpoint was the composite response rate defined either as an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, or a ≥ 50% reduction in prostate-specific antigen (PSA50), or a reduction in the circulating tumor-cell count from ≥ 5 per 7.5 ml of blood to < 5 per 7.5 ml. All patients had prior treatment with docetaxel and 49 (98%) with abiraterone or enzalutamide. Sixteen of 49 (33%) evaluable patients had a response. Overall, 14 of the 16 responders had homozygous deletions, deleterious mutations, or both in DNA-repair genes — including BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2.

This was followed by TOPARP-B, an open-label, phase II trial in which men with HRR-mutated mCRPC that had progressed on ≥1 taxane therapy were treated with olaparib 400 mg or 300 mg twice daily in a randomized fashion.⁹ The primary endpoint was identical to the TOPARP-A trial. A targetable HRR gene aberration was found in 161 of 592 (27.2%) patients who underwent a targeted next-generation tumor sequencing. However, sequencing could not be performed on 119 (17%) of consented patients because of insufficient or poor-quality tissue. The confirmed composite response rate was 54.3% in the 400 mg cohort and 39.1% in the 300 mg cohort (p=0.14). Median radiographic progression-free survival (rPFS) was 5.5 months (95% CI: 4.4 – 8.3) in the 400 mg cohort and 5.6 months (3.7 – 7.7) in the 300 mg cohort. The predefined criteria for success were met for the 400 mg regimen but not for the 300 mg regimen.

These promising results served as the ‘precursor’ for PROfound, a randomized, open-label, phase III trial of olaparib 300 mg twice daily versus physician’s choice of standard of care therapy in men with HRR-mutated mCRPC who had disease progression while receiving a novel hormonal agent (e.g., enzalutamide or abiraterone). Patients were assigned to one of two cohorts based on their HRR gene alteration. Cohort A included patients with BRCA1, BRCA2, or ATM alterations, irrespective of co-occurring alterations in any other HRR genes. Cohort B had patients with alterations in any of the other 12 HRR genes (BRIP1, BARD1, CDK12, CHEK 1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L). Patients within each cohort were randomized in 2:1 fashion to olaparib versus standard of care . The primary endpoint was the rPFS in cohort A.

The confirmed objective response rate (ORR) was 33% in the olaparib group and 2% in the standard of care  group (odds ratio 20.9; 95% CI: 4.2 – 379.2; p<0.001). The median time to pain progression was also significantly longer in the olaparib group (HR: 0.44; 95% CI: 0.22 – 0.91; p=0.02). The final overall survival (OS) analysis demonstrated that olaparib improved OS in cohort A from a median of 14.7 to 19.1 months (HR: 0.69, 95% CI: 0.50 – 0.97). Notably, 84% of patients with imaging-based disease progression had crossed over from the standard of care  arm to olaparib at the time of analysis, which highlights the efficacy of earlier use of olaparib in this setting.¹⁰

The data from PROfound formed the basis for the FDA-approval of olaparib 300 mg PO twice daily in men with HRR-mutated mCRPC after progression on enzalutamide or abiraterone.⁴

Rucaparib

The first PARP inhibitor to be approved by the FDA for the treatment of prostate cancer patients was rucaparib. On May 15, 2020, rucaparib was granted accelerated approval for patients with mCRPC and BRCA mutations (germline or somatic) who had progressed following treatment with androgen receptor-directed therapy and a taxane-based chemotherapy.³ This approval was based on the results of TRITON2, which was initially published in 2020¹¹ and most recently updated in 2023.¹² TRITON2 is an international, open-label, phase II trial that evaluated the safety and efficacy of rucaparib 600 mg twice daily in mCRPC patients with DNA damage response (DDR) gene alterations who had progressed after 1–2 lines of an androgen receptor pathway inhibitor and one taxane-based chemotherapy. The efficacy cohort included 277 patients, of whom 172 (62.1%) had a deleterious germline or somatic BRCA alteration with 21.3%, 5.4%, 3.1%, 4%, and 4.7% having ATM, CDK12, CHEK2, PALB2, and other DDR gene mutations, respectively. A confirmed objective response was observed in 46% of BRCA patients with measurable disease (10% complete response). A superior response was observed among BRCA2 patients (48% versus 30% for BRCA1), which is potentially secondary to an increased frequency of biallelic mutations among BRCA2 patients and a greater coexistence of TP53 mutations among BRCA1-mutated men.¹³ The objective response was consistent irrespective of whether the BRCA mutation was somatic or germline and whether other DDR mutations were present or absent. All four patients with PALB2 mutations and measurable disease had an objective partial response, with none of the ATM-, CDK12-, CHEK2-mutated patients experiencing an objective response. A confirmed PSA50 response was observed in 53% and 55% of BRCA and PALB2-mutated patients, compared to 3.4–14% among patients with other DDR gene mutations. The median overall survival was 17.2 months for BRCA patients, compared to 11.1–14.6 months among ATM, CDK12, and CHEK2-mutated patients.

Following the promising results of TRITON2, the phase 3 TRITON3 trial was published in 2023. This was a randomized phase 3 trial of mCRPC patients with a BRCA1, BRCA2, or ATM alterations who experienced disease progression following treatment with a second-generation androgen receptor pathway inhibitor. Patients underwent 2:1 randomization to receive oral rucaparib (600 mg twice daily) or a physician’s choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median PFS according to independent review. There were 405 patients randomized to receive rucaparib (n=270) or the control group (n=135). At 62 months follow-up, imaging-based PFS was significantly prolonged in the rucaparib group compared to the control group, both in the BRCA subgroup (11.2 and 6.4 months, respectively; HR: 0.50; 95% CI: 0.36 – 0.69) and in the intention-to-treat population (10.2 and 6.4 months, respectively; HR: 0.61; 95% CI: 0.47 – 0.80; p<0.001 for both comparisons). No significant PFS benefit was observed in the ATM subgroup.

In the BRCA subgroup, the median OS was 24.4 versus 20.8 months in favor of rucaparib (HR: 0.81, 95% CI: 0.58 – 1.12, p=0.21).¹⁴

Talazoparib

TALAPRO-1 was an open-label, phase II trial that evaluated talazoparib 1 mg/day in patients with evidence of progressive mCRPC who had measurable soft-tissue disease and evidence of one of 11 DDR mutations who had progressed following taxane-based chemotherapy (48% both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide (98% of population). The primary endpoint was confirmed ORR. There were 128 patients enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumor activity population). After a median follow-up of 16.4 months, the ORR was 30% (95% CI: 21.2 – 39.6%).¹⁵

Niraparib

GALAHAD was a multicenter, open-label, single arm phase II trial of 289 mCRPC patients with DNA repair gene defects and disease progression following a prior next-generation androgen signaling inhibitor and a taxane, who received niraparib 300 mg orally once daily. The primary endpoint was ORR in patients with BRCA alterations and measurable disease. At a median follow-up of 10 months, the ORR in the measurable BRCA cohort was 34.2%. The median duration of objective response was 5.6 months. Conversely, the ORR in the measurable non-BRCA cohort was 10.6%. Median rPFS (8.1 versus 3.7 months) and OS (13.0 and 9.6 months) were both longer in the BRCA cohort, compared to the non-BRCA cohort.¹⁶

Management of Side Effects of PARP Inhibitors

The adverse event/safety profiles of all PARP inhibitors overlap considerably. The most common (any CTCAE grade) clinical side effects in phase III trials of rucaparib, olaparib and niraparib include:¹⁷

• Nausea: ~75%
• Fatigue: 60–70%
• Vomiting: ~35%
• Constipation: 20–40%
• Dysgeusia: 10–40%
• Anorexia: ~25%
• Abdominal pain: 25–30%
• Diarrhea: 20–30%
• Headache: 20–25%
• Cough: 10–15%

The most common (any CTCAE grade) lab abnormalities were:

• Anemia: 40–50%
• Thrombocytopenia: 15–60%
• Neutropenia: 20–30%
• Alanine aminotransferase (ALT) elevation: 5–36%
• Aspartate aminotransferase (AST) elevation: 2–28%
• Increased serum creatinine level: 10–15%

While nausea is the most common side effect of PARP inhibitor therapy, it tends to be mild in most cases. This side effect can be managed by taking the medication after a meal and an antiemetic (prochlorperazine or a 5-HT3 antagonist such as ondansetron) may be considered in patients who develop moderate or severe nausea and/or vomiting with PARP inhibitor therapy.

Close monitoring of patients following PARP inhibitor therapy initiation is required, particularly  in the first three months, as hematologic adverse effects usually occur early, but not invariably, and regular blood counts should continue while patients are on treatment. Anemia is the most common hematologic toxicity observed with PARP inhibitors, with grade 3–4 anemia observed in 22% of patients on olaparib, 27% of patients on rucaparib, and 31% of patients on niraparib first-line maintenance therapy ovarian cancer trials.^18-21 The management of such events may include dose reductions and/or interruptions, with transfusions reserved for symptomatic anemic events or if the hemoglobin level falls to <7 g/dL. Thrombocytopenia appears to be more common with niraparib at 61%, as opposed to olaparib (14%) or rucaparib (28%). The niraparib FDA label thus recommends obtaining weekly platelet levels during the first month of therapy.

Elevated serum creatinine level occurs within the first few weeks of therapy and is thought to be an on-target effect due to the inhibition of renal transporter proteins. Thus, serum creatinine-based estimation of renal function may be inaccurate in patients receiving PARP inhibitor therapy. Alternative methods of glomerular filtration rate (GFR) estimation such as radionuclide scan or serum-cystatin C must be used in cases where a more accurate GFR estimate is necessary. Elevation of AST and ALT also tends to typically occur within the first two cycles and can be transient. Treatment interruption may not be required for mild AST/ALT elevations, but serum bilirubin levels must be checked in all patients to evaluate for drug-induced liver injury.

Owing to their mechanism of action, there was a concern regarding treatment-emergent myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with PARP inhibitor therapies. However, it appears that the risk of MDS/AML is <1.5%. Of the 2,351 patients treated in olaparib monotherapy trials, only 28 (<1.5%) developed MDS/AML. Of these, 25/28 patients had a BRCA mutation, two patients had a wild-type germline BRCA, and one patient had unknown BRCA mutation status. The duration of olaparib varied from < 6 months to > 2 years and all had received previous chemotherapy with platinum and/or other DNA damaging agents, or radiotherapy.¹⁷ If pancytopenia occurs at any point during PARP inhibitor therapy, treatment must be interrupted as per guidelines for the drug, and appropriate evaluation for MDS and AML must be undertaken. Therapy must be discontinued permanently if a diagnosis of MDS or AML is confirmed.

Another important consideration is the potential for clinically-significant drug-drug interactions (DDI) with all PARP inhibitors. Rucaparib and olaparib are primarily metabolized by different members of the cytochrome P450 enzyme family, resulting in only a partial overlap in DDIs. Niraparib is metabolized in the liver by carboxylesterase-catalyzed amide hydrolysis with cytochrome P450 playing only a negligible role.²² Many commonly used drugs (such as phenytoin, carbamazepine, ketoconazole, ciprofloxacin, digoxin) have uni- or bi-directional interactions with PARP inhibitors. Thus, careful attention must be paid to minimize DDI by avoiding, discontinuing, adjusting the dose, or clinical/lab monitoring of these medications before and during PARP therapy. Involving a dedicated oncology pharmacist, where available, may be a valuable aid in this treatment setting.

Conclusions and Future Directions

PARP inhibitor monotherapy has demonstrated promising outcomes for the treatment of HRR-mutated mCRPC patients with evidence of disease progression following treatment with an androgen receptor pathway inhibitor and/or taxane-based chemotherapy. As a result, there has been an increased interest in ‘moving up’ these agents along the disease spectrum, as well as combining PARP inhibitors with other agents that may have a synergistic mechanism of action.

Published March 2024

Introduction