Talazoparib Monotherapy in Metastatic Castration-Resistant Prostate Cancer with DNA Repair Alterations (TALAPRO-1): An Open-Label, Phase 2 Trial – Expert Commentary

Genotoxic therapies have a long history in a variety of cancers, and recent interest in the poly(ADP-ribose) polymerase (PARP) enzymes as an avenue to command synthetic lethality has led to successes in advanced prostate cancer.  Thus far two PARP inhibitors (PARPi) are approved for metastatic castration resistant prostate cancer (mCRPC) in men harboring alterations in genes that are critical to homologous recombination (HR).  The agents are rucaparib and olaparib, supported by the TRITON2 and PROfound studies, respectively.1,2 Herein authors de Bono et al. deploy talazoparib, a potent inhibitor of PARP catalytic activity, in a heavily pretreated mCRPC population.  Notably, this open-label phase 2 trial (TALAPRO-1) was conducted in men who had previously received one or two taxane chemotherapies and progressed on at least on ARSI.3  Selection required the presence of a genomic alteration in one of a group of genes, irrespective of germline or somatic origin, or zygosity.  Among those 1425 men screened, 1297 did not have a qualifying HRR gene alteration, meaning approximately only 9% of screened subjects had evidence of deficient homologous recombination (by the author’s chosen definition), lower than some previously reported rates of up ~20%.  Safety was assessed across 127 subjects who received at least one dose and antitumor activity among 104 with measurable disease.

The primary endpoint was objective response rate by blinded independent central review. The confirmed objective response rate was 29.8% (95% CI 21.2-39.6).  Accordingly, the study was powered with a sample size of 100 to detect an ORR of 23%, with the lower bound of 95% CI of 15.2%. Median duration of treatment was similar in the safety and antitumor activity populations (6.1 vs 6.2 months, IQRs 3.6-10.8 and 3.6-9.9, respectively). 

As is increasingly appreciated as relevant, a post hoc analysis was performed along with specific genomic alteration. It should be noted that their selection criteria were limited to SNVs and short indels. Confirmed objective responses were most frequently in those with BRCA2 alterations (46%, 26/57), which was also the largest group, and in BRCA1-altered subjects (50%, 2/4).  Objective responses in those with PALB2 (25%, 1/4) and ATM (12%, 2/17) were infrequent. Overall responses were more common in the non-visceral disease group (38%, 26/68) as compared to visceral (14%, 5/36).  Similar to objective response rates, PSA50 responses were common in BRCA1 or BRCA2 (66%, 39/59), and PALB2 (75%, 3/4) groups, but infrequent in ATM 12%, 2/17) and other gene alterations (6%, 1/18).  CTC conversions followed a similar pattern. At a median follow up 15.4 months (IQR 11.1-22.1), median rPFS was 5.6 months (95% CI 3.7-8.8) overall, with 11.2 months (95% CI 7.5-19.2) in those with either BRCA1 or BRCA2 alterations.  ATM alterations afforded a median rPFS of 3.5 months (95% CI 1.7-8.3).  Median time to objective response was 3.4 months (IQR 1.8-5.4).

Exploratory analyses included a comparison of germline and somatic origin of qualifying alterations (limited to those subjects with both germline and somatic assessments).  A majority of these subjects had somatic alterations (62%, 44/71), as compared to 35% (25/71) with germline alterations.  The frequency of objective responses was not different between the two groups (28% v 26%, p=1.0 by two-sided Fisher’s exact). In contrast, narrowly higher rates of objective response were observed in samples with loss of heterozygosity versus those heterozygous (40% v 13%, OR 4.22 [95% CI 1.06-20.94], p=0.039).

Most (95%) of the 127 men in the safety population experienced any all-cause treatment-emergent adverse events (tAE).  Of these, the most common grade 3 or 4 tAEs were anemia (31%), thrombocytopenia (9%), or neutropenia (8%).  Serious tAEs included pulmonary embolism (6%, 8/127). No myelodysplastic syndromes or acute myeloid leukemia were observed over the relatively short follow-up for the emergence of such events.

To place this study in the context of other significant peer studies of PARPi in mCRPC, talazoparib showed promising antitumor activity in heavily pretreated men with mCRPC.  Notably, and as similar to prior studies with other PARPi, activity appeared most pronounced in those men with BRCA2 alterations.  The ORR to olaparib in PROfound was 33.3% among subjects with alterations in BRCA1, BRCA2, or ATM and, as the authors point out, this was in a less heavily pretreated population.2  Certainly, cross-study comparisons are fraught, however.

In TALAPRO-1, the authors observed a very low frequency of BRCA1 alterations (4 of 104 in the antitumor activity population).  For overall analysis, these were grouped with those with BRCA2 alterations due to “anticipated similar functional effect” of alterations in these two genes.  Although reasonable given the numbers in this study, to avoid under- or overinterpretation of efficacy in BRCA1-altered tumors, some caution should be used in assuming true equivalence between BRCA1 and BRCA2 alterations in clinical practice.  Ongoing genomic research efforts will highlight functional differences if any.  In any event, it appears that BRCA1 may be infrequently inactivated in mCRPC.  Finally, and also similar to prior studies, ATM-altered tumors appear less sensitive to PARPi monotherapy, as compared to BRCA1/2, and the authors highlight this may be related to gene dosage as both responders with ATM alterations had loss of heterozygosity.

PARP inhibition appears firmly established as a therapy for molecularly selected men with mCRPC.  There are active efforts to widen the population of men who may benefit from PARPi, either through the identification of other biomarkers to predict sensitivity (e.g. genomic scores, additional genes) and in combination, such as in phase 3 TALAPRO-2 trial which will evaluate efficacy in combinations with enzalutamide in men with and without HRR alterations (NCT03395197).4


Written by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine, Division of Hematology and Medical Oncology at Weill Cornell Medicine, and Assistant Attending physician at NewYork-Presbyterian Hospital


References:

  1. Abida W, Patnaik A, Campbell D, Shapiro J, Bryce AH, McDermott R, Sautois B, Vogelzang NJ, Bambury RM, Voog E, Zhang J, Piulats JM, Ryan CJ, Merseburger AS, Daugaard G, Heidenreich A, Fizazi K, Higano CS, Krieger LE, Sternberg CN, Watkins SP, Despain D, Simmons AD, Loehr A, Dowson M, Golsorkhi T, Chowdhury S; TRITON2 investigators. Rucaparib in Men with Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol. 2020 Nov 10;38(32):3763-3772. doi: 10.1200/JCO.20.01035.
  2. Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Roubaud G, Özgüroğlu M, Kang J, Burgents J, Gresty C, Corcoran C, Adelman CA, de Bono J; PROfound Trial Investigators. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Dec 10;383(24):2345-2357. doi: 10.1056/NEJMoa2022485.
  3. De Bono JS, Mehra N, Scagliotti GV, Castro E, Dorff T, Stirling A, Stenzl A, Fleming MT, Higano CS, Saad F, Buttigliero C, van Oort IM, Laird AD, Mata M, Chen H, Healy CG, Czibere A, Fizazi K. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021 Aug 10;S1470-2045(21)00376-4. doi: 10.1016/S1470-2045(21)00376-4.
  4. https://clinicaltrials.gov/ct2/show/NCT03395197

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