Emerging treatments for metastatic castration-resistant prostate cancer: Immunotherapy, PARP inhibitors, and PSMA-targeted approaches

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Emerging treatments for metastatic castration-resistant prostate cancer: Immunotherapy, PARP inhibitors, and PSMA-targeted approaches Catherine Handy Marshall M.D. , Emmanuel S. Antonarakis M.D. PII: DOI: Reference:

S2468-2942(20)30001-0 https://doi.org/10.1016/j.ctarc.2020.100164 CTARC 100164

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Cancer Treatment and Research Communications

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4 November 2019 30 December 2019

Please cite this article as: Catherine Handy Marshall M.D. , Emmanuel S. Antonarakis M.D. , Emerging treatments for metastatic castration-resistant prostate cancer: Immunotherapy, PARP inhibitors, and PSMA-targeted approaches, Cancer Treatment and Research Communications (2020), doi: https://doi.org/10.1016/j.ctarc.2020.100164

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Emerging treatments for metastatic castration-resistant prostate cancer: Immunotherapy, PARP inhibitors, and PSMA-targeted approaches Catherine Handy Marshall, M.D.

Emmanuel S. Antonarakis, M.D.*

Affiliations: CHM, ESA – The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. *Corresponding Author: Emmanuel S. Antonarakis, M.D, Professor of Oncology and Urology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 201 N. Broadway, Skip Viragh Building, Johns Hopkins University School of Medicine, Baltimore, MD 21287. Email: [email protected]

Disclosures: C.H.M. has received research funding via the Conquer Cancer Foundation from Bristol MyersSquibb and travel support from Dava Oncology. She also serves as a paid consultant to McGraw-Hill publishing company. E.S.A. is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, AstraZeneca, Bristol-Myers Squibb, Clovis, and Merck; he has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck; and he is the co-inventor of a biomarker technology that has been licensed to Qiagen. Funding: This work was partially supported by National Institutes of Health Cancer Center Support Grant P30CA006973

Abstract Recently there has been an explosion of new agents being investigated for the treatment of prostate cancer. These modalities represent new therapies aimed at old targets, or new therapies addressing new targets. This review will highlight three novel and emerging areas of treatment that have the potential to significantly impact the management of metastatic castration-resistant prostate cancer (mCRPC) in the near future: immunotherapy, poly ADPribose polymerase (PARP) inhibitors, and prostate-specific membrane antigen (PSMA)-targeted modalities. Immunotherapy, particularly immune checkpoint blockers, PARP inhibitors, and PSMA-targeted therapies are all increasingly being studied for the treatment of mCRPC although none are currently FDA-approved specifically for prostate cancer. Together these three classes of treatments may drastically change the future landscape of mCRPC. This review will cover what is currently known about the utility of these agents for the treatment of mCRPC, the areas of active research, and how these agents may be useful for patients in the future. It will also emphasize the notion of biomarker selection to help inform which patients are more likely to respond to these therapies. Keywords: prostate cancer, metastatic castration-resistant prostate cancer, immunotherapy, immune checkpoint blockers, PARP inhibitors, targeted therapy, PSMA

Introduction Prostate cancer remains the most common cause of non-cutaneous cancer and the second most common cause of cancer death in men in the United States [1]. It is estimated that this year approximately 31,000 men will die of metastatic castration resistant prostate cancer (mCRPC), the lethal form of the disease [1]. There are six therapies approved by the U.S. Food and Drug Administration (FDA) that improve overall survival in men with mCRPC: docetaxel, sipuleucel-T, abiraterone, enzalutamide, cabazitaxel and radium-223 [2]. Since the approval of radium-223 in 2013, there have not been any new systemic therapies approved in this space; however, there have been significant advancements and an expansion in the classes of therapies used to treat mCRPC. This review will highlight three new and developing areas of treatment that have the potential to revolutionize the management of mCRPC: immunotherapy, poly ADP-ribose polymerase (PARP) inhibitors, and prostate-specific membrane antigen (PSMA)-targeted therapies. Immunotherapy with checkpoint blockade and the use of PARP inhibitors have already dramatically altered the treatment of numerous other cancers [3,4]. PSMA-targeted approaches, while specific to prostate cancer, may exploit therapeutic mechanisms relevant to other diseases. Together these three classes of treatments may drastically change the future landscape of mCRPC and the outcomes of our patients with this disease.

Checkpoint Blockade Immunotherapy Currently, sipuleucel-T, an autologous antigen presenting cell (APC)-based immunotherapy, remains the only immunotherapy modality approved for prostate cancer [5]. Across a broad spectrum of other diseases however, checkpoint inhibitors (antibodies blocking the immune checkpoint receptors CTLA-4 and PD-1/PD-L1) have been successful in producing robust anticancer responses and long-term clinical remissions [6–8]. Unfortunately, clinical trials of men with mCRPC using CTLA-4 or PD-1/PD-L1 inhibitors have been underwhelming with minimal

responses seen when used alone in unselected patients [9–13]. One exception is the histologyagnostic FDA approval of pembrolizumab for all cancers with mismatch repair (MMR) deficiency or microsatellite instability (MSI)-high status, including those with prostate cancer [14,15]. Fortunately, combination therapy inclusive of checkpoint inhibitors or narrowing patient selection to those most likely to benefit, have shown more promise in the treatment of men with certain types of mCRPC. Combination approaches The two most promising strategies for combinatorial immunotherapy for the treatment of mCRPC are in combining two different checkpoint inhibitors or combining one checkpoint inhibitor with enzalutamide, a novel anti-androgen already approved for use in CRPC. The CheckMate-650 study combined the PD-1 inhibitor nivolumab with the anti-CTLA4 antibody ipilimumab in the second- or third-line of treatment for mCRPC [16]. In this study there was a 10% objective response rate (3 out of 30) to combined checkpoint blockade in men who previously received chemotherapy, but more promising was a 26% (6 of 23) objective response rate in men who were chemotherapy-naïve [16]. Toxicities of the combination are higher than with monotherapy, with only one-third of patients being able to receive the full 4 combined doses of immunotherapy and approximately 50% of patients experiencing at least a grade-3 adverse event [16]. Future studies of this combination are likely to investigate alternative doses and schedules of both drugs. Currently, research is ongoing to determine if this combination improves outcomes for specific subgroups of patients including those listed below as well as those with AR-V7–positive disease [17] (NCT03061539, NCT02601014) and those with highly inflamed tumors or DNA-repair gene mutations (NCT03061539)(Table 1). Another promising combination involves combining PD-1 inhibitors with enzalutamide, an antiandrogen that blocks androgen receptor signaling and transcriptional programs [18]. In KeyNote-365, men with mCRPC that had progressed on abiraterone (pre-chemotherapy) were treated with pembrolizumab plus enzalutamide. This study included 69 patients and showed a 33% PSA response rate (18 out of 54 evaluable patients) and a 20% objective response rate (5 out of 25 evaluable patients) [19]. In another trial of 28 men with chemotherapy-naïve mCRPC who had progressive disease while on enzalutamide, pembrolizumab was added to ongoing enzalutamide therapy [20]. Eighteen percent (5 of 28) had PSA declines of at least 50%, and 25% of those with measurable disease (3 of 12) had objective responses [20]. A randomized phase III trial of the combination of pembrolizumab and enzalutamide vs. enzalutamide alone is currently ongoing (NCT03834493; Table 1). Genomic selection Another promising approach in the use of checkpoint inhibitors in prostate cancer relies on better and more specific patient selection (Figure 1). The first example of this came from colon cancer which, similar to prostate cancer, has minimal responses to single-agent checkpoint inhibition [21]. However, it was noted that patients with mismatch repair-deficient (dMMR) colon cancers have 10 to 100 times more somatic mutations than those with MMR-proficient tumors and increased immune infiltration due to novel antigens [21]. The clinical importance of this was demonstrated in a landmark study where the response to single-agent pembrolizumab was compared in patients with and without dMMR cancers. Those with dMMR cancers had a 40% objective response rate and 78% 12-month progression-free survival rate, compared to those with mismatch repair-proficient colorectal cancer where there were no objective responses and an 11% 12-month progression-free survival rate [22]. This study led to the tumor-agnostic approval of pembrolizumab for dMMR (or MSI-high) cancers, regardless of histologic origin [23].

Within prostate cancer, it is estimated that approximately 3-5% of tumors harbor mutations in mismatch repair genes and therefore may benefit from pembrolizumab [24]. There have been two retrospective studies to assess the efficacy of PD-1 inhibitors in mCRPC harboring mismatch repair mutations. In one study of 13 mCRPC patients with germline or somatic mutations in mismatch repair genes (MSH2, MSH6, MLH2, or PMS2), there was a 50% PSA50 (PSA decline of >50%) response rate among the four patients who received anti–PD-1 agents [14]. Notably, these patients were also very sensitive to standard androgen deprivation therapy (ADT), with a median PSA reduction of 99% and a median PSA progression free survival of 55 months [14]. In a second larger retrospective review, 32 mCRPC patients were identified as having MSI-high or dMMR tumors. Eleven of those patients received treatment with singleagent PD-1 or PD-L1 inhibitor, with 6 (54%) having clinical benefits; 6 with PSA50 responses and 4 with radiographic responses [15]. Given the biomarker-specific approval of pembrolizumab in this space and the early evidence of benefit for this small subset of prostate cancer patients, all patients with mCRPC should undergo somatic genomic testing to interrogate for MMR deficiency which is consistent with the National Comprehensive Cancer Network (NCCN) guidelines [25]. There is also ongoing research on whether the combination of PD-1 and CTLA4 inhibitors would be more efficacious in these genomically-selected patients (NCT03061539; Table 1). In addition to MSI-h/dMMR status, there are preliminary data suggesting that other molecular subtypes may also predict sensitivity to checkpoint immunotherapy (Figure 1). For example, prostate cancers with mutations affecting the homologous recombination DNA-repair pathway may also have a high degree of genomic instability that may predict sensitivity to immunotherapy [26]. In the KeyNote-199 trial of single-agent pembrolizumab for docetaxelrefractory mCRPC, there was a signal of greater benefit in those patients with somatic BRCA1/2 or ATM mutations (12% objective response rate) when compared to those without these mutations (5% objective response rate) [11]. A similar trend was also seen in the CheckMate650 study [16], favoring greater responses in homologous repair-deficient mCRPC patients. Clinical trials addressing this question are ongoing (NCT03040791, NCT03248570; Table 1). The last subset of prostate cancer patients who may benefit from immunotherapy are those with inactivation of CDK12 (Figure 1). Tumors with CDK12 biallelic mutations have a unique immune signature, the result of multiple focal tandem duplications, and an increase in gene fusions with an increase in neoantigens and subsequent T-cell infiltration [26]. This may represent another genomically-defined subtype of prostate cancer that may benefit from PD-1 inhibitor therapy [27]. Among all cancers, prostate cancers have the highest proportion of biallelic inactivation of CDK12, with estimates of approximately 4-7% of CRPC tumors harboring this mutation [26,28,29]. In an initial report, four mCRPC patients with CDK12 biallelic loss were treated with anti-PD-1 therapy, and 2 of the 4 had PSA50 responses (one also had objective tumor shrinkage) [26]. A second analysis evaluated anti-PD-1 efficacy in 8 CDK12-mutated mCRPC patients; 3 of 8 (38%) had either a PSA50 or an objective tumor response [30]. A larger clinical trial is underway to test if this subtype of mCRPC is more susceptible to combined checkpoint immunotherapy using ipilimumab plus nivolumab (NCT03570619; Table 1). Finally, there are case reports of prostate cancer patients with POLE mutations (involving the proofreading DNA polymerase epsilon enzyme) that result in an ultra-mutated phenotype with >100 mutations/Megabase despite an MSI-stable signature [31]. This may be another gene mutation that results in responsiveness to anti-PD1 immunotherapy by virtue of a very high number of predicted mutation-associated neoantigens (Figure 1). However, these mutations only affect about 0.1% of mCRPC cases [32].

PARP inhibition Poly ADP-ribose polymerase (PARP) inhibitors cause cancer cell death through “synthetic lethality” whereby the combination of PARP inhibition in tumors with mutations in homologous recombination genes may result in loss of compensatory DNA repair mechanisms, leading to death of the cancer cell due to unrepairable DNA damage [33]. PARP inhibitors were first FDAapproved in ovarian and breast cancer for women with germline BRCA1/2 mutations [34]. More recently, we have learned that approximately 12% of men with mCRPC will have germline DNA repair pathway mutations, and 20-25% will have somatic mutations in DNA-repair pathway genes [35,36]. Given the high prevalence of DNA-repair mutations in mCRPC, PARP inhibitors were studied as a treatment for prostate cancer. One of the earliest clinical trials was the TOPARP-A trial: a single-arm, phase II trial of 50 genomically-unselected men with mCRPC treated with the PARP inhibitor olaparib (400mg twice a day). In this trial, 16 of 49 evaluable patients had a mutation in one of the DNA repair genes (defined in this trial as having an alteration in BRCA1/2, ATM, CHEK2, FANCA, PALB2, HDAC2, MLH3, ERCC3, MRE11, or NBN). Fourteen of the 16 patients (88%) with a mutation in one of these DNA-repair genes had a response to olaparib, in comparison to a response rate of only 2 of 33 patients (6%) in those without a mutation in DNA repair pathways [37]. TOPARP-B was a genomically selected phase II trial of olaparib in men with mCRPC and pathogenic mutations in DNA damage response pathways [38]. Overall there was a 54% response rate with a median progression free survival of 5.4 months [38]. In the largest Phase III trial done thus far, the PROfound study randomized patients with mCRPC and at least one DNA repair mutation (defined as BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and/ or RAD54L) to olaparib or physicians choice (abiraterone or enzalutamide) [39]. For the cohort overall, the median radiographic progression free survival was 5.8 months in those treated with olaparib compared to 3.5 months for those treated with physician’s choice of AR-targeted therapy (hazard ratio 0.49; 95% CI 0.38, 0.63), solidifying the benefit that PARP inhibitors can have in homologous repair-deficient prostate cancer [39]. This trial is likely to lead to the FDA-approval of olaparib in mCRPC previously treated with a novel hormonal agent, at least for patients with BRCA2 mutations, and possibly also for those with BRCA1 and ATM mutations. Although it seems clear that response rates to olaparib are higher in genomically-selected populations, not all DNA-repair genes are likely to be as susceptible (Figure 1). A retrospective study of 23 consecutive men with mCRPC who were treated with off-label olaparib showed that while 13 of 17 (76%) patients with BRCA1/2 mutations had a PSA50 response, no responses were seen among the six patients with ATM mutations [40]. In the TOPARP-A study, 4 of 6 patients (67%) with ATM mutations and 7 of 19 patients (37%) in TOPARP-B with ATM mutations had a response to olaparib.[37,38] Of note, the TOPARP studies did have a different definition of response that included RECIST response in those with measurable disease, PSA50 response, or CTC conversion [37,38]. In the PROfound study, there also seems to be a greater benefit for those with BRCA1/2 mutations compared to ATM mutations although this was an exploratory analysis [39]. Rucaparib, another oral PARP inhibitor, was studied for the treatment of mCRPC in the TRITON2 study. An interim analysis of TRITON2 demonstrated a 47.5% objective response rate in patients with BRCA1/2 mutations (germline or somatic) compared to a 0% objective response rate in patients with ATM mutations [41]. Preliminary data from TRITON2 and from

retrospective reviews also show that patients with CDK12 mutations may not respond as well to respond to rucaparib (or olaparib), with no objective responses seen in the TRITON2 study and none in a retrospective review of 11 men with CDK12 mutations treated with olaparib or rucaparib [30,41]. GALAHAD is a Phase II study of another PARP inhibitor, niraparib (once daily dosed medication in comparison to olaparib and rucaparib which are twice a day) [42]. This trial enrolled patients with biallelic DNA repair mutations, and demonstrated a 38% (5 of 13 patients) objective response rate and a 57% (13 of 23) PSA50 response rate in those with biallelic BRCA1/2 mutations [42]. Patients with other biallelic DNA repair mutations only had an 11% (1 of 9) objective response rate and a 6% (1 of 16) PSA50 response rate, by comparison [42]. Based on this early evidence, it seems that men with prostate cancers harboring mutations in BRCA1/2 will have the greatest response rates to PARP inhibitors. Whether or not men with other mutations in DNA repair genes will have meaningful responses remains to be seen [43]. Nevertheless, because of the high prevalence of DNA-repair pathway gene mutations and the potential relevance for treatment, the National Comprehensive Cancer Network (NCCN) Guidelines now recommend germline and somatic genetic testing for all men with metastatic prostate cancer [44]. There are currently at least three open clinical trials studying the use of PARP inhibitors in patients with mCRPC and mutations in DNA-repair pathway genes (NCT02952534, NCT02975934, NCT03012321) that are likely to shed more light on the therapeutic relevance of this class of drugs in DNA repair-deficient mCRPC. PSMA-targeting agents The final class of emerging therapies in advanced prostate cancer are directed towards the cellsurface protein, prostate-specific membrane antigen (PSMA). PSMA is a type-II transmembrane glycoprotein that is upregulated and is generally specific to prostate cancer [45]. While there are other tissues in the body that express PSMA (such as the salivary glands, small intestine, and renal tubules), this is at much lower levels, making PSMA a valid target for therapeutics in mCRPC [46]. Radioligands The PSMA-targeted therapy furthest along in development is the radioligand drug incorporating the beta-emitter lutetium-177 (177Lu-PSMA-617). In a systematic review of all the prospective and retrospective studies of 177Lu-PSMA-617 summarizing the experience of 17 studies and 671 total patients, 75% of patients (95% confidence interval 70-79%) experienced PSA declines, 37% had objective responses, and 38% had stable radiographic disease [47]. The most common adverse events of 177Lu-PSMA-617 include dry mouth (i.e. xerostomia, related to salivary gland expression of PSMA), nephrotoxicity, gastrointestinal disturbance, and myelosuppression [47]. Additional studies investigating the effectiveness of 177Lu-PSMA-617 are ongoing (NCT03511664, NCT03454750, NCT03403595, NCT03828838, NCT03042468, NCT03392428, NCT01140373; Table 1); the largest of which is the registration study, the VISION trial. The VISION trial is a randomized, phase III trial of 750 patients with taxane-pretreated mCRPC with positive PSMA-PET imaging, comparing treatment with 177LuPSMA-617 versus standard of care; overall survival is the primary endpoint [48]. While 177Lu-PSMA-617 is the most widespread PSMA-directed radioligand entity being studied, there are others on the horizon including other small molecules and other radionuclides, e.g. the alpha-emitting actinium-225 (225Ac-PSMA-617) which is more potent with shorter ranges than

beta-emitters [49,50]. Lastly, 177Lu-J591, a radiolabeled humanized monoclonal antibody against PSMA, has also been tested [51]. Early phase trials were limited by myelosuppression [51]. More recently, fractionated dosing showed improved side effect profiles with less toxicity, while also showing PSA50 response rates of 29% [52]. Trials are ongoing with 177Lu-J591 in combination with other therapies (NCT03545165, NCT00859781) and with the alpha-emitter actinium-225 (NCT03276572)(Table 1). CAR-T cells Chimeric antigen receptor (CAR) T-cells are an approach to deliver adoptive T-cell transfer therapy where gene transfer technology has been used to generate transgenic T-cell receptors that have specificity for a particular tumor antigen [53]. Once in vivo and engaged with the target antigen, the T-cells then initiate an inflammatory response that results in cytolytic killing of the antigen-expressing cancer cell [54]. In prostate cancer, PSMA has been used as the target for production of CAR-T cells. In the first phase I trial of PSMA-targeted CAR-T cells, the product was given together with continuous infusion of low-dose IL-2, and 3 of the 5 patients successfully engrafted (defined as 20% engraftment of CAR-T cells) [55]. Unlike the radioligand therapies, there were no anti-PSMA toxicities observed in that trial, and two of the three patients with engraftment had PSA50 responses [55]. Another Phase I trial, in 7 patients, of autologous activated PSMA-targeted T-cells showed that these can be safely given up to doses of 3x107 cells/kilogram with persistence of the activated T-cells in peripheral blood for up to two weeks [56]. In this study, one patient had a long-term response with stable disease for over 16 months, suggesting clinical activity [56]. Another product in development is a PSMA-directed/TGFβ-insensitive CAR-T cell that is in a phase I clinical trial. The unique feature of this cell product is the dominant-negative TGFβ receptor that seeks to overcome the immunosuppressive microenvironment of mCRPC, associated with high levels of TGFβ (NCT03089203) [57]. Finally, another T-cell product uses PSMA-specific CAR-T memory stem cells and is expected to enter Phase I trials in early 2020 [58,59]. Cytokine release syndrome (requiring tocilizumab), and neurologic toxicities, are the most common and serious adverse events seen with CAR-T cells [53]. Additional studies investigating the safety and efficacy of CAR-T cells in prostate cancer are ongoing (NCT04053062, NCT03089203; Table 1).

Bispecific T cell engagers Bispecific T-cell engagers (BiTEs) are a new class of small molecules that consist of one singlechain variable fragment bound to a T-cell specific molecule (commonly CD3), that is connected to another single-chain variable fragment containing a tumor-associated antigen; PSMA in the case of those being developed for prostate cancer [60]. In this way, PSMA-positive prostate cancer cells can theoretically come into close proximity with CD8+ and CD3+ T-cells. This approach was first FDA-approved with blinatumomab, an anti-CD19 x anti-CD3 BiTE, for the treatment of acute lymphoblastic leukemia (ALL) [61]. The first-in-human trial of a PSMA-targeted BiTE in mCRPC was done with pasotuxizumab, a PSMA x CD3 BiTE that was given as a continuous IV infusion [62]. This phase I trial of 16 patients did show reasonable safety. Fever was the most common adverse reaction (94% of patients) and infections and lymphopenia (44% each) were the most common grade >3 toxicities [62]. There was a signal of efficacy with a dose-dependent PSA response and two relatively long-term responders (lasting 14 and 19 months) [62]. A phase I trial is currently

underway using AMG-160 (a half-life extended PSMA-directed BiTE; NCT03792841), given alone or in combination with a PD-1 inhibitor, and other BiTE agents are also under development as well [63,64]. Conclusion In addition to monotherapy approaches using the new classes of mCRPC agents outlined above, combinations of these therapies with each other and with standard therapies are also being explored. It is clear that these therapies are likely to be used in some capacity for at least some of our patients with mCRPC. In addition, there will likely be other classes of drugs, for example additional genomically-targeted agents, which may also become relevant for a subset of men with mCRPC. Where in the sequence of therapies these novel drugs might be placed remains unanswered, as does how the sequencing of prior therapies might impact the efficacy of these novel agents. Nevertheless, there is considerable progress that has been made and many new therapies (beyond AR blockade and chemotherapeutics) are now moving into the clinic for patients with mCRPC. Unraveling the mechanisms of synergy and resistance remains our challenge for the future.

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Figure 1. Emerging therapeutics for patients with metastatic castration-resistant prostate cancer, and the subpopulations of patients who may derive the greatest benefit.

Table 1. Select trials of emerging therapies in metastatic castration-resistant prostate cancer (mCRPC). Identifier

Trial Name

Phase

Primary objective/ Primary outcome measure

Immune Checkpoint Inhibitors NCT03834493

NCT03040791 NCT03248570

Pembrolizumab Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (KEYNOTE-641) Nivolumab in Prostate Cancer With DNA Repair Defects (ImmunoProst) Pembrolizumab in Metastatic Castration Resistant Prostate Cancer (mCRPC) With or Without DNA Damage Repair Defects

Phase III Phase II

Phase II

NCT03061539

Nivolumab plus Ipilimumab Treatment in Prostate Cancer With an Immunogenic Signature Phase II

NCT02601014

NCT03570619

Biomarker-driven study of nivolumab and ipilimumab in treating patients with metastatic hormone-resistant prostate cancer expressing AR-V7 (STARVE-PC) Immunotherapy using Nivolumab plus Ipilimumab in Patients With Metastatic Cancers and CDK12 Mutations (IMPACT)

Phase II

Overall Survival (OS) Radiographic Progression-free Survival (rPFS) PSA response rate Objective response rate (ORR) in mCRPC subjects with proficient DNA damage repair (Group 1) and defective DNA damage repair (Group 2), using immune-related response criteria (irRC) Composite response rate (any one of the following):  Radiological response  PSA response ≥50%  Conversion of CTCs from ≥5 to <5 cells/7.5ml PSA responses (>50% PSA decline) ORR

Phase II

PARP Inhibitors NCT02952534

NCT02975934

NCT03012321

NCT03148795

NCT02854436

A Study of Rucaparib in Patients With Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON2) Rucaparib Versus Physician's Choice of Therapy in Patients With Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON3) Randomized Phase II Trial of Abiraterone, Olaparib, or Abiraterone plus Olaparib in Patients With Metastatic castration-resistant prostate cancer with DNA Repair Defects (BRCAaway) A study of Talazoparib in Men with DNA-Repair Defects and Metastatic Castration-Resistant Prostate Cancer (TALAPRO-1) An Efficacy and Safety Study of Niraparib in Men with Metastatic Castration-Resistant Prostate Cancer and

Phase II

ORR PSA Response rPFS

Phase III

Phase II

PFS in mCRPC patients with canonical DNA repair defects in BRCA1, BRCA2, or ATM. ORR

Phase II Phase II

ORR

DNA-Repair Anomalies (GALAHAD)

PSMA-Targeted Therapies NCT03454750 NCT03403595

NCT03828838 NCT03042468 NCT03490838 NCT03276572 NCT03939689

NCT03792841 NCT03577028 NCT04053062 NCT03089203 NCT03545165 NCT00859781

NCT03276572

177

Radiometabolic Therapy with Lu-PSMA-617 in Castration-Resistant Prostate Cancer (Lu-PSMA) 177 Lu-EB-PSMA-617 in Patients with Metastatic Castration-resistant Prostate Cancer

Phase II Phase I

177

Lu-PSMA-617 in Low-Volume Metastatic Prostate Cancer 177 Phase I Dose-escalation study of Fractionated LuPSMA-617 for Progressive Metastatic CRPC 177 Lu-PSMA-R2 in Patients with PSMA-PET Positive Metastatic Castration Resistant Prostate Cancer 225 Phase I Trial of Ac−J591 in Patients With mCRPC 131 Study of I-PSMA-1095 Radiotherapy in Combination With Enzalutamide in mCRPC Patients Who Are Chemo-Naive and Progress on Abiraterone (ARROW) Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 160 in Subjects With mCRPC Study of HPN424 in Patients with Advanced Prostate Cancer PSMA-CAR T in Treating Patients with Refractory Castrate-Resistant Prostate Cancer PSMA-TGFβRDN CAR T Cells for Castrate-Resistant Prostate Cancer 177Lu-J591 and 177Lu-PSMA-617 Combination for mCRPC 177Lu Radiolabeled Monoclonal antibody HuJ591 (177Lu-J591) and ketoconazole in patients with Prostate Cancer Phase I Trial of 255Ac-J591 in Patients with mCRPC

Phase I/II Phase I Phase I/II Phase I

Disease control rate, toxicity Standardized uptake value of 177 Lu-EB-PSMA-617 in normal organs and mCRPC Dose delivered to tumor and organs at risk DLT (dose limiting toxicity), recommended phase II dose DLT; PSA50 response rate Safety; DLT PSA response rate

Phase II Phase I/II Phase I Phase I/II Phase I

Safety; DLT DLT Incidence of toxicity Incidence of toxicity

Phase II

DLT, cumulative maximum tolerated dose, PSA response Proportion free of radiographic metastasis

Phase I

DLT

Phase I/II