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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:

• Radium-223 (Xofigo®) for mCRPC patients with symptomatic bone metastases and no known visceral metastatic disease (2013)¹
• Lutetium 177 vipivotide tetraxetan (PLUVICTO®) for prostate-specific membrane antigen (PSMA)-positive mCRPC patients who had previously been treated with an ARPI and taxane-based chemotherapy

In this Center of Excellence article, we will discuss the existing evidence informing the regulatory approvals of radium-223 and Lu-PSMA, as well as emerging radioligands, including combination approaches, in the mCRPC treatment space.

Radium-223

Radium-223 is a targeted alpha emitter that selectively binds to areas of increased bone turnover in bone metastases and emits high-energy alpha particles of short range (<100 μm). Radium-223 acts as a bone-seeking calcium mimetic and binds into newly formed bone stroma, especially within the microenvironment of osteoblastic or sclerotic metastases. Double-stranded DNA breaks result secondary to the high-energy alpha-particle radiation. This results in a potent and highly localized cytotoxic effect in the target areas. Furthermore, the short path of the alpha particles also theoretically minimizes the toxic effects on adjacent healthy tissue, including the bone marrow.³

The ALSYMPCA trial was a phase III randomized controlled trial (RCT) of 921 mCRPC patients randomized 2:1 to receive six IV injections of radium-223 (50 kBq/Kg) or matching placebo. All patients received additional best standard of care. Of note, prior docetaxel treatment was permitted (57% of included patients). Patients receiving radium-223 demonstrated significantly improved median overall survival (14 versus 11.2 months; HR: 0.70, 95% CI: 0.55 – 0.88): 

Use of radium-223 was further associated with significantly prolonged time to a first symptomatic skeletal event (15.6 versus 9.8 months, p<0.001) and a significantly higher percentage of radium-223-treated patients achieved clinically meaningful improvements in quality-of-life outcomes (i.e., ≥10-point improvement in the FACT-P total score; 25% versus 16%, p = 0.02). Grade 3–4 adverse events were observed less frequently in the treatment arm (56% versus 62%). Notable grade ≥3 adverse events included anemia (13% in both arms) and thrombocytopenia (6% versus 2%). Febrile neutropenia was observed in only one patient in each arm.³ 

Real-world prospective evaluation of the outcomes of radium-223-treated patients is of utmost importance given the known external validation (i.e., generalizability) limitations of RCTs to real-world practice. REASSURE (NCT02141438) is an ongoing, global multicenter, prospective, observational, single-arm study of radium-223 use in clinical practice between 2014 and 2017 (n = 1,465):

Results of an interim analysis, at a medium follow-up of 11.5 months, were published in 2023.⁴ All six planned cycles of radium-223 treatment were completed by 59% of patients. Treatment-emergent serious adverse events occurred in 21% of patients, and drug-related treatment-emergent adverse effects of any grade in 35% of patients. The most common drug-related treatment-emergent adverse events were diarrhea (11%), nausea (9%), and anemia (8%). Drug-related adverse events leading to radium-223 discontinuation and death occurred in 6% and 1% of patients, respectively. In the 6 months following completion of radium-223 therapy, 15% of patients had grade 3–4 hematologic toxicities (anemia: 12%, thrombocytopenia: 4%, neutropenia: 1%, pancytopenia <1%).

The median overall survival was 15.6 months (95% CI: 14.6–16.5) and disease progression was the main cause of death (77% of deaths). Overall, 32% of patients received ≥1 subsequent systemic life-prolonging anticancer therapy (48% never received taxane therapy): 

During treatment, 55% of patients had a clinically meaningful pain response (≥2 points improvement in the “pain at its worst” item of the BPI-SF scale), and fractures occurred in 5% of patients. Twenty-one patients developed a second primary malignancy during or after receipt of radium-223. Notably, 16/21 patients had received prior (n = 15) or concurrent radiotherapy (n = 1).

The results of a real-world analysis of the Komodo Research Dataset, an administrative claims dataset of >140 million individuals from over 150 private insurance providers in the United States (commercial and Medicare), were presented at ASCO GU 2024. This study included 1,376 radium-223 users. The prescribing physician was most commonly a medical oncologist (52%). Radium-223 was most commonly prescribed in the 2^nd (35%) and 3^rd line (25%) settings. Of note, nearly half of the patients (49%) had visceral metastases, and ≥5 cycles of radium-223 were completed by 46% of patients in the cohort (54% of those surviving ≥6 months). Radium-223 was utilized as a combination therapy by 26% of the overall population, predominately with enzalutamide: 

The results of a Spanish real-world study from seven Galician hospitals of 146 mCRPC patients receiving radium-223 in the ≥2^nd line setting were presented at ASCO GU 2023. At a median follow-up of 9.6 months, the median overall survival was 12 months (95% CI: 9.7–16). The median overall survival was 18 months for those receiving radium-223 in the 2^nd line setting and 9.4 months in the 3^rd line setting:⁶  

177Lutetium–PSMA-617

PSMA is a transmembrane protein expressed in all forms of prostate tissue, including carcinoma. The PSMA gene is located on the short arm of chromosome 11 in a region that is not commonly deleted in prostate cancer, thus making it highly prevalent in all forms of prostate cancer, including mCRPC. Importantly, PSMA is relatively poorly expressed in other organs (apart from salivary), therefore PSMA-targeted theranostic treatment allows for relatively specific targeted therapy. PSMA does have an internalization signal that allows for internalization of the extracellular component into an endosomal compartment.⁷ This has allowed for the combination of PSMA-617 and the beta-emitter lutetium to deliver targeted ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment. 

There are two major trials that have led to the regulatory approval of ¹⁷⁷Lu-PSMA-617 in the post-taxane and ARPI mCRPC setting: VISION and TheraP.^8,9

VISION is an international, open-label, phase 3 trial that evaluated ¹⁷⁷Lu-PSMA-617 in mCRPC patients previously treated with an ARPI and 1–2 taxane regimens and who had PSMA-positive ⁶⁸Ga-PSMA-PET/CT scans. Overall, 831 patients were randomly assigned in a 2:1 ratio to receive either ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for 4–6 cycles) plus protocol-permitted standard care or standard care alone. At a median follow-up of 20.9 months, ¹⁷⁷Lu-PSMA-617 plus standard of care significantly prolonged both radiographic progression-free survival (median: 8.7 versus 3.4 months; HR: 0.40, p < 0.001) and overall survival (median: 15.3 versus 11.3 months; HR: 0.62; 95% CI: 0.52 to 0.74, p < 0.001): 

Patient reported outcomes as evaluated by the FACT-P and Brief Pain Inventory scores favored the ¹⁷⁷Lu-PSMA-617 arm with delays in time to worsening of 7.3 and 11.4 months, respectively:

While a higher rate of grade 3–5 treatment-emergent adverse events was observed with ¹⁷⁷Lu-PSMA-617 (28% versus 4%) at the time of initial reporting, overall therapy was well tolerated. It bears note that treatment exposure was more than three times longer in the ¹⁷⁷Lu-PSMA-617 group than in the control group. Bone marrow toxicity with grade ≥3 anemia, leukopenia, and thrombocytopenia was observed in 13%, 2.5%, and 8% of patients in the ¹⁷⁷Lu-PSMA-617 arm, respectively. Although 39% of ¹⁷⁷Lu-PSMA-617 treated patients experienced any grade xerostomia, none were grade 3 or worse: 

TheraP was an open label, phase II trial of 200 mCRPC men who were randomized to either ¹⁷⁷Lu-PSMA-617 or cabazitaxel. To screen into the study, all men had both ⁶⁸Ga-PSMA-11 and ¹⁸F-FDG PET/CT and were required to have high PSMA-expression (≥1 site with SUVmax ≥20) and no sites of FDG-positive/PSMA-negative disease. All patients had progressive disease with rising PSA ≥20 ng/mL after docetaxel and 91% had received prior enzalutamide or abiraterone. There were 200 patients were randomized 1:1 to ¹⁷⁷Lu-PSMA-617 6-8 GBq every 6 weeks for up to 6 cycles of therapy or cabazitaxel 20 mg/m² every three weeks for up to 10 cycles:

After a median follow up of 13 months, ¹⁷⁷Lu-PSMA-617 significantly improved PSA progression-free survival compared with cabazitaxel (HR 0.63, 95% CI 0.46 to 0.86) and was associated with a much higher PSA50 response (66% vs 37%): 

Grade 3–4 toxicity was observed in 54% of men on cabazitaxel compared to 35% of patients who received ¹⁷⁷Lu-PSMA-617. Rates of thrombocytopenia, dry mouth, and dry eyes were seen more frequently in patients receiving ¹⁷⁷Lu-PSMA-617, as expected due to normal PSMA expression in the salivary and lacrimal glands.⁹

Based on the results of these trials, the current guidelines strongly recommend considering the use of ¹⁷⁷Lu-PSMA-617 in taxane and ARPI-pre-treated mCRPC patients who have evidence of PSMA-expressing metastatic lesions as per either ⁶⁸Ga or ¹⁸F-DCFPyL PSMA-PET/CT.

Presented at ESMO 2023, PSMAfore was the first ¹⁷⁷Lu-PSMA-617 trial to assess radioligand therapy in the docetaxel-naïve mCRPC population. Eligible adults for PSMAfore had mCRPC, were candidates for ARPI change after one progression on prior ARPI, and had ≥1 PSMA positive lesions and no exclusionary PSMA negative lesions by ⁶⁸Ga-PSMA-11 PET/CT. Randomization was 1:1 to open-label ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for 6 cycles) or ARPI change (abiraterone or enzalutamide). Importantly, patients randomized to ARPI could crossover to ¹⁷⁷Lu-PSMA-617 following centrally reviewed radiographic progression. The trial design for PSMAfore is as follows:

Overall, there were 468 patients randomized. As follows is the patient disposition at the second interim OS analysis, noting that 84.2% of patients that had an rPFS event in the ARPI change subsequently went on to receive crossover ¹⁷⁷Lu-PSMA-617: 

At the primary analysis (median follow-up, 7.3 months; n = 467), the primary endpoint of rPFS was met (HR 0.41, 95% CI 0.29 to 0.56), which was similar at the second interim analysis (HR 0.43, 95% CI 0.33 to 0.54): 

Among men with measurable disease, the objective response rate was 50.7% for ¹⁷⁷Lu-PSMA-617 versus 14.9% for ARPI change. The median duration of response was 13.63 months (95% CI 11.56 – NE) for ¹⁷⁷Lu-PSMA-617 versus 10.05 months (95% CI 4.63 – NE) for ARPI change. As follows is a summary of the radiographic response rates, highlighting that patients in the ¹⁷⁷Lu-PSMA-617 arm had a complete response rate of 21.1% versus 2.7% in the ARPI change arm: 

Patients receiving ¹⁷⁷Lu-PSMA-617 had a confirmed PSA decrease rate >=50% in 57.6% of patients compared to 20.4% of patients in the ARPI change arm. Time to symptomatic skeletal events also favored the ¹⁷⁷Lu-PSMA-617 arm (HR 0.35, 95% CI 0.22 to 0.57). Time to composite health related quality of life or pain worsening as summarized by the FACT-P total score (HR 0.59, 95% CI 0.47 to 0.72) and BPI-SF pain intensity scale (HR 0.69, 95% CI 0.56 to 0.85), respectively, also favored ¹⁷⁷Lu-PSMA-617. Additionally, at the second interim analysis (45.1% of target deaths), 123/146 (84.2%) patients with reviewed radiographic progression who discontinued ARPI crossed over to receive ¹⁷⁷Lu-PSMA-617. In the pre-specified cross-over adjusted analysis, there was a trend favoring ¹⁷⁷Lu-PSMA-617, but no statistical difference in OS between the groups: 

In the unadjusted, intention to treat analysis for OS, the HR was 1.16 (95% CI 0.83 to1.64). For ¹⁷⁷Lu-PSMA-617 vs ARPI change, the incidence of grade ≥3 adverse events was 33.9% (most commonly anemia and dry mouth) versus 43.1%, serious adverse events 20.3% vs 28.0%, and adverse events leading to discontinuation 5.7% vs 5.2%, respectively. 

The radium lutetium (RALU) study was a retrospective, multicenter study evaluating the safety of ¹⁷⁷Lu-PSMA-617 in 49 German mCRPC patients previously treated with radium-223. Overall, 92% of patients had received ≥1 line of taxane-based chemotherapy, and 63% had received ≥3 life-prolonging therapies (docetaxel, cabazitaxel, abiraterone, enzalutamide, and radium-223): 

The median ¹⁷⁷Lu-PSMA-617 therapy duration was 4.9 months, and the median time from the last radium-223 injection to the first ¹⁷⁷Lu-PSMA-617 dose was 9.3 months (range: 1–42). Grade 3–4 treatment-emergent adverse events were experienced by 41% of patients, grade 3–4 anemia and thrombocytopenia occurred in 18% and 2% of patients, respectively, grade 1–2 xerostomia occurred in 27% of patients; none had grade 3–4 dry mouth. There were no grade 5 toxicities that occurred.

The median overall survival was 12.6 months from the 1^st dose of ¹⁷⁷Lu-PSMA (95% CI: 8.8–16.1). During ¹⁷⁷Lu-PSMA, 29% of patients achieved a PSA50 response:¹¹ 

Actinium-225

Similar to radium-223, actinium-225 (²²⁵Ac) is an alpha emitter, which delivers significantly higher energy levels compared to β-emitters (4–9 MeV vs. 0.1–2.2 MeV). Combined with shorter path lengths, this results in a higher linear energy transfer and a greater probability of generating DNA double-strand breaks on interaction with cell nuclei. This makes them more effective to tumor cellular killing with significantly fewer DNA hits.¹²

WARMTH Act is an international cohort study of 488 mCRPC patients who received ²²⁵Ac-PSMA radioligand therapy following disease progression with earlier line agents.¹³ The mean patient age was 68 years, and the median baseline PSA level was 170 ng/ml. PSMA-avidity in the mCRPC lesions, and thus treatment eligibility, was determined primarily using PET (95%). This was a heavily pre-treated population with 53% of patients having received ≥3 prior lines of therapy for mCRPC. Indeed, 91% of patients received ²²⁵Ac-PSMA as a last line therapy option because they had exhausted or were ineligible for other treatment options. Prior therapies included:

• Docetaxel: 66%
• Cabazitaxel: 21%
• Abiraterone: 39%
• Enzalutamide: 39%
• ¹⁷⁷Lu-PSMA: 32%
• Radium-223: 4$

Patients received a median of two (IQR:2–4) treatment cycles, and 57% of patients completed their ²²⁵Ac-PSMA radioligand therapy as planned. Reasons for interruption included favorable response to treatment (n = 84), disease progression (n = 24), logistical issues with supply availability (n = 34), xerostomia (n = 11), and unstable clinical condition (n = 8).

Any PSA decline after ≥1 cycle of ²²⁵Ac-PSMA was observed in 73% of patients, with a PSA50 response observed in 57% of patients. 33% of patients had a radiographic response based on ⁶⁸Ga PSMA-PET/CT findings of minimal residual disease. The administered activity of ²²⁵Ac-PSMA radioligand therapy was reduced for salivary gland protection in these patients: 

The median follow-up duration was 9 months, and the median progression-free survival was 9 months (95% CI: 5–17.5). At the time of data collection, 63% of patients had died, with all deaths secondary to mCRPC and its complications. The median overall survival was 15.5 months (95% CI: 13.4–18.3). Patients who did not achieve a PSA50 response, those with liver or peritoneal metastases, and anemia at baseline had worse survival outcomes with ²²⁵Ac-PSMA on multivariable analysis. No treatment-related death was recorded. Notably, only 10% of patients who died received another form of treatment after disease progression.

The most common adverse event was xerostomia. This was observed in 68% of patients after the 1^st cycle of treatment and in ≥86% of patients who received ≥2 cycles; however, only 2% of patients discontinued treatment secondary to xerostomia. After ²²⁵Ac-PSMA radioligand therapy, any grade of anemia was observed in 81%, leukopenia in 44%, and thrombocytopenia in 54%. Grade ≥3 anemia, leukopenia, and thrombocytopenia were observed in 13%, 4%, and 7% of patients, respectively. It bears note, however, that a significant proportion of patients had baseline bone marrow dysfunction.

Select Radioligand Combination Therapies

One example of a radioligand combinatory approach that allows for the targeting of cells without PSMA expression is the combination of ¹⁷⁷Lu-PSMA-617 + enzalutamide. There is a close relationship between the androgen and PSMA receptors, with upregulation of PSMA expression in response to androgen blockade observed in mCRPC. This increased PSMA expression is associated with poor survival in CRPC patients receiving ARPIs. Increased PSMA expression increases dsDNA breaks and cell death with ¹⁷⁷Lu-PSMA-617 therapy, increasing the depth of treatment response. This reduces/eliminates the high PSMA expressing clonal population, leaving a low PSMA expression clonal population more likely to respond to ARPIs. The ENZA-p trial investigators hypothesized that using both treatments together may lead to potentially deeper and longer patient responses, compared to ARPI monotherapy.

ENZA-p (ANZUP 1901) was an open label, randomized phase 2 trial across 15 centers in Australia of 162 mCRPC patients who had not previously received a taxane or an ARPI in the mCRPC setting, had ⁶⁸Ga-PSMA-PET/CT-positive disease, and ≥2 risk factors for early progression on enzalutamide. These patients underwent 1:1 randomization to enzalutamide +/- ¹⁷⁷Lu-PSMA-617:  

Of 220 screened patients, 160 met the eligibility criteria and were randomized (enzalutamide + Lu-PSMA, n = 83; enzalutamide, n = 79). The PSMA PET imaging screen failure rate was 18%. In the combination arm, 81% of patients received all 4 doses of ¹⁷⁷Lu-PSMA-617, with a median follow-up was 20 months.

This trial met its primary endpoint, with the addition of ¹⁷⁷Lu-PSMA-617 to enzalutamide improving PSA progression-free survival from 7.8 to 13 months (HR: 0.43, 95% CI: 0.29–0.63, p < 0.001). rPFS (data maturity: 60%) also favored the combination arm (median: 16 versus 12 months; HR: 0.67, 95% CI: 0.44 – 1.01).

A PSA50 response was observed in 93% of patients in the ¹⁷⁷Lu-PSMA-617 + enzalutamide arm, compared to 68% of enzalutamide-treated patients. The corresponding PSA90 responses were 78% and 37%, respectively: 

Grade 3–5 adverse events were observed in 40% and 41% of patients in the intervention and control arms, respectively. Grade 3 events that only occurred in the intervention arm were anemia (4%) and decreased platelet count (1%):¹⁴

AlphaBet is an ongoing phase I/II trial evaluating the combination of radium-223 + Lu-177 PSMA-I&T in mCRPC patients. In a pre-clinical LNCaP xenograft model, this combination, compared to single agent therapy, was associated with improved PSA response.¹⁶ 

In AlphaBet, 36 mCRPC patients will receive up to 6 cycles of ¹⁷⁷Lu-PSMA-I&T 7.4 GBq intravenously every 6 weeks + ²²³Ra in a two-step dose escalation (28 kBq/kg – 55 kBq/kg, then in expansion at the determined safest dose) intravenously every 6 weeks. The primary study objectives are to establish the ‘safe dose’ and to evaluate the anti-tumor activity. Secondary outcomes include side effects, survival outcomes, and patient-reported outcomes: 

LuCAB is a phase I/II study of cabazitaxel in combination with ¹⁷⁷Lu-PSMA-617 in mCRPC patients. The addition of cabazitaxel is hypothesized to address potential mechanisms of resistance to ¹⁷⁷Lu-PSMA-617:

• Underlying PSMA-negative disease
• Tumor microenvironment related sensitivity (low sensitivity with hepatic/visceral metastases, high sensitivity with nodal disease)
• Micrometastatic disease not receiving adequate radiation from ¹⁷⁷Lu-PSMA-617
• Underlying molecular factors that may confer radioresistance

LuCAB is recruiting 35 to 40 mCRPC patients with disease progression after docetaxel and an ARPI and who have PSMA-avid disease (SUVmax ≥15 and no FDG PET/CT discordant disease) to receive up to 6 cycles of ¹⁷⁷Lu-PSMA-617 7.4 GBq intravenously six weekly plus cabazitaxel at escalating doses as illustrated below. The primary study objective is to establish whether ¹⁷⁷Lu-PSMA-617 and cabazitaxel can be combined and used at standard doses. Secondary outcomes include anti-tumor activity, patient-reported outcomes, and side effects: 

Conclusions

The field of radioligand therapy has experienced significant growth over the past decade. While only two agents (Radium-223 and ¹⁷⁷Lu-PSMA-617) are currently approved for the treatment of mCRPC patients, additional options, including ²²⁵Ac, are emerging and demonstrate promising efficacy and safety outcomes in heavily pre-treated settings. Furthermore, novel radioligand therapy combinations are emerging to overcome resistance mechanisms of current radioligand therapies.

Bladder cancer remains the sixth most commonly diagnosed cancer in the United States, with an estimated 82,290 incident cases in 2023.¹ Because of the persistent recurrence risk of NMIBC in a highly comorbid population, there has been an FDA-led drive towards developing novel treatment options for these patients. The following article will highlight recent advances in this disease space with a specific focus on the oncolytic adenovirus agent cretostimogene grenadenorepvec, and the registration trial in intermediate risk non-muscle invasive bladder cancer (NMIBC), PIVOT-006. 

Introduction

Introduction

Since the United States Food and Drug Administration (FDA) approval of mitoxantrone in 1996¹ and docetaxel in 2004² for the treatment of patients with metastatic castrate-resistant prostate cancer, we have witnessed the approval of numerous additional agents/combinations in this disease space:

Introduction

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Introduction

Figure 1: The current landscape of FDA combination approvals in Metastatic Hormone Sensitive Prostate Cancer (mHSPC)^1-12 

Thus, this has changed the standard of care for treatment intensification for these men. This article will focus a discussion on the implementation of treatment for Metastatic Hormone Sensitive Prostate Cancer (mHSPC) in North America, specifically highlighting the landscape and challenges of treatment intensification, and the importance of disease volume and timing of metastasis for selecting the optimal treatment in the mHSPC disease space.

The Enigma of (Lack of) Treatment Intensification

Despite the approval and availability of multiple mHSPC treatment intensification strategies, there remains a clear underutilization of these combination strategies in real-world practice. The following discussion will highlight several of the key studies looking at contemporary treatment intensification across several North American jurisdictions.

Ryan et al. reported treatment utilization trends of mHSPC patients between January 2014 and July 2019 from two large U.S databases: (i) Optum’s de-identified Clinformatics Data Marta Database (COM/MA), which includes claims from commercial and Medicare Advantage plans for 13 million people across the United States and (ii) Centers for Medicare & Medicaid Services-sourced Medicare Fee-for-Service (FFS) Research Identifiable Files Sample.¹³  A total of 19,841 mHSPC patients (6,517 COM/MA and 13,324 Medicare-FFS) were identified with a median follow up of 9.6 – 10.5 months. Notably, 38% of COM/MA and 48% of Medicare-FFS patients remained untreated or deferred treatment during the study period, whereas 45% and 46%, respectively, were treated with first line ADT monotherapy only. Abiraterone acetate or docetaxel was used as first line therapy in 13% (COM/MA) and 2%

(Medicare-FFS) of patients. Approximately 43% and 38% of patients, respectively, only received ADT monotherapy (with or without a first-generation androgen signaling inhibitors) during the entire mHSPC period despite the availability of other more potent therapies. It is important to note that apalutamide and enzalutamide were added to evidence-based guidelines as mHSPC treatments after the end of the study period (July 31, 2019) and were not considered as mHSPC therapy in the current study. When stratified by year of index date, in the COM/MA database, treatment with first line ADT monotherapy decreased numerically from 48% to 43% among patients diagnosed with mHSPC in 2015 – 2017 versus 2018 – 2019. While the overall use of abiraterone or docetaxel remained similar in the two periods (12% - 14%), the relative use of abiraterone acetate increased among patients diagnosed in 2018 - 2019 (10%) versus 2015 - 2017 (5%), whereas the use of docetaxel decreased in 2018 - 2019 (4%) compared with 2015 – 2017 (7%).

Figure 2: First line therapy in patients with mHSPC by year of index data in the Clinformatics Data Marta Database¹³ 

Analysis from the Veterans Health Administration (VHA) database was reported by Freedland et al.¹⁴  for 1,395 mHSPC patients treated between April 2013 and March 2018. Across the five-year study period, 63% of patients received ADT alone as first line treatment while ADT + non-steroidal anti-androgen was used in 24%, ADT + docetaxel in 8%, and ADT + abiraterone for the remaining 5%. Treatment trends over time did demonstrate an overall decrease in ADT only (66% to 60%) or ADT + non-steroidal anti-androgen (31% to 17%) utilization between 2014 and 2017-2018, with a corresponding increase in utilization of ADT+ docetaxel (3% to 9%) and ADT + abiraterone (1% to 15%). Nonetheless, despite increased adoption of treatment intensification in VHA mHSPC patients, there remains a clear underutilization of appropriate treatment intensification.

Figure 3: Treatment trends over time among patients with mHSPC in the Veterans Health Administration¹⁴

A comparison of patients in the four treatment groups demonstrated that patients receiving ADT and docetaxel, compared to the ADT only cohort, were younger (65.8 versus 73.4 years) and had fewer comorbidities (National Cancer Institute comorbidity score 1.1 versus 1.5), but had greater disease burden in terms of higher PSA (338.1 ng/ml versus 256.4 ng/ml) and overall metastatic burden. ADT + abiraterone patients were older (75.3 versus 73.4 years), generally had fewer cardiovascular comorbidities and lower PSA (238.3 versus 256.5 ng/ml) but had increased metastasis (other sites including bone: 80% versus 73%).

A combined analysis from the VHA and Medicare database was presented at ESMO 2022. The authors identified 33,641 and 5,561 men in the Medicare and VA cohorts, respectively. Similar to the prior report by Freedland et al.,    ¹⁴  the authors demonstrated that the proportion of patients receiving treatment intensification with novel hormonal therapy or docetaxel increased over time, although by 2018/2019, still less than one third of patients with mHSPC received first line ADT plus docetaxel or ADT plus a novel hormonal agent.

Figure 4: Utilization of first line treatment intensification over time for mHSPC patients in the VHA and Medicare databases

While there were changes in treatment approaches between 2010 and 2014, the authors did not find any changes in overall survival in 2012–2014 compared with 2010–2011, though there was improvement in overall survival by 12% and 15% in the Medicare and VA cohorts, respectively, in 2015–2018/2019 versus 2010–2011, after adjusting for baseline characteristics, suggesting that diffusion of these intensified treatment approaches provides a population-level survival benefit.

Figure 5: Overall survival for mHSPC patients in the VHA and Medicare databases

A Medicare analysis of treatment intensification trends among racial minorities was presented by Freedland et al. at ASCO 2021. Compared to White, non-Hispanic men, Black men were less likely to receive treatment intensification (ADT + docetaxel or novel hormonal therapy) during 2010-2014 (2.6% versus 3.2%), 2015-2016 (8.7% versus 10.4%), and 2017 (14.2% versus 15.1%).

Using provincial data from Ontario, Canada, Wallis et al.¹⁵  identified 3,556 patients diagnosed with de novo mHSPC between 2014 and 2019. Of note, 78.6% of patients received ADT alone (with or without an anti-androgen), 11.2% received treatment intensification with docetaxel, 1.5% received abiraterone acetate and prednisone, with the remaining 8.7% receiving a “non-ADT” regimen. Patients receiving docetaxel were comparatively younger (mean age 72.6 years) and healthier (mean Charlson Comorbidity Index score of 0.15). The median PSA at diagnosis was lower among patients who received conventional ADT (88 ng/mL) compared with ADT intensification regimens (121 ng/mL and 152 ng/mL for the abiraterone and docetaxel cohorts, respectively). A time-stratified analysis representing the uptake of ADT intensification regimens before and after the pivotal 2017 LATITUDE trial,⁸  demonstrated that abiraterone acetate plus prednisone prescriptions increased from 0.5% to 3% in the pre- versus post-LATITUDE period, respectively, whereas docetaxel treatment dropped from 12% to 10%. As was reported by Ryan et al.¹³, these data suggest that the pivotal data from LATITUDE and STAMPEDE resulted in a substitution of intensification approach (from docetaxel to abiraterone) rather than a broadening of the patient population receiving treatment intensification.

Given the underwhelming utilization of treatment intensification for mHSPC patients in the real-world setting, barriers to improved adoption need to be further understood. At ASCO 2022, Freedland et al. provided the first granular assessment as to reasons for or against treatment intensification. This study examined data from medical charts of patients initiating mHSPC treatment from July 2018 to November 2021 based on a retrospective review of multiple US academic/community practices. This was a survey of oncologists and urologists who treated these patients to provide reasons for treatment choices, including PSA goals and explicit reasons for not prescribing novel hormonal agents. This analysis included 621 patients who were treated by 65 oncologists and 42 urologists. In the first line setting, most mHSPC patients received ADT ± non-steroidal anti-androgen alone (69%), while treatment intensification rates with ADT + novel hormonal agent (26%) or ADT + chemohormonal therapy (4%) were low. Following the initial treatment course, an additional 166 patients (27%) received subsequent treatment intensification while still castration-sensitive, prior to progression to castration resistant disease.

When the physicians were queried about reasons for not using novel hormonal agents, the most frequently cited reasons were:

1. “Novel hormonal therapy would need to have a better/more tolerable side effect profile/fewer adverse events than my chosen regimen” (38%)
2. “I would need to have seen clinical trial evidence of survival improvements on novel hormonal therapies including a wider range of prostate cancer patients” (31%)
3. “Novel hormonal therapies would need to be reimbursed by patients’ insurance” (26%)

Figure 6: Reasons given by providers for not using novel hormonal therapy

Regarding treatment goals for PSA response, physicians more frequently reported a relative reduction than an absolute PSA reduction (85% versus 51%). Oncologists considered a median PSA reduction of 50% (IQR 25-75%) adequate versus 75% (IQR 50-90%) among urologists. Urologists were more likely to utilize treatment intensification in the first line setting or subsequently in patients who were still castration-sensitive (p < 0.01). Furthermore, physicians who aimed for deeper PSA reductions of 75-100% were more likely (OR: 1.63, p = 0.034) to provide treatment intensification in the first-line setting compared with physicians with less aggressive PSA goals (0 – 49%). The authors concluded that physician survey results suggest that perceptions of tolerability and lack of efficacy and financial considerations affect novel hormonal therapy use. In practice, non-guideline driven PSA reduction goals are associated with low rates of treatment intensification, and these results clearly demonstrate the need for further medical education.

Treating Implementation: Using Disease Volume and Timing of Metastasis to Guide Treatment Selection

Patients with mHSPC at the time of diagnosis are defined as having de novo or synchronous metastatic disease. Additionally, there is a subset of men initially diagnosed with non-metastatic disease, many of whom had received prior definitive local treatment, who will have progression to a metastatic state prior to development of castration resistance; this is known as metachronous mHSPC. This distinction between synchronous (i.e. de novo) and metachronous presentations is of utmost clinical importance given the known differences in underlying genomic mutational profiles and prognoses, influencing the subsequent choice of treatment intensification.¹⁶  These two cohorts can be further subdivided based on the volume of metastatic disease at presentation: low and high volumes. The CHAARTED high-volume criteria have been widely adopted in clinical practice, with high volume patients defined as follows: presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis.¹⁷ 

As such four distinct subgroups become clinically relevant (median OS per CHAARTED and GETUG-15 among men receiving ADT alone, i.e., the control groups in these trials):

1. Synchronous and high volume: 3 years
2. Synchronous and low volume: 4.5 year
3. Metachronous and high volume: 4.5 years
4. Metachronous and low volume: ~8 years

While early, aggressive treatment intensification with triplet regimens, with or without primary radiotherapy, may seem attractive in this cohort of patients to maximize survival outcomes, the reality is that such “maximal” treatment intensification is unnecessary in the majority of these patients. Furthermore, treatment toxicity, both from a pathophysiologic and financial standpoint, must be considered in these patients. As such, a nuanced approach to the treatment of such patients, guided by the aforementioned four presentations (synchronous high volume, synchronous low volume, metachronous high volume, and metachronous low volume) is needed. Arguably, over the next several years, particularly until reliable biomarkers become available, this will be how most clinicians implement treatment for mHSPC patients in North America.

Synchronous High Volume mHSPC

Based on the results from PEACE-1¹⁸  and ARASENS¹⁰, as well as subgroup analysis from ENZAMET³, it appears that this patient cohort, particularly those who are chemotherapy-fit, are most likely to benefit from triplet therapy with docetaxel + androgen receptor pathway inhibitor (ARPI) + ADT.

The PEACE-1 trial¹⁸  employed a 2x2 design to assess, (separately and combined) the impact of the addition of abiraterone + prednisone +/- radiation therapy to standard of care therapy in men with de novo mHSPC. Among patients with high volume disease, the addition of abiraterone + prednisone to standard of care resulted in a 53% improvement in rPFS with a median rPFS of 1.6 years in the standard of care arm and 4.1 years in the standard of care plus abiraterone + prednisone arm (HR: 0.47, 95% CI: 0.36 to 0.60). The addition of abiraterone + prednisone to standard of care in patients with low volume disease still resulted in a 42% improvement in rPFS with median rPFS of 2.7 years on the standard of care arm versus not yet reached in the standard of care plus abiraterone + prednisone + ADT arm (HR: 0.58, 95%: CI 0.39 to 0.87). With regards to overall survival in patients with a de novo presentation, a benefit was seen mainly in those with high-volume disease (median overall survival 5.1 versus 3.6 years; HR: 0.77, 95% CI: 0.62 to 0.96), with a marginal, non-significant improvement in those low volume de novo disease (median overall survival not reached; HR: 0.93, 95% CI: 0.69 to 1.28). The overall survival data is immature for the low volume patients due to a small number of events.

Notably, 81% of patients in the ADT plus docetaxel standard of care control arm subsequently received a next generation hormonal therapy at the time of disease progression. This suggests that early intensification with the addition of abiraterone + prednisone to standard of care therapy results in improvement in rPFS and OS compared to sequential therapy.

ADT + Docetaxel + Darolutamide

The ARASENS trial evaluated the addition of darolutamide to standard of care therapy consisting of ADT + docetaxel versus ADT + docetaxel alone.¹⁰  Darolutamide + ADT + docetaxel prolonged overall survival for high volume mHSPC (HR 0.69, 95% CI 0.57-0.82).¹⁹ 

Figure 7: Overall survival of darolutamide + ADT + docetaxel vs ADT + docetaxel for high volume disease patients in the ARASENS trial

ADT + Enzalutamide vs ADT

While the ENZAMET trial was designed to compare the combination of ADT + enzalutamide versus ADT + standard nonsteroidal antiandrogen, the study design allowed for previous/concurrent use of docetaxel. In this trial, six cycles of docetaxel were given to 65% of patients in the enzalutamide group versus 76% in the standard of care group. Updated results of the ENZAMET trial were published in 2023⁴, with survival outcomes stratified by disease volume (high versus low) and presentation (synchronous versus metachronous). Based on these subgroup analyses, patients with synchronous, high-volume mHSPC had a clinical benefit, albeit not statistically significant, for ADT + enzalutamide versus ADT + standard nonsteroidal antiandrogen whether they were planned to have docetaxel (HR: 0.79, 95% CI: 0.57 to 1.10) or in the intention to treat analysis (HR: 0.70, 95% CI: 0.47 to 1.04).

Figure 8: Overall survival in ENZAMET for patients with synchronous high volume mHSPC

Results from these three trials provide strong evidence to support the use of a triplet regimen approach in patients with synchronous, high volume mHSPC. It bears note, however, that routine use of docetaxel may not be feasible in patients with contraindications to taxane therapy, including poor performance status, blood dyscrasias, and peripheral neuropathy. Such patients would likely benefit from ARPI addition to standard ADT. 

Synchronous Low Volume mHSPC

For patients with low volume disease, there appears to be a potential late clinical benefit to triplet therapy of ADT + docetaxel + darolutamide, however, with few events and additional follow-up time likely required, there is no statistically significant benefit at this point (HR: 0.68, 95% CI: 0.41 to 1.13)

Figure 9: Overall survival of darolutamide + ADT + docetaxel vs ADT + docetaxel for low volume disease patients in ARASENS

Similarly, for patients treated in the ENZAMET trial with low volume synchronous disease, there was no benefit for ADT + enzalutamide versus ADT + standard nonsteroidal antiandrogen for those planned for docetaxel (HR: 0.57, 95% CI: 0.29 to 1.12). 

Figure 10: Overall survival of enzalutamide + ADT + docetaxel vs ADT + docetaxel + non-steroidal anti-androgen for synchronous low volume disease patients

ARATs + ADT

There is consistent evidence across all major published phase III trials to support an overall survival benefit to the addition of an ARPI to ADT in patients with synchronous low-volume disease. This is reflected, as follows:

• LATITUDE (abiraterone + ADT versus ADT alone; all de novo): HR 0.72, 95% CI 0.47 to 1.10⁹
• STAMPEDE (abiraterone + ADT versus ADT alone; >90% de novo): HR 0.64, (95% CI 0.42 to 0.96)¹⁰
• TITAN (apalutamide + ADT versus ADT alone; 10% prior docetaxel): HR 0.52, 95% CI 0.35 to 0.79¹¹
• ENZAMET (enzalutamide + ADT versus non-steroidal antiandrogen + ADT): HR 0.58, 95% CI 0.32 to 1.04    ⁴ 
• ARCHES (enzalutamide + ADT versus ADT alone; 18% prior docetaxel): HR 0.66, 95% CI 0.43 to 1.03¹²

As such, ARPI addition to ADT has become the backbone of any treatment approach in patients with synchronous, low volume prostate cancer.

Primary Radiotherapy for synchronous, low volume mHSPC patients

Beyond systemic treatment intensification, local prostate-directed therapy may allow for local treatment intensification. While a surgical approach using radical prostatectomy has been described, high quality data are limited to radiotherapy. Of note, the SWOG 1802 trial is accruing patients with a surgical arm in the setting of mHSPC to further assess the impact of cytoreductive prostatectomy in this disease space. Three trials to date have evaluated the role of local radiotherapy in the prostate in patients with mHSPC.

STAMPEDE (Arm H) was an open label, randomized controlled phase III trial of 2,061 men at 117 hospitals across Switzerland and the UK.¹¹  This trial randomized patients with de novo mHSPC in a 1:1 fashion to standard of care + radiotherapy or standard of care alone. Men allocated to radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomization. The primary outcome of this trial was overall survival. Subgroup analysis by metastatic volume (CHAARTED criteria) was planned a priori. Median follow up for STAMPEDE Arm H was 37 months, median patient age was 68 years, and median PSA was 97 ng/ml. 18% of patients received early docetaxel. In the overall cohort, radiotherapy improved failure-free survival (HR: 0.76, 95% CI:0.68 to 0.84) but not overall survival (HR: 0.92, 95% CI: 0.80 to 1.06). However, when stratified by metastatic burden, overall survival benefits were seen in the low volume group (HR: 0.68, 95% CI: 0.52 to 0.90) with restricted mean survival time improved by 3.6 months from 45.4 to 49.1.¹¹  

Figure 11: Overall survival in low metastatic burden patients with mHSPC and radiotherapy to the prostate primary in STAMPEDE Arm H

HORRAD was a multicenter prospective randomized clinical trial of 432 patients with previously untreated, de novo mHSPC at 28 centers across The Netherlands between November 2004 and September 2014.    ²⁰  All eligible patients had a PSA >20 ng/ml and documented bone metastases on bone scan. Patients were randomized in a 1:1 fashion to either ADT with EBRT or ADT alone, with a primary endpoint of overall survival. The median PSA was 142 ng/mL and over a median follow up of 47 months, the median overall survival was non-significantly different at 45 months in the radiotherapy + ADT arm compared to 43 months in ADT alone arm (HR: 0.90, 95% CI: 0.70 to 1.14). 

Results of the efficacy and safety of prostate radiotherapy for patients with low volume, de novo mHSPC from the PEACE-1 trial were recently presented at ASCO 2023. The addition of prostate radiotherapy to standard of care + abiraterone was associated with significant rPFS benefits (median 7.5 versus 4.4 years, p=0.02). Conversely, addition of radiotherapy to standard of care therapy alone was not associated with rPFS benefits (median 2.6 versus 3.0 years; HR: 1.11, 95% CI: 0.67 to 1.84, p=0.61).

The addition of prostate radiotherapy to either standard of care alone or standard of care therapy + abiraterone was not associated with overall survival improvements. In the standard of care + abiraterone arms, addition of prostate radiotherapy was associated with modest, non-significant OS benefits (HR: 0.77, 95% CI: 0.51 to 1.16, p=0.21). Similarly, addition of prostate radiotherapy to standard of care alone did not improve overall survival (HR: 1.18, 95% CI: 0.81 to 1.71, p=0.39).

Interestingly, addition of prostate radiotherapy to standard of care +/- abiraterone in the low-volume cohort was associated with significant improvements in the time to serious genitourinary events (p=0.0006). This overall benefit was consistent irrespective of whether patients had prostate radiotherapy added to standard of care + abiraterone (p=0.003) or standard of care therapy alone (p=0.048). 

The majority of patients with synchronous, low volume mHSPC benefit from early systemic treatment intensification with ARPI addition to ADT. Such patients should also be offered primary radiotherapy to the prostate gland in the appropriate clinical settings. 

Metachronous High Volume mHSPC

Given that the PEACE-1 trial included patients with de novo mHSPC only, ARASENS and ENZAMET provide the available data to assess the benefit of triplet therapy in this mHSPC subgroup. In ARASENS, the overall survival for patients with high volume mHSPC had a prespecified subgroup analysis for assessing recurrent (metachronous) disease (n =117) with a clinical benefit, but no statistically significant benefit (HR: 0.70, 95% CI: 0.39 to 1.24). In the ENZAMET trial, there was no benefit to treatment intensification for triplet therapy (HR: 1.18, 95% CI: 0.66 to 2.11).

Figure 14: Overall survival of enzalutamide + ADT + docetaxel vs ADT + docetaxel + non-steroidal anti-androgen for metachronous high volume disease patients in ENZAMET

When considering patients with mHSPC along a risk continuum, from good risk (metachronous low volume: 8-year median overall survival with ADT alone) to poor risk (synchronous high volume: 3-year median overall survival with ADT alone), patients with synchronous low volume and metachronous high volume (median overall survival: 4.5 years with ADT alone) mHSPC may both be considered as intermediate risk disease. As such, the clinical treatment approach for these two subgroups has seen significant overlap. ARPI + ADT have similarly served as the backbone for treatment of these patients. Patients with metachronous, high volume mHSPC have historically accounted for only a small proportion of patients in the published phase III trials, and as such, post-hoc analyses have been underpowered for evaluating this subgroup. Results from the ARCHES trial have demonstrated a 23% decreased hazard of overall mortality in this subgroup with addition of enzalutamide to ADT (HR: 0.77, 95% CI: 0.39 to 1.50).⁵  Similar results were found in the ENZAMET trial (HR: 0.73, 95% CI: 0.37 to 1.44).

Results from the STOPCAP M1 collaborative meta-analysis of individual patient data from GETUG-15, STAMPEDE, and CHAARTED demonstrated that docetaxel addition to ADT in patients with metachronous, high volume prostate cancer is associated with significant improvements in overall survival (HR: 0.64, 95% CI: 0.42 to 0.99),²¹  which was consistent on follow-up analyses.²² 

 Given the relatively increased toxicity with taxanes, along with a subset of patients being “chemotherapy unfit”, it appears that doublet therapy with an ARPI + ADT is the favored treatment approach in patients with metachronous high volume disease, with docetaxel reserved for select patients with higher volume of disease.

Metachronous Low Volume mHSPC

Similar to metachronous high volume patients, the subgroup analyses of triplet therapy trials assessing metachronous low volume mHSPC patients remain limited. In ARASENS, metachronous low volume disease patients (n = 51) had too few overall mortality events to provide adequate samples size for powered analyses. For the ENZAMET trial, the HR for metachronous low volume patients was 0.64 (95% CI: 0.18 to 2.28).

Subgroup analyses have consistently demonstrated an overall survival benefit to ARPI addition in patients with low volume mHSPC. Results from the ARCHES trial demonstrated a 37% improved hazard of overall survival with enzalutamide addition to ADT in patients with metachronous low volume mHSPC (HR: 0.63, 95% CI: 0.26 to 1.54). From the ENZAMET trial, patients with metachronous low volume disease had a clinical and statistically significant benefit (HR of 0.47, 95% CI: 0.28 to 0.79).

Importantly, there is consistent evidence against the use of docetaxel in this mHSPC subgroup. Results from the CHAARTED trial demonstrated a minimal overall survival in this subgroup (HR: 0.77, 95% CI: 0.51 to 1.18). Furthermore, results from the STOPCAP meta-analysis using CHAARTED and GETUG-AFU15 data demonstrated no overall survival benefit to docetaxel addition (HR: 1.07, 95% CI: 0.75 to 1.54).

Table 1: A summary of overall survival by volume and timing of metastases from the key registration

Conclusions

Published November 2023

Part of an Independent Medical Education Initiative Supported by  LOXO@Lilly

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

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

Introduction

Introduction

Introduction

Gemcitabine + Docetaxel

• 1 year: 60%
• 2 years: 50%
• 5 years: 30%

Device-assisted Administration of Intravesical Chemotherapy

• Cohort 1: TAR-200 + cetrelimab (PD-1 inhibitor)
• Cohort 2: TAR-200 alone (target sample size 50, currently enrolled: 23)
• Cohort 3: Cetrelimab alone (target sample size 50, currently enrolled: 24)

Radiofrequency-induced Thermochemotherapy

Hyperthermic Intravesical Chemotherapy

Photodynamic Therapy

Enfortumab Vedotin

Erdafitinib

Conclusions